Peripheral Nerve AXONAL NEUROPATHIES Hereditary
Post on 31-May-2015
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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
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