Charcot–Marie–Tooth disease (peroneal muscular atrophy)

Published on 05/05/2015 by admin

Filed under Internal Medicine

Last modified 22/04/2025

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56 Charcot–Marie–Tooth disease (peroneal muscular atrophy)

Instruction

Examine this patient’s legs.

Salient features

Examination

• Wasting of muscles of calves and thighs that stops abruptly, usually in the lower third of the thigh, and is described as ‘stork’ or ‘spindle’ legs, ‘fat bottle’ calves and ‘inverted champagne bottles’ (Fig. 56.1)

• Pes cavus (high arched foot) or pes planus (flat foot), clawing of toes, contractures of the Achilles tendon

• Weakness of dorsiflexion, foot drop

• Absent ankle jerks, plantars are downgoing or equivocal

• Mild sensory impairment or no sensory loss. Some patients have decreased responses to pain in the stocking distribution.

image

Fig. 56.1 Charcot–Marie–Tooth disease. (A,B) Muscle wasting of the legs and the lower third of the thigh. (C–E) Foot deformities of different severities, with high arches, hammer toes and callosities. (F) Severe atrophy of intrinsic hand muscles (main en griffe, claw hand).

(With permission from Pareyson D, Marchesi C 2009.)

Proceed as follows:

• Feel for lateral popliteal nerve thickening (seen in some cases only)

• Look at the hands for small muscle wasting and clawing

• Tell the examiner that you would like to:

• Know whether there is a family history of disease
• Look for enlarged greater auricular nerves
• Examine the spine for scoliosis
• Examine the gait (high-steppage gait of foot-drop).

Note: There are two distinctive clinical features of this disease:

1 The muscular atrophy begins in the distal portions of the affected muscles in the lower and upper limbs, unlike the global atrophy of motor neuron disease or muscular dystrophy. The atrophy then creeps upwards, involving all muscles.

2 Second, the degree of disability is minimal in spite of marked deformity.

Diagnosis

This patient has ‘inverted champagne bottle’ legs with sensory neuropathy (lesion), which is caused by hereditary Charcot–Marie–Tooth disease (aetiology). She has severe foot-drop and requires calipers (functional status).

Advanced-level questions

What are the phenotypic types of Charcot–Marie–Tooth disease?

Charcot–Marie–Tooth disease (CMT) is divided in two major phenotypic types according to electrophysiological, clinical and nerve biopsy evaluations:

• Glial myelinopathy (type 1): a demyelinating neuropathy (marked slowing of conduction in motor nerves; absent deep tendon reflexes)

• Neuronal axonopathy (type 2): an axonal neuropathy (little or no slowing of nerve conduction; normal deep tendon reflexes)

• Distal spinal muscular atrophy.

What is the mode of inheritance?

• Each type can be inherited in a dominant, recessive or X-linked fashion. There are also autosomal dominant intermediate forms of CMT that can have features of both axonal and demyelinating neuropathies. Mutations in 31 known genes and additional unidentified loci can produce CMT:

• Some common genes include PMP22, MPZ, PRX, GDAP1, and EGR2
• MPZ (encoding myelin protein zero is a member of the immunoglobulin superfamily; it may be important not only in forming myelin but also in cell signalling), GDAP1 and GJB1 are known to be associated with CMT type 1, but select mutations in these genes can also cause CMT type 2
• NEFL is known to be associated with CMT type 2, but select mutations convey a CMT type 1 phenotype
• Dominant intermediate forms of CMT have been reported to be associated with MPZ mutations
• Specific recessive alleles related to CMT have also been reported for EGR2 and PMP22
• Two mutations in SH3TC2 (encoding the SH3 domain and tetratricopeptide repeats 2) cause autosomal recessive CMT (N Engl J Med 2010;362:1181–91)
• Of the 31 genes in 39 known CMT loci, only 15 are currently available for clinical testing.

• Current evidence-based clinical guidelines for distal symmetric polyneuropathy recommend genetic testing consisting of screening for common mutations, including the CMT1A duplication copy-number variant and point mutations of the X-linked GJB1.

• Whole genome sequencing is emerging to be the diagnostic tool in this condition.

What other uncommon features may these patients have?

Optic atrophy, retinitis pigmentosa, spastic paraparesis.

In which other conditions is pes cavus seen?

Friedreich’s ataxia.

What is the natural history of the disease?

The disease usually arrests in middle life.

How does the forme fruste of the disease manifest?

The forme fruste may be seen in family members of patients with CMT and manifests as pes cavus and absent ankle jerks.

Mention other hereditary neuropathies

• Roussy–Lévy syndrome (where features of progressive muscular atrophy may be combined with tremor and ataxia)

• Hereditary amyloidosis

• Refsum’s disease (phytanic acid accumulates in the central and peripheral nervous systems)

• Fabry’s disease (where there is a deficiency of α-galactosidase)

• Tangier disease

• Bassen–Kornzweig disease (abetalipoproteinaemia, absence of LDL, and vitamin E deficiency)

• Metachromatic leukodystrophy (where galactosyl sulfatide accumulates in the central and peripheral nervous systems).

Mention a few conditions that Charcot is credited to have described for the first time

• Ankle clonus

• Tabes dorsalis and Charcot’s joints

• Multiple sclerosis

• Peroneal muscular atrophy

• Multiple cerebral aneurysms, called Charcot–Bouchard aneurysms

• Hysteria.

The syndrome was originally described by JM Charcot (1825–1923) and P Marie (1853–1940) in 1886 at the Saltpêtrière in Paris, and independently by HH Tooth at St Bartholomew’s Hospital and the National Hospital for Nervous Diseases, Queen Square, London.

P Marie was a world-famed neurologist. He published extensively on aphasia. He succeeded Charcot’s lineage of Raymond, Brissaud and Dejerine at the Saltpêtrière in 1918.

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