Charcot-Marie-Tooth Disease
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Direct answer
Charcot-Marie-Tooth disease is the commonest inherited peripheral neuropathy, causing slowly progressive distal weakness and sensory loss that begins in the legs. It is genetically heterogeneous, with demyelinating CMT1 and axonal CMT2 forms, and CMT1A, the commonest type, is caused by a duplication of the PMP22 gene. Classic signs include pes cavus, foot drop and inverted champagne bottle legs.
What you must remember
- Inheritance: Mostly autosomal dominant, with X-linked forms and rarer recessive forms also described.
- CMT1A: Duplication of PMP22 on chromosome 17p11.2, causing demyelination with uniformly slow nerve conduction.
- HNPP: Deletion of PMP22, causing recurrent pressure palsies at sites such as the fibular head.
- Early foot signs: Pes cavus and hammer toes from distal intrinsic muscle weakness are often the first clue.
- Champagne bottle legs: Distal calf wasting with relatively preserved thighs, giving an inverted champagne bottle outline.
- Nerve conduction: Motor conduction velocity below about 38 m/s suggests demyelinating CMT1, while axonal CMT2 keeps velocities near normal.
- Management: Physiotherapy, ankle-foot orthoses, foot surgery and pain control; no disease-modifying drug is established yet.
Demyelinating and axonal forms compared
The two main groups are separated by nerve conduction studies, because the mechanism of damage differs. The table compares them as an examiner would expect.
| Feature | CMT1 (demyelinating) | CMT2 (axonal) |
|---|---|---|
| Motor conduction velocity | Markedly slowed | Near normal |
| Compound muscle action potential | Relatively preserved | Reduced amplitude |
| Nerve appearance | Enlarged, palpable nerves | Usually not enlarged |
| Example genes | PMP22, MPZ | MFN2 and others |
Conduction velocity is the single most useful test for classifying the form, with a threshold near 38 m/s used in most texts. Genetic testing then identifies the specific gene, such as PMP22 duplication in CMT1A, and the result guides counselling for relatives.
Clinically, CMT1A usually begins in childhood or adolescence with a slowly progressive course. A careful family history matters, because a parent often has mild or unrecognised foot deformity and weakness. Examining the parents and siblings, including their feet and reflexes, is often the quickest way to confirm an autosomal dominant pattern.
Where the exam tries to catch you
Examiners separate CMT1A from HNPP and from axonal forms by the test and the gene.
- Trap: Diagnosing an inherited motor neuropathy from foot deformities without nerve conduction studies Correct: conduction studies separate demyelinating from axonal forms and help distinguish CMT from other neuropathies.
- Trap: Assuming all CMT causes slow nerve conduction Correct: CMT2 is axonal, so conduction velocities stay near normal while the amplitudes fall.
- Trap: Mistaking HNPP for CMT1A because both involve PMP22 Correct: HNPP results from a deletion causing recurrent pressure palsies, while CMT1A results from a duplication causing progressive distal neuropathy.
Frequently asked questions
Which gene duplication causes CMT1A?
CMT1A is caused by a duplication of the PMP22 gene on chromosome 17p11.2, which increases production of a myelin protein. It is the most common cause of Charcot-Marie-Tooth disease. Genetic testing for the duplication is the usual confirmatory investigation.
What distinguishes hereditary neuropathy with liability to pressure palsies from CMT1A?
Hereditary neuropathy with liability to pressure palsies results from a deletion of PMP22, causing recurrent focal neuropathies at pressure points such as the fibular head. CMT1A results from a PMP22 duplication and causes a slowly progressive distal neuropathy. Nerve conduction studies typically show focal slowing at entrapment sites in the deletion form.
Why do patients with Charcot-Marie-Tooth disease develop pes cavus?
Pes cavus develops from an imbalance between relatively unopposed peroneal muscle action and weakened intrinsic and tibialis anterior muscles, which raises the arch. Hammer toes and foot drop often follow as the disease progresses. Early orthoses and foot assessment help limit the deformity.
What is the management of Charcot-Marie-Tooth disease?
Management of Charcot-Marie-Tooth disease is supportive and multidisciplinary, including physiotherapy, occupational therapy and ankle-foot orthoses for foot drop. Foot surgery may be considered for a painful deformity, and neuropathic pain is treated as usual. No disease-modifying drug is currently established, so genetic counselling is important for affected families.