Peripheral Nerve AXONAL NEUROPATHIES Hereditary
Transcript of Peripheral Nerve AXONAL NEUROPATHIES Hereditary
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Peripheral Nerve
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AXONAL NEUROPATHIES
HereditaryVasculitisParaproteinaemicSystemic diseases – diabetes, sarcoidosis,vitamin deficiencies, connective tissue disease,alcohol, organ failure, malignanciesInfectiousToxicIdiopathic
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DEMYELINATING NEUROPATHIES
Hereditary
Acquired inflammatory neuropathies
Paraproteinaemic neuropathies
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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
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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
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2. HEREDITARY NEUROPATHIES (MULTISYSTEM)
Disorders of lipid metabolism
Porphyrias
Defective DNA repair
Mitochondrial disorders
Hereditary ataxias
Miscellaneous
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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)
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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)
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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
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CLASSIFICATION OF CMT
CMT1 Demyelinating (<38 m/s)
CMT2 Axonal (>38 m/s)
CMT intermediate (30 – 45 m/s)
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CLASSIFY CMT 1 (DEMYELINATING)
Demyelinating CMT 1 (<38 m/s)
Dejerine Sottas Disease (<10 m/s)
Congenital Hypomyelinating Neuropathy (dysmyelination)
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CLASSIFICATION CMT
Autosomal dominant
Autosomal recessive
X-linked
“Sporadic”
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CLASSIFICATION CMT
CMT1 ADARX-linked
DSD ADAR
CHN ADAR
HNPP AD
CMT2 ADARX-linked
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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
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CMT 1 LEGS
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PES CAVUS
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HSAN I TOE
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HSAN I FEET
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HSAN I FEET
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CMT 1 HANDS
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CMT 1 ONION BULBS
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CMT 1 TEASED FIBRES
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CMT1 AD
CMT 1A duplication PMP-22mutations PMP-22
CMT 1B mutations P0
CMT 1C mutations LITAF/SIMPLE
CMT 1D mutations EGR2
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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
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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
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CONGENITAL HYPOMYELINATING NEUROPATHY (CHN)
CHN A AD mutation PMP-22
CHN B AD mutation Po
CHN C AD/AR mutation EGR2
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HNPP
Autosomal dominant
Episodic, recurrent demyelinating neuropathy
Reduced motor / sensory conduction velocities
Pathology sausage like myelin thickenings (tomacula)
Linked to chromosome 17
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HNPP
HNPP chromosome 17 deletion
PMP-22 point mutations
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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
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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
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CMT X1
Linked to Xq13.1
Gap junction protein connexin 32 in that area
Mutations in connexin 32 in X-linked HMSN I families
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HMSN II (CMT 2)
Similar phenotype to HMSN I
Later age of onset
Axonal neuropathy (normal motor nerve conduction velocities)
Patholgy axonal
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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
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CMT 2 (RECESSIVE)
CMT2 AR A LMNA
CMT2 AR B 8q21.3
CMT2 AR C 19q13.3
CMT2 AR D GDAP1
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CMT 2 (X-LINKED)
CMT 2X Xq24 - 26
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INTERMEDIATE CMT
CX 32
PO
GDAP1
?NFL
DI CMT 10q24.1-q25.1
DI CMT 19p12-p13
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Peripheral nerve
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Peripheral Nerve
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Peripheral Nerve
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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
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CMT DIAGNOSIS FLOW CHART
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WHY DIAGNOSE CMT ?
Definite diagnosis
Prognosis
Prevents unnecessary tests (eg. Nerve biopsy)
Genetic counselling family / diagnostic / predictive / ante-natal
Treatment therapy / orthopaedic
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TREATMENT OF CMT
Gene therapy
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CMT GENE THERAPY
Transgenic mouse study CMT 1A
Regulation of PMP-22 overexpression possible
Overexpression causes demyelination
Demyelination corrected when ovexpression turned off