Peripheral Nerve

AXONAL NEUROPATHIES

HereditaryVasculitisParaproteinaemicSystemic diseases – diabetes, sarcoidosis,vitamin deficiencies, connective tissue disease,alcohol, organ failure, malignanciesInfectiousToxicIdiopathic

DEMYELINATING NEUROPATHIES

Hereditary

Acquired inflammatory neuropathies

Paraproteinaemic neuropathies

CLASSIFICATION OF THE INHERITED NEUROPATHIES

1. Neuropathies in which the neuropathy is the soleor primary party of the disease

2. Neuropathoes in which the neuropathy is part of a more widespread neurological or multisystemdisorder

1. HEREDITARY NEUROPATHIES (SOLE)

Charcot-Marie-tooth disease (CMT)

Hereditary neuropathy with liability to pressure palsies (HNPP)

Hereditary sensory and autonomic neuropathies (HSAN / HSN)

Familial amyloid polyneuropathy (FAP)

Hereditary motor neuronopathies (HMN / SMA)

X-linked bulbospinal neuronopathy

2. HEREDITARY NEUROPATHIES (MULTISYSTEM)

Disorders of lipid metabolism

Porphyrias

Defective DNA repair

Mitochondrial disorders

Hereditary ataxias

Miscellaneous

IS THE NEUROPATHY HEREDITARY?

Family history

Long history / slowly progressive

Foot deformity (eg. Pes cavus)

Positive sensory symptoms usually not prominent

Neurophysiology

Lack of other cause / ? hereditary (esp. axonal)

CLASSIFICATION

Charcot-Marie-Tooth disease (CMT)

Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)

Distal Hereditary Motor Neuronopathy (dHMN / dSMA)

Hereditary Sensory and Autonomic Neuropathy (HSAN / HSN)

HMSN (CMT) CLINICAL CLASSIFICATION

I Demyelinating

II Axonal

III Severe demyelinating / hypomyelinating

IV Refsum’s Disease

V + Pyramidal

VI + Optic atrophy

VII + Deafness

VIII + Pigmentory retinopathy

CLASSIFICATION OF CMT

CMT1 Demyelinating (<38 m/s)

CMT2 Axonal (>38 m/s)

CMT intermediate (30 – 45 m/s)

CLASSIFY CMT 1 (DEMYELINATING)

Demyelinating CMT 1 (<38 m/s)

Dejerine Sottas Disease (<10 m/s)

Congenital Hypomyelinating Neuropathy (dysmyelination)

CLASSIFICATION CMT

Autosomal dominant

Autosomal recessive

X-linked

“Sporadic”

CLASSIFICATION CMT

CMT1 ADARX-linked

DSD ADAR

CHN ADAR

HNPP AD

CMT2 ADARX-linked

HMSN I (CMT 1)

Slowly progressive distal wasting and weakness

Onset 1st or 2nd decade

Areflexia, distal sensory loss and foot deformity

Demyelinating (slow motor nerve conduction velocities)

Pathology hypertrophic, demyelinating

CMT 1 LEGS

PES CAVUS

HSAN I TOE

HSAN I FEET

HSAN I FEET

CMT 1 HANDS

CMT 1 ONION BULBS

CMT 1 TEASED FIBRES

CMT1 AD

CMT 1A duplication PMP-22mutations PMP-22

CMT 1B mutations P0

CMT 1C mutations LITAF/SIMPLE

CMT 1D mutations EGR2

HMSN III (DEJERINE-SOTTAS DISEASE (DSD))

Severe demyelinating / hypomyelinating neuropathy

Early onset

Extremely slow motor nerve conduction velocities

Pathology demyelination / amyelination / basal lamina onionbulbs / classical onion bulbs

DEJERINE SOTTAS DISEASE (DSD)

DSD A AD/AR mutation PMP-22

DSD B AD/AR mutation Po

DSD C AD mutation EGR2

DSD D AD 8q23 – q24

CONGENITAL HYPOMYELINATING NEUROPATHY (CHN)

CHN A AD mutation PMP-22

CHN B AD mutation Po

CHN C AD/AR mutation EGR2

HNPP

Autosomal dominant

Episodic, recurrent demyelinating neuropathy

Reduced motor / sensory conduction velocities

Pathology sausage like myelin thickenings (tomacula)

Linked to chromosome 17

HNPP

HNPP chromosome 17 deletion

PMP-22 point mutations

CMT 1 AR (RECESSIVE)

CMT1 AR A (CMT4A) GDAP1

CMT1 AR B1 (CMT4B1) MTMR2

CMT1 AR B2 (CMT4B2) SBF2

CMT 1AR C SH3/TPR

CMT1 AR D (HMSNL) NDRG1

CMT1 AR E (CCFND) 18q

CMT1 AR F (CMT4F) Periaxin

CMT1 AR G (HMSNR) 10q22-q23

CMT1 X-LINKED

Clinically similar to CMT1

No male to male transmission

Males more severe than females

Males demyelinating / females axonal

Patchy neurophysiology

Central nervous system involvement

CMT X1

Linked to Xq13.1

Gap junction protein connexin 32 in that area

Mutations in connexin 32 in X-linked HMSN I families

HMSN II (CMT 2)

Similar phenotype to HMSN I

Later age of onset

Axonal neuropathy (normal motor nerve conduction velocities)

Patholgy axonal

CMT 2 (AXONAL / DOMINANT)

CMT 2A KIF1B

CMT 2B RAB7

CMT 2C unknown

CMT 2D GARS

CMT 2E NF-L

CMT 2F 7q11-q21

CMT 2 Po

CMT 2G (HMSNP) 3q13.1

CMT 2 (RECESSIVE)

CMT2 AR A LMNA

CMT2 AR B 8q21.3

CMT2 AR C 19q13.3

CMT2 AR D GDAP1

CMT 2 (X-LINKED)

CMT 2X Xq24 - 26

INTERMEDIATE CMT

CX 32

PO

GDAP1

?NFL

DI CMT 10q24.1-q25.1

DI CMT 19p12-p13

Peripheral nerve

Peripheral Nerve

Peripheral Nerve

MOLECULAR DIAGNOSIS

Chromosome 17 duplication / deletion widely available

PMP-22, P0 and CX-32 specialised laboratories

EGR2, NF-L, KIFIBß, MTMR2, NDRG1, Periaxin, GDAP1,LMNA research laboratories only

CMT DIAGNOSIS FLOW CHART

WHY DIAGNOSE CMT ?

Definite diagnosis

Prognosis

Prevents unnecessary tests (eg. Nerve biopsy)

Genetic counselling family / diagnostic / predictive / ante-natal

Treatment therapy / orthopaedic

TREATMENT OF CMT

Gene therapy

CMT GENE THERAPY

Transgenic mouse study CMT 1A

Regulation of PMP-22 overexpression possible

Overexpression causes demyelination

Demyelination corrected when ovexpression turned off