Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease is the commonest inherited peripheral neuropathy. It causes slowly progressive distal weakness, wasting and sensory loss, with foot deformity (pes cavus), and is divided into demyelinating (CMT1), axonal (CMT2) and intermediate forms.

The prevalence is about 1 in 2,500 people. The commonest type is CMT1A (about 50% of cases), caused by a duplication of PMP22 on chromosome 17. Onset is usually in the first two decades, and men and women are equally affected.

Genetics. Inheritance is autosomal dominant (PMP22, MPZ, MFN2, GJB1 on the X chromosome in X-linked CMT), autosomal recessive, or X-linked. Over 100 genes are described.

Course. Slow progression over decades. Most patients remain ambulant, with ankle foot orthoses in later life. Life expectancy is normal in most.

Pathophysiology.

Mutations in genes affecting myelin structure (PMP22, MPZ) or axonal transport and mitochondrial function (MFN2) cause length dependent degeneration of peripheral nerves.

Longest nerves fail first, giving the distal pattern.

• Foot deformity (pes cavus, hammer toes), difficulty running and tripping, steppage gait and ankle sprains.
• Distal leg wasting ("inverted champagne bottle" legs), then weakness and wasting of the hands.
• Reduced or absent ankle reflexes; sensory loss in a stocking glove pattern; tremor in some.
• Neuropathic pain, cramps, scoliosis and hip dysplasia; rare hearing loss, optic atrophy or vocal cord palsy in specific types.
• Family history of similar features, which may be mild.

Red flags.

• Rapid progression or subacute worsening (superimposed immune neuropathy, toxic exposure).
• Respiratory or bulbar weakness.
• Severe early onset (Déjerine-Sottas phenotype) with delayed milestones.
• Exposure to neurotoxic drugs such as vincristine.

• Clinical examination and family history; nerve conduction studies show uniform slowing (under 38 m/s in motor conduction velocity) in CMT1, and reduced amplitudes in CMT2.
• Genetic testing: PMP22 duplication first for demyelinating type, then a multigene panel or exome.
• Nerve biopsy is rarely needed.
• Assessment of foot deformity, scoliosis and hip; hearing and vision tests in selected types.
• Exclude acquired causes: diabetes, B12 deficiency, thyroid disease, alcohol, toxins and chronic inflammatory demyelinating polyneuropathy.

Differential diagnosis. Hereditary neuropathy with liability to pressure palsies, distal hereditary motor neuropathy, chronic inflammatory demyelinating polyneuropathy, acquired axonal neuropathies, spinal muscular atrophy, Friedreich ataxia and myopathies.

• No curative treatment exists; management is supportive and multidisciplinary.
• Physiotherapy with stretching and gentle strengthening, aerobic exercise, and balance training; avoid overwork weakness.
• Ankle foot orthoses and custom footwear; orthopaedic foot surgery for severe deformity; hand therapy and aids.
• Avoid neurotoxic drugs: vincristine (strictly), paclitaxel, cisplatin, amiodarone, nitrofurantoin, isoniazid, dapsone, and prolonged metronidazole or linezolid; review before any new drug.
• Neuropathic pain: amitriptyline 10 mg orally at night, increased to 30 to 50 mg, maximum 75 mg (50 mg in older adults). Review at 6 to 8 weeks. Monitor sedation, anticholinergic effects, postural hypotension and mood; baseline ECG over age 40 or with cardiac risk. Avoid after recent myocardial infarction, with arrhythmia, in angle closure glaucoma or urinary retention; reduce dose in hepatic impairment.
• Pregabalin as an alternative: 75 mg orally twice daily, increased after 1 week to 150 mg twice daily, then to a maximum of 300 mg twice daily (600 mg daily). Monitor sedation, weight gain, oedema, mood and misuse. Adjust for renal function: creatinine clearance 30 to 59 mL/min, 75 to 300 mg daily; 15 to 29 mL/min, 25 to 150 mg daily; under 15 mL/min, 25 to 75 mg daily. Avoid in pregnancy unless benefit outweighs risk.
• Keep a healthy weight, stop smoking and avoid alcohol excess; vaccinations as usual.
• Genetic counselling; prenatal and preimplantation testing are available.

Monitoring. Annual review with strength, function, foot and spine assessment; review hearing and vision in specific types.

Referral and escalation. Neuromuscular and genetics services; orthotics and orthopaedics; pain service for refractory pain.

Special groups. Pregnancy: neuropathy may worsen temporarily, so plan delivery and anaesthesia review. Children: school adaptations, footwear and scoliosis screening.