77
Amr Hasan, M.D. Associate Professor of Neurology Cairo University Dysmylelination syndromes
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Amr Hasan MD Associate Professor of Neurology
Cairo University
Dysmylelination syndromes
Myelination 4Stage
Inferior to superior posterior to anterior
5 - 15 months matures by 3 years
Failure developmental delay dysmyelinating disease
ldquodemyelinationrdquo used when there is loss of myelin
ldquohypomyelinationrdquo which means that too little myelin is formed and this deficiency is permanent
ldquodysmyelinationrdquo used when the process of myelination is disturbed leading to abnormal patchy or irregular myelination
ldquodelayed myelinationrdquo used when the process of myelination is retarded but progressing
Stage IV Failures of Myelination
Dysmyelinating Disorders
Metachromatic leukodystrophy
Krabbes disease
Adrenoleukodystrophy
Zelweger disease
Canavans disease
Alexanders disease
Others
Clinical Presentation of
Leukodystrophy
Developmental delay relentless regression
Seizures
UMN signs
Failure to thrive (less common)
+- Dysmorphisms
hellipwith adult presentation
bull Metachromatic Leukodystrophy
bull Krabbeacute globoid cell leukodystrophy
bull Adrenoleukodystrophy adrenomyeloneuropathy
bull Refsum disease
bull Pelizaeus-Merzbacher disease (Lowenberg-Hill type)
bull Alexander disease
Mutations bull arylsulfatase A gene (ARSA) on chromosome 22q13
bull Autosomal recessive inheritance
bull ARSA mutations ndash type O and type R
bull Type O ndash infantile form bull Type R ndash adult form bull OR heterozygote ndash juvenile form
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy Late infantile (18-24 months)
The infantile form includes the following
Gait disturbances
Memory deficits
Seizures (may be present)
Loss of motor developmental milestones
Decreased attention span
Speech disturbances
Decline in school performance
Metachromatic
Leukodystrophy Early juvenile form
The early juvenile form includes the following
Gait disturbances
Tremors
Clumsiness
Loss of previously achieved skills
Intellectual decline
Behavioral changes
Seizures (possible)
Onset after puberty Presenting symptoms bull Personality and mental changes leading to dementia bull Seizures bull Behavioural changes
bull Hypospontaneity and blunted affect bull Inattention and hyperactivity
bull Often misdiagnosed as schizophrenia or bipolar disorder Later symptoms bull Movementpostural disorders bull Dementia by 3rd or 4th decade of life bull Progressive corticobulbar corticospinal cerebellar changes
Metachromatic
Leukodystrophy
Investigations Spinal fluid ndash moderately elevated protein at 15 ndash 30 gL Urine bull Deficiency in arylsulfatase A activity (or in leukocytes) bull Metachromatic granules
Cholecystogramultrasound ndash decreased gall bladder function
Evoked potentials ndash abnormalities in ABR VEP SSEP
Nerve conduction velocities decreased MRI ndash symmetric diffuse signal abnormalities
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
SPARING SUBCORTICAL U SHAPED FIBRES
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy (cont)
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy
Metachromatic Leukodystrophy (cont)
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Myelination 4Stage
Inferior to superior posterior to anterior
5 - 15 months matures by 3 years
Failure developmental delay dysmyelinating disease
ldquodemyelinationrdquo used when there is loss of myelin
ldquohypomyelinationrdquo which means that too little myelin is formed and this deficiency is permanent
ldquodysmyelinationrdquo used when the process of myelination is disturbed leading to abnormal patchy or irregular myelination
ldquodelayed myelinationrdquo used when the process of myelination is retarded but progressing
Stage IV Failures of Myelination
Dysmyelinating Disorders
Metachromatic leukodystrophy
Krabbes disease
Adrenoleukodystrophy
Zelweger disease
Canavans disease
Alexanders disease
Others
Clinical Presentation of
Leukodystrophy
Developmental delay relentless regression
Seizures
UMN signs
Failure to thrive (less common)
+- Dysmorphisms
hellipwith adult presentation
bull Metachromatic Leukodystrophy
bull Krabbeacute globoid cell leukodystrophy
bull Adrenoleukodystrophy adrenomyeloneuropathy
bull Refsum disease
bull Pelizaeus-Merzbacher disease (Lowenberg-Hill type)
bull Alexander disease
Mutations bull arylsulfatase A gene (ARSA) on chromosome 22q13
bull Autosomal recessive inheritance
bull ARSA mutations ndash type O and type R
bull Type O ndash infantile form bull Type R ndash adult form bull OR heterozygote ndash juvenile form
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy Late infantile (18-24 months)
The infantile form includes the following
Gait disturbances
Memory deficits
Seizures (may be present)
Loss of motor developmental milestones
Decreased attention span
Speech disturbances
Decline in school performance
Metachromatic
Leukodystrophy Early juvenile form
The early juvenile form includes the following
Gait disturbances
Tremors
Clumsiness
Loss of previously achieved skills
Intellectual decline
Behavioral changes
Seizures (possible)
Onset after puberty Presenting symptoms bull Personality and mental changes leading to dementia bull Seizures bull Behavioural changes
bull Hypospontaneity and blunted affect bull Inattention and hyperactivity
bull Often misdiagnosed as schizophrenia or bipolar disorder Later symptoms bull Movementpostural disorders bull Dementia by 3rd or 4th decade of life bull Progressive corticobulbar corticospinal cerebellar changes
Metachromatic
Leukodystrophy
Investigations Spinal fluid ndash moderately elevated protein at 15 ndash 30 gL Urine bull Deficiency in arylsulfatase A activity (or in leukocytes) bull Metachromatic granules
Cholecystogramultrasound ndash decreased gall bladder function
Evoked potentials ndash abnormalities in ABR VEP SSEP
Nerve conduction velocities decreased MRI ndash symmetric diffuse signal abnormalities
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
SPARING SUBCORTICAL U SHAPED FIBRES
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy (cont)
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy
Metachromatic Leukodystrophy (cont)
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
ldquodemyelinationrdquo used when there is loss of myelin
ldquohypomyelinationrdquo which means that too little myelin is formed and this deficiency is permanent
ldquodysmyelinationrdquo used when the process of myelination is disturbed leading to abnormal patchy or irregular myelination
ldquodelayed myelinationrdquo used when the process of myelination is retarded but progressing
Stage IV Failures of Myelination
Dysmyelinating Disorders
Metachromatic leukodystrophy
Krabbes disease
Adrenoleukodystrophy
Zelweger disease
Canavans disease
Alexanders disease
Others
Clinical Presentation of
Leukodystrophy
Developmental delay relentless regression
Seizures
UMN signs
Failure to thrive (less common)
+- Dysmorphisms
hellipwith adult presentation
bull Metachromatic Leukodystrophy
bull Krabbeacute globoid cell leukodystrophy
bull Adrenoleukodystrophy adrenomyeloneuropathy
bull Refsum disease
bull Pelizaeus-Merzbacher disease (Lowenberg-Hill type)
bull Alexander disease
Mutations bull arylsulfatase A gene (ARSA) on chromosome 22q13
bull Autosomal recessive inheritance
bull ARSA mutations ndash type O and type R
bull Type O ndash infantile form bull Type R ndash adult form bull OR heterozygote ndash juvenile form
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy Late infantile (18-24 months)
The infantile form includes the following
Gait disturbances
Memory deficits
Seizures (may be present)
Loss of motor developmental milestones
Decreased attention span
Speech disturbances
Decline in school performance
Metachromatic
Leukodystrophy Early juvenile form
The early juvenile form includes the following
Gait disturbances
Tremors
Clumsiness
Loss of previously achieved skills
Intellectual decline
Behavioral changes
Seizures (possible)
Onset after puberty Presenting symptoms bull Personality and mental changes leading to dementia bull Seizures bull Behavioural changes
bull Hypospontaneity and blunted affect bull Inattention and hyperactivity
bull Often misdiagnosed as schizophrenia or bipolar disorder Later symptoms bull Movementpostural disorders bull Dementia by 3rd or 4th decade of life bull Progressive corticobulbar corticospinal cerebellar changes
Metachromatic
Leukodystrophy
Investigations Spinal fluid ndash moderately elevated protein at 15 ndash 30 gL Urine bull Deficiency in arylsulfatase A activity (or in leukocytes) bull Metachromatic granules
Cholecystogramultrasound ndash decreased gall bladder function
Evoked potentials ndash abnormalities in ABR VEP SSEP
Nerve conduction velocities decreased MRI ndash symmetric diffuse signal abnormalities
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
SPARING SUBCORTICAL U SHAPED FIBRES
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy (cont)
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy
Metachromatic Leukodystrophy (cont)
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Stage IV Failures of Myelination
Dysmyelinating Disorders
Metachromatic leukodystrophy
Krabbes disease
Adrenoleukodystrophy
Zelweger disease
Canavans disease
Alexanders disease
Others
Clinical Presentation of
Leukodystrophy
Developmental delay relentless regression
Seizures
UMN signs
Failure to thrive (less common)
+- Dysmorphisms
hellipwith adult presentation
bull Metachromatic Leukodystrophy
bull Krabbeacute globoid cell leukodystrophy
bull Adrenoleukodystrophy adrenomyeloneuropathy
bull Refsum disease
bull Pelizaeus-Merzbacher disease (Lowenberg-Hill type)
bull Alexander disease
Mutations bull arylsulfatase A gene (ARSA) on chromosome 22q13
bull Autosomal recessive inheritance
bull ARSA mutations ndash type O and type R
bull Type O ndash infantile form bull Type R ndash adult form bull OR heterozygote ndash juvenile form
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy Late infantile (18-24 months)
The infantile form includes the following
Gait disturbances
Memory deficits
Seizures (may be present)
Loss of motor developmental milestones
Decreased attention span
Speech disturbances
Decline in school performance
Metachromatic
Leukodystrophy Early juvenile form
The early juvenile form includes the following
Gait disturbances
Tremors
Clumsiness
Loss of previously achieved skills
Intellectual decline
Behavioral changes
Seizures (possible)
Onset after puberty Presenting symptoms bull Personality and mental changes leading to dementia bull Seizures bull Behavioural changes
bull Hypospontaneity and blunted affect bull Inattention and hyperactivity
bull Often misdiagnosed as schizophrenia or bipolar disorder Later symptoms bull Movementpostural disorders bull Dementia by 3rd or 4th decade of life bull Progressive corticobulbar corticospinal cerebellar changes
Metachromatic
Leukodystrophy
Investigations Spinal fluid ndash moderately elevated protein at 15 ndash 30 gL Urine bull Deficiency in arylsulfatase A activity (or in leukocytes) bull Metachromatic granules
Cholecystogramultrasound ndash decreased gall bladder function
Evoked potentials ndash abnormalities in ABR VEP SSEP
Nerve conduction velocities decreased MRI ndash symmetric diffuse signal abnormalities
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
SPARING SUBCORTICAL U SHAPED FIBRES
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy (cont)
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy
Metachromatic Leukodystrophy (cont)
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Clinical Presentation of
Leukodystrophy
Developmental delay relentless regression
Seizures
UMN signs
Failure to thrive (less common)
+- Dysmorphisms
hellipwith adult presentation
bull Metachromatic Leukodystrophy
bull Krabbeacute globoid cell leukodystrophy
bull Adrenoleukodystrophy adrenomyeloneuropathy
bull Refsum disease
bull Pelizaeus-Merzbacher disease (Lowenberg-Hill type)
bull Alexander disease
Mutations bull arylsulfatase A gene (ARSA) on chromosome 22q13
bull Autosomal recessive inheritance
bull ARSA mutations ndash type O and type R
bull Type O ndash infantile form bull Type R ndash adult form bull OR heterozygote ndash juvenile form
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy Late infantile (18-24 months)
The infantile form includes the following
Gait disturbances
Memory deficits
Seizures (may be present)
Loss of motor developmental milestones
Decreased attention span
Speech disturbances
Decline in school performance
Metachromatic
Leukodystrophy Early juvenile form
The early juvenile form includes the following
Gait disturbances
Tremors
Clumsiness
Loss of previously achieved skills
Intellectual decline
Behavioral changes
Seizures (possible)
Onset after puberty Presenting symptoms bull Personality and mental changes leading to dementia bull Seizures bull Behavioural changes
bull Hypospontaneity and blunted affect bull Inattention and hyperactivity
bull Often misdiagnosed as schizophrenia or bipolar disorder Later symptoms bull Movementpostural disorders bull Dementia by 3rd or 4th decade of life bull Progressive corticobulbar corticospinal cerebellar changes
Metachromatic
Leukodystrophy
Investigations Spinal fluid ndash moderately elevated protein at 15 ndash 30 gL Urine bull Deficiency in arylsulfatase A activity (or in leukocytes) bull Metachromatic granules
Cholecystogramultrasound ndash decreased gall bladder function
Evoked potentials ndash abnormalities in ABR VEP SSEP
Nerve conduction velocities decreased MRI ndash symmetric diffuse signal abnormalities
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
SPARING SUBCORTICAL U SHAPED FIBRES
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy (cont)
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy
Metachromatic Leukodystrophy (cont)
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
hellipwith adult presentation
bull Metachromatic Leukodystrophy
bull Krabbeacute globoid cell leukodystrophy
bull Adrenoleukodystrophy adrenomyeloneuropathy
bull Refsum disease
bull Pelizaeus-Merzbacher disease (Lowenberg-Hill type)
bull Alexander disease
Mutations bull arylsulfatase A gene (ARSA) on chromosome 22q13
bull Autosomal recessive inheritance
bull ARSA mutations ndash type O and type R
bull Type O ndash infantile form bull Type R ndash adult form bull OR heterozygote ndash juvenile form
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy Late infantile (18-24 months)
The infantile form includes the following
Gait disturbances
Memory deficits
Seizures (may be present)
Loss of motor developmental milestones
Decreased attention span
Speech disturbances
Decline in school performance
Metachromatic
Leukodystrophy Early juvenile form
The early juvenile form includes the following
Gait disturbances
Tremors
Clumsiness
Loss of previously achieved skills
Intellectual decline
Behavioral changes
Seizures (possible)
Onset after puberty Presenting symptoms bull Personality and mental changes leading to dementia bull Seizures bull Behavioural changes
bull Hypospontaneity and blunted affect bull Inattention and hyperactivity
bull Often misdiagnosed as schizophrenia or bipolar disorder Later symptoms bull Movementpostural disorders bull Dementia by 3rd or 4th decade of life bull Progressive corticobulbar corticospinal cerebellar changes
Metachromatic
Leukodystrophy
Investigations Spinal fluid ndash moderately elevated protein at 15 ndash 30 gL Urine bull Deficiency in arylsulfatase A activity (or in leukocytes) bull Metachromatic granules
Cholecystogramultrasound ndash decreased gall bladder function
Evoked potentials ndash abnormalities in ABR VEP SSEP
Nerve conduction velocities decreased MRI ndash symmetric diffuse signal abnormalities
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
SPARING SUBCORTICAL U SHAPED FIBRES
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy (cont)
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy
Metachromatic Leukodystrophy (cont)
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Mutations bull arylsulfatase A gene (ARSA) on chromosome 22q13
bull Autosomal recessive inheritance
bull ARSA mutations ndash type O and type R
bull Type O ndash infantile form bull Type R ndash adult form bull OR heterozygote ndash juvenile form
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy Late infantile (18-24 months)
The infantile form includes the following
Gait disturbances
Memory deficits
Seizures (may be present)
Loss of motor developmental milestones
Decreased attention span
Speech disturbances
Decline in school performance
Metachromatic
Leukodystrophy Early juvenile form
The early juvenile form includes the following
Gait disturbances
Tremors
Clumsiness
Loss of previously achieved skills
Intellectual decline
Behavioral changes
Seizures (possible)
Onset after puberty Presenting symptoms bull Personality and mental changes leading to dementia bull Seizures bull Behavioural changes
bull Hypospontaneity and blunted affect bull Inattention and hyperactivity
bull Often misdiagnosed as schizophrenia or bipolar disorder Later symptoms bull Movementpostural disorders bull Dementia by 3rd or 4th decade of life bull Progressive corticobulbar corticospinal cerebellar changes
Metachromatic
Leukodystrophy
Investigations Spinal fluid ndash moderately elevated protein at 15 ndash 30 gL Urine bull Deficiency in arylsulfatase A activity (or in leukocytes) bull Metachromatic granules
Cholecystogramultrasound ndash decreased gall bladder function
Evoked potentials ndash abnormalities in ABR VEP SSEP
Nerve conduction velocities decreased MRI ndash symmetric diffuse signal abnormalities
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
SPARING SUBCORTICAL U SHAPED FIBRES
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy (cont)
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy
Metachromatic Leukodystrophy (cont)
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy Late infantile (18-24 months)
The infantile form includes the following
Gait disturbances
Memory deficits
Seizures (may be present)
Loss of motor developmental milestones
Decreased attention span
Speech disturbances
Decline in school performance
Metachromatic
Leukodystrophy Early juvenile form
The early juvenile form includes the following
Gait disturbances
Tremors
Clumsiness
Loss of previously achieved skills
Intellectual decline
Behavioral changes
Seizures (possible)
Onset after puberty Presenting symptoms bull Personality and mental changes leading to dementia bull Seizures bull Behavioural changes
bull Hypospontaneity and blunted affect bull Inattention and hyperactivity
bull Often misdiagnosed as schizophrenia or bipolar disorder Later symptoms bull Movementpostural disorders bull Dementia by 3rd or 4th decade of life bull Progressive corticobulbar corticospinal cerebellar changes
Metachromatic
Leukodystrophy
Investigations Spinal fluid ndash moderately elevated protein at 15 ndash 30 gL Urine bull Deficiency in arylsulfatase A activity (or in leukocytes) bull Metachromatic granules
Cholecystogramultrasound ndash decreased gall bladder function
Evoked potentials ndash abnormalities in ABR VEP SSEP
Nerve conduction velocities decreased MRI ndash symmetric diffuse signal abnormalities
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
SPARING SUBCORTICAL U SHAPED FIBRES
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy (cont)
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy
Metachromatic Leukodystrophy (cont)
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Metachromatic
Leukodystrophy Late infantile (18-24 months)
The infantile form includes the following
Gait disturbances
Memory deficits
Seizures (may be present)
Loss of motor developmental milestones
Decreased attention span
Speech disturbances
Decline in school performance
Metachromatic
Leukodystrophy Early juvenile form
The early juvenile form includes the following
Gait disturbances
Tremors
Clumsiness
Loss of previously achieved skills
Intellectual decline
Behavioral changes
Seizures (possible)
Onset after puberty Presenting symptoms bull Personality and mental changes leading to dementia bull Seizures bull Behavioural changes
bull Hypospontaneity and blunted affect bull Inattention and hyperactivity
bull Often misdiagnosed as schizophrenia or bipolar disorder Later symptoms bull Movementpostural disorders bull Dementia by 3rd or 4th decade of life bull Progressive corticobulbar corticospinal cerebellar changes
Metachromatic
Leukodystrophy
Investigations Spinal fluid ndash moderately elevated protein at 15 ndash 30 gL Urine bull Deficiency in arylsulfatase A activity (or in leukocytes) bull Metachromatic granules
Cholecystogramultrasound ndash decreased gall bladder function
Evoked potentials ndash abnormalities in ABR VEP SSEP
Nerve conduction velocities decreased MRI ndash symmetric diffuse signal abnormalities
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
SPARING SUBCORTICAL U SHAPED FIBRES
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy (cont)
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy
Metachromatic Leukodystrophy (cont)
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Metachromatic
Leukodystrophy Early juvenile form
The early juvenile form includes the following
Gait disturbances
Tremors
Clumsiness
Loss of previously achieved skills
Intellectual decline
Behavioral changes
Seizures (possible)
Onset after puberty Presenting symptoms bull Personality and mental changes leading to dementia bull Seizures bull Behavioural changes
bull Hypospontaneity and blunted affect bull Inattention and hyperactivity
bull Often misdiagnosed as schizophrenia or bipolar disorder Later symptoms bull Movementpostural disorders bull Dementia by 3rd or 4th decade of life bull Progressive corticobulbar corticospinal cerebellar changes
Metachromatic
Leukodystrophy
Investigations Spinal fluid ndash moderately elevated protein at 15 ndash 30 gL Urine bull Deficiency in arylsulfatase A activity (or in leukocytes) bull Metachromatic granules
Cholecystogramultrasound ndash decreased gall bladder function
Evoked potentials ndash abnormalities in ABR VEP SSEP
Nerve conduction velocities decreased MRI ndash symmetric diffuse signal abnormalities
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
SPARING SUBCORTICAL U SHAPED FIBRES
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy (cont)
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy
Metachromatic Leukodystrophy (cont)
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Onset after puberty Presenting symptoms bull Personality and mental changes leading to dementia bull Seizures bull Behavioural changes
bull Hypospontaneity and blunted affect bull Inattention and hyperactivity
bull Often misdiagnosed as schizophrenia or bipolar disorder Later symptoms bull Movementpostural disorders bull Dementia by 3rd or 4th decade of life bull Progressive corticobulbar corticospinal cerebellar changes
Metachromatic
Leukodystrophy
Investigations Spinal fluid ndash moderately elevated protein at 15 ndash 30 gL Urine bull Deficiency in arylsulfatase A activity (or in leukocytes) bull Metachromatic granules
Cholecystogramultrasound ndash decreased gall bladder function
Evoked potentials ndash abnormalities in ABR VEP SSEP
Nerve conduction velocities decreased MRI ndash symmetric diffuse signal abnormalities
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
SPARING SUBCORTICAL U SHAPED FIBRES
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy (cont)
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy
Metachromatic Leukodystrophy (cont)
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Investigations Spinal fluid ndash moderately elevated protein at 15 ndash 30 gL Urine bull Deficiency in arylsulfatase A activity (or in leukocytes) bull Metachromatic granules
Cholecystogramultrasound ndash decreased gall bladder function
Evoked potentials ndash abnormalities in ABR VEP SSEP
Nerve conduction velocities decreased MRI ndash symmetric diffuse signal abnormalities
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
SPARING SUBCORTICAL U SHAPED FIBRES
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy (cont)
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy
Metachromatic Leukodystrophy (cont)
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Metachromatic
Leukodystrophy
SPARING SUBCORTICAL U SHAPED FIBRES
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy (cont)
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy
Metachromatic Leukodystrophy (cont)
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
SPARING SUBCORTICAL U SHAPED FIBRES
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy (cont)
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy
Metachromatic Leukodystrophy (cont)
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Metachromatic Leukodystrophy (cont)
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy
Metachromatic Leukodystrophy (cont)
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Metachromatic
Leukodystrophy
Metachromatic Leukodystrophy
Metachromatic Leukodystrophy (cont)
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Metachromatic Leukodystrophy
Metachromatic Leukodystrophy (cont)
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Metachromatic Leukodystrophy (cont)
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Krabbeacute (Globoid Cell) Leukodystrophy Decreased oligodendrocytes in areas of demyelination Globoid cells ndash periodic acid-Schiff (PAS) staining cells in CNS white matter Genetics bull Galactocerebroside szlig-galactosidase (GALC gene
chromosome 14) bull Autosomal recessive Epidemiology bull 1 in 100000 births bull More in Druze community in Northern Israel and two Arab
villages near Jerusalem (carrier rate 16)
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Krabbeacute (Globoid Cell) Leukodystrophy
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Pure neurologic condition
Onset at 3-8 months of age
Irritability intermittent fevers heightened
startle reflex feeding problems
Develop seizures opisthotonus
Deafness and blindness by 9 months
Krabbeacute (Globoid Cell) Leukodystrophy
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Forms
bull Early onset ndash in infancy bull Late onset ndash extremely uncommon in childhood to adulthood Late-onset presentation bull Progressive amaurosis in childhood bull Progressive gait impairment (spasticity dystonia) bull Dementia
Investigations bull CT ndash periventricular hyperdensities bull MRI ndash confluent periventricular signal abnormalities
bull cerebral and cerebellar involvement bull Electrophysiology ndash peripheral demyelination
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Krabbeacute (Globoid Cell) Leukodystrophy
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
hypointense basal ganglia and THALAMI
Krabbeacute (Globoid Cell) Leukodystrophy
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Krabbeacute (Globoid Cell) Leukodystrophy
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Peroxisomes
Peroxisomes (microbodies) are simple membrane-bound vesicle with a diameter of 01 to 10 um Peroxisomes are multifunctional organelles containing more than 50 enzymes involved in such diverse activities as the oxidation of very-long-chain fatty acids (VLCFAs) and the synthesis of plasmalogens
These organelles were named ldquoperoxisomesrdquo because they are the site of synthesis and degradation of hydrogen peroxide (H2O2) a highly reactive and toxic oxidizing agent
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Peroxisome Function
Synthesis
ndash Plasmologens (ether-phospholipids)
ndash Bile acid from mevalonate
Catabolism
ndash -oxidize very long chain fatty acids (esp C240
and C260) pristanic acid and bile acid
intermediates
ndash -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
ndash Lysine via pipecolic acid and glutaric acid
ndash Glyoxylate to prevent conversion to oxalate
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Peroxisomal Disorders
16 disorders
ndash 15 are autosomal recessive
ndash 1 is X-linked (adrenoleukodystrophy)
Predominant features
ndash Dysmorphisms
ndash Neurologic dysfunction
ndash Liver disease
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Peroxisomal Disorders
Biosynthesis Defects ndash Zellweger spectrum disorders (ZD IRD NR)
ndash Rhizomelia chondrodysplasia punctata
Single Peroxisomal Enzyme Deficiencies ndash Adrenoleukodystrophy (ABCD1 on Xq28)
ndash RCDP type 2 (GNPAT on 1q421-423)
ndash RCDP type 3 (AGPS on 2q33)
ndash Refsum (PHYHPAHX on 10p15-p14)
ndash Glutaric aciduria type 3 ()
ndash Mulibrey nanism (TRIM on 17q22-23)
ndash 9 others
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Zellweger Spectrum Disorders
Dysmorphism (large fontanelle high forehead abn ears
micrognathia lowbroad nose redundant skin folds)
Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy cataracts ON atrophy)
Liver disease (hepatomegaly cholestasis hyperbilirubinemia)
Failure to thrive
Death in first year of life
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures
Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares
Hypertelorism
Epicanthal folds
High arched palate
Micrognathia
Redundant skin folds of neck
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Zellweger Syndrome
From Google Images
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Zellweger syndrome
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Zellweger syndrome
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
MRI Features include
ventricular enlargement
abnormal gyration patterns
ndash pachygyria especialy medial gyri around peri-rolandic regions
ndash polymicrogyria laterally
Zellweger syndrome
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD) a clinical continuum
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Zellweger Spectrum Disorders
Classic Zellweger (CZ)
Neonatal adrenoleukodystrophy (NALD) ndash Somewhat less severe than CZ
ndash May lack dysmorphisms altogether
ndash Neonatal or infantile onset of seizures hypotonia and progressive leukodystrophy
ndash May have pachypolymicrogyria
Infantile Refsum disease (IRD) ndash Least severe phenotype regression over time
ndash May be asymptomatic at birth
ndash No progressive leukodystrophy
ndash Variable expressivity of cognitive dysfunction
ndash Deafness and vision changes (retinopathy)
ndash May survive to adulthood
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Adrenoleukodystrophy (ALD)
Peroxisomal disorders include adrenoleukodystrophy (and Refsum disease)
Accumulation of very long chain fatty acids (VLCFA)
bull In adrenals ndash Addisonrsquos disease bull In white matter ndash leukodystrophy
Genetics bull ALD protein (ABCD1 gene) mutation on X chromosome bull X-linked disorder
Forms bull Childhood ALD bull Adrenomyeloneuropathy (AMN) ndash adolescent and adult men
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Symptoms bull Adrenal impairment bull Difficulty walking (spasticity) bull Urinary disturbance impotence bull Cognitive emotional disturbance Progresses over decades Female carriers may have progressive paraparesis moderate sensory loss peripheral neuropathy Normal adrenal function Blood tests bull For VLCFA bull Genetic testing
MRI ndash confluent posterior white matter changes
Adrenoleukodystrophy (ALD)
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Childhood cerebral form ~35
ndash Onset - ~6-12 yrs (survival several years)
ndash 90 with adrenal insufficiency
Adrenomyeloneuropathy (AMN) ~50
ndash Spastic paraparesis and sphincter dysfunction
ndash Onset - ~2nd-5th decade (survival decades)
ndash 23 with adrenal insufficiency
Other phenotypes ~15
ndash Addison disease only
ndash Adult-onset cerebral involvement - dementia
Female heterozygotes- 50 with mild AMN-like Sx
Multiple phenotypes of X-ALD
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
CLASSIC X-ALD
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
X-ALD
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Adrenoleukodystrophy
bilateral symmetrical pareitooccipital WM involvement progression form posteior to anterior progressive atrophy
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Adrenoleukodystrophy
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Adrenoleukodystrophy (cont)
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Refsum disease
Another peroxisomal disorder Accumulation of phytanic acid in blood and tissues Genetics bull Phytanoyl-CoA hydroxylase (PAHX chromosome 10) bull Peroxin-7 (PEX7 gene chromosome 6) bull Autosomal recessive
OMIM (Online Mendelian Inheritance in Man) httpwwwncbinlmnihgoventrez
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Presents from childhood to age 50 (peak 20)
Features
bull Retinitis pigmentosa
bull Peripheral neuropathy
bull Ataxia
bull Elevated CSF protein
bull Nystagmus
bull Anosmia
bull Ichthyosis
bull Epiphyseal dysplasia
Refsum disease
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Treatment
bull Most treatable lipid storage disorder
bull Control by diet restrictions against phytanic acid
bull dairy
bull tuna cod haddock
bull lamb stewed beef
bull white bread white rice boiled potatoes
bull egg yolk
bull Plasmapheresis as supplement initially
Refsum disease
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Xq22 mutation in proteolipid protein 1 (PLP1)
Onset in first few months of life with rotary
head movements rotary nystagmus amp motor
delay
Then ataxia tremor choreoathetosis
spasticity
Seizures
Optic atrophy and ocular impairments
MRI Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Pelizaeus-Merzbacher disease
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Newborn-like pattern
EXTENSIVE DYMYLINATION
increased white matter signal on T2WI
decreased signal in basal ganglia and thalamus
atrophy
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Pelizaeus-Merzbacher disease
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Alexander disease
Disorder of astrocytes of glial fibrillary acidic protein (GFAP)
Rosenthal fibers ndash cytoplasmic eosinophilic hyaline inclusions in astrocytes
Genetics bull Dominant mutations bull GFAP gene on chromosome 17
Forms bull Infantile juvenile and adult-onset forms exist
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Alexander Disease
AD mutation in GFAP at 17q2131
Onset at around 6 months (birth ndash 2 yrs)
Psychomotor regression spasticity and
seizures
Juvenile patients have ataxia and spasticity
Adult patients have MS-like presentation
Diffuse demyelination especially in frontal
lobes
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Adult form characterized by
bull Sleep disturbances and constipation from childhood
bull Other features develop at 3rd-4th decade
bull Bulbar signs ataxia and pyramidal signs
bull Mild dysmorphic features
bull progressive kyphosis
bull arched palate
bull short neck
bull MRI - atrophy of the medulla without signal abnormalities
bull Also can be confused with multiple sclerosis
Alexander disease
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Symmetrical white matter involvement Frontal lob involved early then extending posteriorly External capsule affected Internal capsule relatively spared
Alexander disease
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Alexander disease
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Alexander disease
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Alexander disease
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Canavans disease
AR deficiency of asparto-acylase
Macrocephaly lack of head control and
developmental delays by the age of three to five
months
Develop severe hypotonia and failure to achieve
independent sitting ambulation or speech
Hypotonia eventually changes to spasticity
Life expectancy is usually into the teens
Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
nonspecific diffuse involvement of white matter SPARING INTERNAL CAPSULE
Canavans disease
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Courtesy Dr Isabelle Desguerre Paris Necker Hospital
Canavans disease
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
NAA
Courtesy Dr Ralph Lachman
Canavan disease
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
Testing for Leukodystrophy
Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate not clinically useful lab due to
timing in equilibrium with alanine
Alanine (order via Plasma amino acids)
THANK YOU
THANK YOU
