NeurologyTier 1Disease (DEADMAN)

Peripheral neuropathy - hereditary

Description

Genetically determined, length-dependent, slowly progressive motor and/or sensory neuropathy
Charcot-Marie-Tooth (CMT) = hereditary motor and sensory neuropathy (HMSN) - the dominant group

Classification - by nerve conduction velocity, then by gene

	Motor NCV (median)	Type
CMT1 - demyelinating	<38 m/s	AD; CMT1A (PMP22 duplication) is the commonest of all
CMT2 - axonal	>38 m/s, low CMAP amplitude	AD; MFN2 commonest
Intermediate	25-45 m/s	CMTX1 (GJB1/connexin-32) - X-linked, males severe, females mild
CMT4	Demyelinating	Autosomal recessive, early and severe
Dejerine-Sottas (CMT3)	Very slow (<10 m/s)	Infantile onset, severe, hypertrophic nerves

HNPP (hereditary neuropathy with liability to pressure palsies) - PMP22 DELETION (the reciprocal of CMT1A); recurrent painless focal palsies at entrapment sites after trivial compression

Other hereditary neuropathies

Hereditary sensory and autonomic neuropathy (HSAN) - painless injury, ulceration, Charcot joints
Hereditary transthyretin (ATTRv) amyloid neuropathy - the one that must not be missed: it is treatable
Fabry disease - small fibre, burning acral pain, angiokeratomata, X-linked
Refsum disease - phytanic acid; retinitis pigmentosa + deafness + cerebellar signs + ichthyosis
Porphyria - acute motor-predominant, with abdominal pain and psychiatric features
Friedreich ataxia, mitochondrial disease, leukodystrophies (metachromatic, Krabbe), abetalipoproteinaemia, Tangier disease

Epidemiology

CMT prevalence ~1 in 2,500 - the commonest inherited neuromuscular disease
CMT1A (PMP22 duplication) accounts for ~50-70% of CMT1 and ~40% of all genetically confirmed CMT
CMTX1 (GJB1) ~10-15%; MPZ and MFN2 make up most of the rest
Onset in the first two decades for CMT1; CMT2 and CMTX often later
M=F overall (CMTX1 is more severe in males)

Aetiopathogenesis

*CMT1A - 1.5 Mb duplication at 17p11.2 containing PMP22***
- Gene dosage effect: duplication -> CMT1A; deletion -> HNPP
- -> abnormal compact myelin -> demyelination and remyelination -> "onion bulbs" -> palpable nerve thickening
CMT2 - axonal genes: MFN2 (mitochondrial fusion), MPZ, GDAP1, NEFL, HSPB1, RAB7
*CMTX1 - GJB1 (connexin-32) - gap junctions in Schwann cell paranodal loops; X-linked, so no male-to-male transmission*
Length-dependent axonal degeneration explains why the longest nerves fail first: peronei and intrinsic foot muscles -> pes cavus and foot drop, then hands
Muscle imbalance across the growing foot (strong tibialis posterior, weak peronei and tibialis anterior) -> pes cavus + claw toes + Achilles contracture

Diagnosis

Clinical - the classic CMT1 picture

Pes cavus (the earliest and most characteristic sign), variable pes planus in some, toe clawing, Achilles contractures
Symmetrical distal wasting of the legs - "inverted champagne bottle", wasting stopping abruptly at the lower third of the thigh
Bilateral high-stepping (foot drop) gait; frequent ankle sprains, difficulty with heel walking
Later: distal wasting and clawing of the hands, small hand muscle wasting
Mild kyphoscoliosis
Reduced power distally; absent or markedly reduced reflexes (ankle jerks lost first, often globally areflexic)
Sensory disturbance predominantly proprioception and vibration; patients usually complain of weakness and deformity, not numbness
Palpable, thickened peripheral nerves in ~25% of CMT1 (HMSN I) - greater auricular, ulnar at the elbow, common peroneal at the fibular head
Family history - but examine the parents' feet yourself; mild cases are undiagnosed

Causes of clinically palpable thickened nerves

Amyloidosis
Charcot-Marie-Tooth disease (CMT1)
Leprosy (the commonest cause worldwide; thickened with anaesthetic skin patches)
Refsum disease - with retinitis pigmentosa, deafness and cerebellar signs
Dejerine-Sottas disease
Also: acromegaly, neurofibromatosis, CIDP (chronic, so the nerve hypertrophies), sarcoidosis

Features that argue AGAINST hereditary neuropathy

Rapid progression, asymmetry, prominent positive sensory symptoms or pain, autonomic features
These point to an acquired cause - CIDP, vasculitis, paraprotein-associated - which is treatable. Do not attribute a subacute neuropathy to genetics**
*An acquired neuropathy superimposed on CMT is common and easily missed* - a step change in a stable patient deserves a full acquired work-up

Nerve conduction studies

Uniform, symmetric slowing without conduction block or temporal dispersion = inherited demyelinating
- *Non-uniform slowing with conduction block and dispersion = acquired (CIDP)* - the key electrophysiological discrimination
HNPP: focal slowing and conduction block at entrapment sites, with diffuse prolongation of distal motor latencies
Velocity is stable over life in CMT1; amplitude falls slowly

Genetics

*Test PMP22 duplication/deletion first in a demyelinating neuropathy* - high yield, cheap
If negative: targeted next-generation sequencing panel (diagnostic yield ~30%, with variants of unknown significance in a further ~33% - counsel about VUS before testing)
Sequence GJB1 early where the pedigree shows no male-to-male transmission; MFN2 first in early-onset axonal disease
*Always exclude hereditary transthyretin amyloidosis in a progressive axonal neuropathy with autonomic features, cardiomyopathy, carpal tunnel syndrome or vitreous opacity - it is treatable*

Exclude acquired mimics before settling

B12, folate, copper, HbA1c/OGTT, TFT, UEC, LFT, serum protein electrophoresis and free light chains, ESR/CRP, ANA/ENA, HIV, syphilis, hepatitis, heavy metals, alcohol history
Nerve biopsy is rarely needed; skin biopsy for intraepidermal nerve fibre density for small-fibre involvement

Management

No disease-modifying therapy is approved. The gains come from orthopaedics, orthotics, physiotherapy and genetics.

A. Function and deformity

Ankle-foot orthoses for foot drop - the single highest-value intervention
Podiatry: custom insoles, wide shoes, callus and ulcer prevention
Physiotherapy - stretching for Achilles contracture, moderate aerobic and resistance exercise
- Avoid high-intensity eccentric or exhaustive exercise
Occupational therapy - hand function, adaptive devices, workplace assessment
Surgery for fixed deformity: plantar fascia release, tendon transfer, osteotomy, triple arthrodesis in severe cases; scoliosis correction

B. Symptom control

Neuropathic pain (less common than in acquired neuropathy) - amitriptyline, duloxetine, pregabalin
Cramps - stretching, magnesium; quinine is not recommended
Fatigue, restless legs, sleep apnoea (screen - phrenic and diaphragmatic involvement occurs in some genotypes)
Falls prevention; driving assessment

C. Drugs to avoid - the most examinable point

*Neurotoxic drugs can cause abrupt, sometimes irreversible deterioration:*
- Vincristine - absolutely contraindicated in CMT1A
- Cisplatin/oxaliplatin, taxanes, thalidomide, bortezomib
- Amiodarone, nitrofurantoin, metronidazole (prolonged), isoniazid (give pyridoxine), dapsone, phenytoin, disulfiram
- Statins - not contraindicated, but monitor
Give the patient a written list and a MedicAlert

D. Genetics and reproduction

Formal genetic counselling for the patient and family; document the inheritance pattern
CMT1A/HNPP: autosomal dominant, 50% risk to offspring; CMTX1: affected males transmit to all daughters and no sons
Prenatal testing and preimplantation genetic diagnosis available
Cascade screening of at-risk relatives - the practical benefit is avoiding vincristine, not treatment

E. Pregnancy, anaesthesia and other practicalities

Pregnancy may transiently worsen symptoms; higher rate of assisted delivery
Alert anaesthetists - avoid suxamethonium where there is significant wasting; care with regional blocks
HNPP: avoid prolonged limb positioning, leg crossing, elbow leaning, and pad the operating table

F. Investigational

PXT3003 (baclofen/naltrexone/sorbitol) and PMP22-lowering gene therapies for CMT1A remain in trials - none approved
By contrast, ATTRv amyloid neuropathy now has effective therapy (tafamidis, patisiran, vutrisiran, eplontersen) - which is exactly why it must be separated out

Associations

Pes cavus, hammer/claw toes, Achilles contracture, kyphoscoliosis, hip dysplasia
Sensorineural hearing loss - certain genotypes (MPZ, PMP22 point mutations, mitochondrial)
Vocal cord paresis and diaphragmatic weakness - GDAP1, TRPV4
Optic atrophy and pyramidal signs - MFN2 (hereditary motor and sensory neuropathy type VI), complex phenotypes
Glaucoma, cataract in some pedigrees
CMTX1: transient CNS episodes - stroke-like white matter lesions after fever, exertion or altitude
Restless legs syndrome, obstructive sleep apnoea, depression
HNPP: carpal tunnel, ulnar and peroneal palsies after minor compression

Natural history & complications

Slowly progressive over decades; life expectancy is normal in typical CMT1 and CMT2
Most remain ambulant; <5-10% require a wheelchair
*Nerve conduction velocity is set by age 5 and does not change - clinical decline reflects axonal loss, not further demyelination*
Marked intrafamilial variability even with the same mutation
HNPP - episodic, usually with full recovery, but a chronic length-dependent neuropathy accumulates

Worse prognosis

CMT4 (autosomal recessive) and Dejerine-Sottas - early onset, severe, may never walk independently
Male sex in CMTX1
Early-onset scoliosis, respiratory involvement
Superimposed acquired neuropathy or vincristine exposure

Complications

Foot ulceration, Charcot joints (especially in HSAN), recurrent ankle injury
Fixed deformity requiring surgery; scoliosis
Falls and fractures
Respiratory failure in genotypes with diaphragmatic involvement
Hand function loss; loss of employment
Depression, chronic pain

Monitor

Annual: CMT Examination Score/CMTNS, gait and orthotic review, foot skin integrity
Scoliosis in growing patients; hearing; respiratory function if symptomatic
Review the drug list at every prescription for neurotoxic agents
Family cascade testing and reproductive planning

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