Inherited neuropathies: Charcot–Marie–Tooth and others
- Lesion
Gene defects in myelin or axons cause slowly worsening weakness and wasting of the feet and lower legs, often with high arches.
What it is
Inherited neuropathies are a large group, most of them forms of Charcot–Marie–Tooth disease (hereditary motor and sensory neuropathy). CMT1, the demyelinating type, is most often due to duplication of PMP22 on chromosome 17 (CMT1A); CMT2 is axonal, often from MFN2 mutations; CMTX is X-linked from GJB1 (connexin 32). Deletion of the same PMP22 region causes hereditary neuropathy with liability to pressure palsies. Other inherited neuropathies include hereditary sensory and autonomic neuropathies (painless injuries), familial transthyretin amyloidosis, acute porphyrias, Refsum and Fabry disease and the leukodystrophies (Krabbe, metachromatic, adrenomyeloneuropathy).
Structure
- CMT1: hypertrophic nerves with prominent onion bulbs and thinly myelinated or demyelinated axons.
- CMT2: loss of large myelinated axons without onion bulbs.
- HNPP: focal sausage-shaped thickenings of myelin (tomacula) on teased fibres.
- Metachromatic leukodystrophy: metachromatic sulfatide deposits in Schwann cells; Krabbe: globoid cells in the CNS and demyelinated nerves.
Step by step
- PMP22 is a dosage-sensitive myelin protein made by Schwann cells.
- An extra copy (duplication) overloads Schwann cells, which make unstable myelin that breaks down.
- Repeated demyelination and remyelination form onion bulbs and slow conduction.
- Secondary axonal loss of the longest fibres produces distal wasting and weakness.
- A missing copy (deletion) makes myelin vulnerable to pressure: recurrent pressure palsies.
Clinical notes
- Family history of high arches and 'clumsy ankles' with slow conduction studies points to CMT1A.
- Genetic testing (PMP22 copy number first) confirms the diagnosis; there is no cure, but orthoses and surgery help.
- Porphyria attacks are worsened by many drugs; safe-drug lists matter.
Test yourself
Think of the answer, then tap the question to see it.
What causes CMT1A?
Duplication of the PMP22 gene on chromosome 17.
What causes hereditary neuropathy with liability to pressure palsies?
Deletion of the PMP22 gene region.
What are the clinical signs of CMT?
Distal wasting of legs, pes cavus, hammer toes, foot drop and reduced reflexes from childhood or adolescence.
Which protein forms amyloid in familial amyloid polyneuropathy?
Mutant transthyretin.
Connections
Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.
Sources: Charcot-Marie-Tooth disease: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2025); Hereditary neuropathy with liability to pressure palsies: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2025); Transthyretin amyloidosis: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2025).
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Representative model, for educational purposes only.