Hereditary motor and sensory neuropathy

Description

Charcot-Marie-Tooth (CMT) = hereditary motor and sensory neuropathy; commonest inherited neuropathy
Length-dependent, slowly progressive, motor >> sensory

Clinical signature

Pes cavus + hammer toes - the developmental giveaway; present before weakness is noticed
"Inverted champagne bottle" legs - distal wasting stopping at the mid-thigh; upper limb wasting stops above the elbow
Foot drop, steppage gait, frequent ankle sprains
Areflexia (ankles first)
*Minimal sensory symptoms despite florid sensory-nerve involvement* - patients complain of weakness and deformity, not numbness
Palpably thickened nerves (ulnar at elbow, greater auricular, common peroneal) - demyelinating forms
Claw hand, wasted thenar/first dorsal interosseous later
Tremor + neuropathy + thickened nerves = Roussy-Levy variant

Classification

Type	Inheritance	Gene	Physiology
CMT1A (~50%)	AD	PMP22 duplication (17p11.2)	Demyelinating
CMT1B	AD	MPZ	Demyelinating
CMT1X (~10-15%)	X-linked	GJB1 (connexin 32)	Intermediate; males severe, females mild
CMT2	AD	MFN2 commonest	Axonal
CMT4	AR	various	Demyelinating, severe, childhood
HNPP	AD	PMP22 deletion	Tomaculous

**PMP22 dosage disease: duplication -> CMT1A; deletion -> HNPP (hereditary neuropathy with liability to pressure palsies)**
- HNPP = painless recurrent focal palsies at entrapment sites after trivial compression
Demyelinating: repeated de/remyelination -> onion-bulb formation -> nerve hypertrophy
Axonal: mitochondrial/axonal transport failure -> distal axonal degeneration, no nerve thickening

Nerve conduction studies - split demyelinating from axonal first

Uniform slowing, symmetrical, no conduction block - this distinguishes CMT1 from CIDP, where slowing is patchy with conduction block and dispersion
Genetic testing: PMP22 duplication/deletion first (MLPA), then panel/exome
Examine and examine the parents - mild pes cavus in a parent clinches inheritance
Nerve biopsy almost never required

Exclude acquired and treatable mimics

CIDP (responds to steroids/IVIg - CMT does not), diabetes, B12 deficiency, alcohol, paraprotein, amyloid, vasculitis, thyroid
Other hereditary: Friedreich ataxia (pes cavus + ataxia + extensor plantars), hereditary ATTR amyloidosis, Refsum disease, porphyria, Fabry disease, metachromatic leukodystrophy
Pes cavus + upgoing plantars = think Friedreich, not CMT

No disease-modifying therapy. Management is functional, preventive and genetic.

A. Function

Physiotherapy and occupational therapy - stretching to prevent contractures, strengthening, aids
Ankle-foot orthoses for foot drop - the highest-yield single intervention
Podiatry, custom footwear, callus care
Orthopaedic surgery for fixed deformity: tendon transfer, osteotomy, arthrodesis
Avoid immobilisation and rapid deconditioning

B. Symptoms

C. Avoid neurotoxic drugs - flag prominently

Vincristine is absolutely contraindicated (rapid catastrophic deterioration)
Caution: cisplatin/oxaliplatin, taxanes, amiodarone, nitrofurantoin, metronidazole (prolonged), thalidomide, high-dose B6, dapsone, isoniazid, linezolid, phenytoin

D. Surveillance

Respiratory and sleep assessment if diaphragm or vocal cord involvement (MPZ, GDAP1, some CMT2)
Hearing, hip dysplasia and scoliosis in early-onset disease
Pregnancy may accelerate progression; higher rate of operative delivery
Anaesthetic caution - avoid suxamethonium; risk of postoperative respiratory compromise

E. Genetic

Counselling and determination of inheritance pattern before predictive testing (AD 50%, X-linked, AR)
Ascorbic acid trials in CMT1A were negative - do not offer

Pes cavus, hammer toes, claw hand, scoliosis, hip dysplasia
Charcot (neuropathic) joints and distal trophic skin/bone change - from loss of pain and proprioceptive fibres
Essential-type tremor (Roussy-Levy)
Sensorineural hearing loss, optic atrophy, vocal cord palsy (specific genotypes)
Restless legs, sleep-disordered breathing
Glaucoma and cataract in some CMT2 subtypes

Very slowly progressive over decades; most remain ambulant for life
- Only ~5-10% become wheelchair-dependent
Normal life expectancy in CMT1 and CMT2
Step-change deterioration should prompt a search for a second, acquired cause - CIDP superimposed, diabetes, drug toxicity, B12 deficiency
Severe infantile forms (Dejerine-Sottas, CMT4) - delayed walking, marked disability
HNPP - recurrent but usually fully recoverable palsies; mild residual deficit accumulates

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