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MELAS and ITS SISTERS
Prof. Dr. Saad S Al Ani
Senior Pediatric Consultant
Head of Pediatric Department
Khorfakkan Hospital
Sharjah ,UAE
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Case presentation:1
• Kara, 10 year old , is the eldest of 3 children, and was born into pretty boring family histories of good health.
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Cont.
• Kara’s “uniqueness” became obvious when she started school in 2005. Her slowness to complete work, her poor balance and ever poorer sporting skills made Kara simply seem “hard work”!
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Cont.
• The excess body hair• early loss of teeth• her slowness in all tasks• repeated spontaneous vomits• plummeting percentile bands
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Cont.
• an awkward running style• stiff muscles, “stick legs”• stress incontinence • jerky eye movements• poor concentration,• a “failed” OT (occupational
therapy) assessment,
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Cont.
• Straight after turning 8, found her one morning semiconscious and vomiting in bed.
• With a brain scan that looks “moth eaten”
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Cont.
• School is now a social drop in place, as simple tiredness has triggered her last 3 attacks.
• Her motivation to learn is a fading light
• Early dementia has now set in
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Cont.
• She has become increasingly unsteady, even slower in all daily tasks
• Her hearing now requires aids• Her eyesight is slowly disappearing• Her personality is regressing along
with her social graces.
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Case presentation:2
• 12 year old girl with rapid cycling bipolar disease.
• HPI: Mood difficulties began at the age of 8 years with diagnosis of bipolar disease made at 9 years of age.
• Seizure started at 10 years of age.
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Cont.
• Academic achievement has been
very good but her work toward these goals was often obsessive.
• She has shown some decline in academics over the last 2 years.
• Her motivation to be socially accepted has deteriorated.
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Cont.
• HPI: She has shown decline in coordinated motor movements with increased clumsiness.
• PMHx: Chronic constipation (multiple episodes of fecal impaction), hypothyroidism, and seizures.
• Family Hx: Lives with mother and two siblings.– Mother has neuropathy of unclear etiology.– Brother has been diagnosed with ETC complex III
dysfunction and myopathy. (brother has a different father)
– Sister has just been diagnosed with bipolar disorder.
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Cont.
• PE: – CN II-XII intact– Motor: Axial hypotonia– DTRs: Trace in all tendons
tested– Cerebellar: Normal
• Neuroimaging– Normal MRI
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Cont.
• Labs– Elevated lactate > 2 blood draws.– Elevated alanine.– Reduced level of free carnitine.– Presence of ethylmalonic acid in
urine organic acid profile.
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Cont.
• Muscle biopsy– Decreased activity of complex III
of the electron transport chain.– Normal mtDNA– Normal histology on light
microscopy examination.
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• An intracellular organelle.• There are 100 to 1000s of mitochondria/cell.• All mitochondria come from the mother.• Mitochondria have their own DNA.
What are mitochondria?
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• Found in all cell types, except the RBC.• Major functions of mitochondria:
-Makes energy in the form of ATP. -Programmed cell death (apoptosis).
(cont.)
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• The mitochondria use electrons and protons from metabolism and molecular oxygen to reduce water and generate proton-motive force to produce ATP from ADP: oxidative phosphorylation.
(cont.)
Role of ATP (energy)1.Mechanical Work
Muscle contraction
2.Chemical WorkNa+/K+ Ion Pump
3.Synthetic Work [Anabolism]Macromolecules
- Nucleic Acids
- Proteins
- Lipids
- Complex carbohydrates
Why is energy so important?
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Intermediary Energy Metabolism
Chemical Energy
Cars Gasoline
Cells ATP
When this process is dysfunctional, then disease
can occur.
Mitochondrial cytopathies are diseases of energy
production.
Epidemiology
Are these diseases common?
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Frequency
• Prevalence of more than 10.2 per 100,000 for the m.3243A → G mutation in the adult Finnish population.
• In Northern England, the prevalence of this mutation in the adult population has been determined to be approximately 1 per 13,000.
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Epidemiology
• Three large studies looking at the prevalence of mitochondrial disorders have shown:– The majority of adults with
mitochondrial disease have an underlying mtDNA mutation.
– The majority of children with mitochondrial disease have an underlying nuclear DNA mutation.
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Causes of mitochondrial disease
1. DNA (DNA contained in the nucleus of the cell) inheritance
2. mtDNA (DNA contained in the mitochondria) inheritance
3. Combination of mtDNA and nDNA defects
4. Random occurrences
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Mitochondrial Inheritance
Over 1000 proteins localized to mitochondria
13 are mitochondrial-encoded
Remainder are nuclear-encoded
•16.6 kb (vs. 3 billion in the nuclear genome)
•37 genes-22 tRNAs -2 rRNAs
-13 proteinsAll subunits of ETC
•mtDNA is entirely devoted toward energy metabolism
Mitochondrial DNA (mtDNA)
•Over 180 point mutations and almost as many deletions associated with human disease •‘Maternally inherited’•mtDNA come only from the ovum
Inheritance of mtDNA Mutations
Sporadic•Autosomal•Nuclear-encoded regulatory proteins interact with mtDNA (intragenomic communication) and can result in secondary mtDNA mutations
Inheritance of mtDNA Mutations (cont.)
Mitochondrial Inheritance
Multiple organ disease
Mitochondrial vs. Nuclear Genome
Mitochondrial genome has1.Smaller number of genes
2.Higher copy number
3.Less effective repair mechanisms
4.Higher mutation rate
mtDNA vs. Nuclear DNA Mutations
•Nuclear: severe disease of infantile onset•Mito: milder disease of later onset• nuclear mutations predominate
in small children • mtDNA mutations predominate
in those with adult-onset symptoms
•Could be mutations in either genome at any age
Maternal Inheritance
•mtDNA from mother to child(ren)Child has identical sequence as
matrilineal relatives mother—sibs (through mom), maternal
aunts/uncles, maternal grandmother
•High recurrence risk in future sibs of an affected child (with a point mutation), approaching 100% •Marked inter- and intra- familial variation of symptoms, age of onset and severity
Maternal genetic transmission
An affected woman transmits the trait to all her children.
Affected men (represented by squares do not pass the trait to any of their offspring
Clinical Manifestation of Mitochondrial Dysfunction
Multiple organ disease
Mitochondrial Cytopathies: Clinical Features
CNS1.Myoclonus
2.Generalized Seizures
3.Stroke
4.Migraine Headache
5.Ataxia
6.Mental Retardation
7.Psychiatric Disease (?)
Clinical Manifestation of Mitochondrial Dysfunction
Skeletal Muscle1.Myopathy (hypotonia)
2.CPEO(Chronic Progressive External Ophthalmoplegia
)
3.Recurrent Myogloburia
4.Weakness/Fatigue
Clinical Manifestation of Mitochondrial Dysfunction
Bone Marrow1.Siderblastic Anemia
2.Pancytopenia
Renal FunctionFanconi Syndrome
Clinical Manifestation of Mitochondrial Dysfunction
Systemic Symptoms1.Lactic Acidosis
2.Short Stature
3.Fatigue
4.Failure to Gain Weight
5.Asthma
6.Intermittent Air Hunger
Clinical Manifestation of Mitochondrial Dysfunction
Endocrine1.Diabetes Mellitus
2.Hypoparathyroidism3.Exocrine Pancreatic
Failure4.Thyroid Disease
Heart1.Cardiomyopathy
2.Conduction Defects
Clinical Manifestation of Mitochondrial Dysfunction
Vision1.Optic Neuropathy
2.Retinitis Pigmentosa
Hearing1.High-frequency Hearing Loss
2.Aminoglycoside-induced Deafness
Clinical Manifestation of Mitochondrial Dysfunction
Gastrointestinal1.Pseudo-obstruction
2.Constipation3.Vomiting
Liver1.Hypoglycemia
2.Gluconeogenic Defects3.Liver Failure and
Cirrhosis
mtDNA-related Syndromes
1.Mitochondrial encephalopathy, lactic acidosis and stroke-like
episodes (MELAS)
2.Aminoglycoside-induced
deafness3.Cyclic vomiting syndrome
mtDNA-related Syndromes (cont.)
4.Kearns-Sayre syndrome (KSS)
5.Pearson syndrome
6.Leigh disease
7.Neuropathy, ataxia and retinitis pigmentosa (NARP)
mtDNA-related Syndromes (cont.)
8.Mitochondrial
neurogastrointestinal encephalopathy (MNGIE)
8.Myoclonic epilepsy and ragged-red fiber disease (MERRF)
9.Leber’s hereditary optic
neuropathy (LHON)
Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes
(MELAS)
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• Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS)– Stroke-like episodes, onset infancy to
adulthood– Maternally inherited diabetes, deafness,
cognitive impairment, short stature, migraine
– Most common cause is heteroplasmy for A3243G mutation (point mutation in tRNA gene for leucine)
– Other causes include T3271C and other point mutations, large rearrangements and presumed nuclear defects
MELAS
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Mitochondrial encephalopathy, lactic acidosis and cerebrovascular accident syndrome (MELAS) Mitochondrial encephalopathy, lactic acidosis and cerebrovascular accident syndrome (MELAS) in PICU
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Mitochondrial encephalopathy, lactic acidosis and cerebrovascular accident syndrome (MELAS) Mitochondrial encephalopathy, lactic acidosis and cerebrovascular accident syndrome (MELAS) in PICU
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More Characteristics
• MELAS affects no specific race or gender more so than others
• Presentation of the disease occurs with the first stroke-like episode (usually 14-15 yrs of age)
• This is a progressive disorder with a high mortality rate
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How does MELAS work?
• Abnormal mitochondria do not metabolize pyruvate
• Excess pyruvate is reduced to lactic acid which accumulates in blood and other fluids
• Large clumps of abnormal mitochondria form in the walls of small arteries and capillaries in the brain and muscles
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Characteristics
• It is the most common maternally inherited mitochondrial disease
• Clinical Features: Strokes, myopathy, muscle twitching, dementia, and deafness
• To a lesser extent: vomiting, migraine-like headaches, diabetes, droopy eyelids, muscle weakness, and short stature
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MELAS: Mitochondrial staining of intramuscular vessels
Succinic dehydrogenase (SDH) stain
Increased SDH staining of amedium sized perimysial vesselin a MELAS patient.
Normal: Mild SDH staining of amedium sized perimysial vessel.
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Brain pathology in MELAS
• MRI during episode of hemiparesis
• Cortical lesion (Right side, posterior): Spares white matter
• Lesion location – Not confined to territory of single
vessel – Involves only part of territory of
several vessels
• Swelling
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MRI during episode of hemiparesis
FLAIR image
T2 weighted image FLAIR image T2 weighted image
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CT during episode of homonymous hemianopia
Medial occipital lesion (Arrow) Enlarged ventricles
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MELAS: Muscle fiber pathology
Scattered abnormal, vacuolated fibers with clear rim: H & E
Scattered "ragged red" muscle fibers: Gomori trichrome
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Late in disease course
MRI: Severe involvement of occipital cortex
Severly abnormal temporal gray matter.Temporal horn of ventricles is enlarged.
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Diagnosis of Mitochondrial Cytopathies
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Prenatal Diagnosis for mtDNA
Can be done, as chorionic villus and amniocyte mutant loads in certain situations
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Treatment
• Certain vitamin and enzyme therapies
• Diet therapy
• Antioxidant treatments
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Important Points
• Mitochondrial Cytopathies– Suspect when:– > 2 unrelated organ systems are involved.– inheritance seems maternal.– the neurological exam seems paradoxical.– the usual presentation of a syndrome is not “usual” and
history is suspect for a bioenergetic disorder.
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References
• Scaglia, Fernando, MD. MELAS Syndrome. http://www.emedicine.com/ped/topic1406.htm. October 26, 2004
• http://herkules.oulu.fi/isbn9514255674/html/graphic33.gif• Dahl H-HM, Thorburn DR (2001) Mitochodrial Diseases, Am
J Medical Genetics 106:1-115
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