Charcot-Marie-Tooth disease

Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor and sensory neuropathy (HMSN), is the most commonly inherited neuropathy of lower motor (to a lesser degree sensory) neurons.

The prevalence of CMT in one Norwegian study was 82.3 cases per 100,000 people 4

Signs and symptoms usually become first evident in childhood. Typically this starts in the lower limbs with weakness, atrophy and deformity, and later affects the upper limbs. It rarely involves the more proximal musculature and rarely involves the cranial nerves. Sensory changes are present but usually to a lesser degree 5.

It is not a single condition, but a cluster of heterogeneous mutations with many subtypes. As expected the number and classification is in flux. Most frequently it is autosomal dominant in inheritance (although this is variable).

Classification is based on nerve-conduction studies and neuronal pathology divided into demyelinating and non-demyelinating forms 5:

Reduced nerve conduction velocity (<38 m/sec) in upper limb nerves and myelin abnormalities on biopsy (e.g. onion bulb formation). This includes:

  • CMT type 1​
    • Most common4,5
    • Autosomal dominant inheritance, most commonly due to over-expression of peripheral myelin protein 22 (PMP22)5
    • Repeated cycles of demyelination and remyelination result in a thick layer of abnormal myelin around the peripheral axons
    • This form of CMT disease is a disorder of peripheral myelination
    • These changes cause what is referred to as an onion bulb appearance
  • CMT type 4
    • Autosomal recessive inheritance 5

Preserved or mildly affected nerve conduction velocity (>38 m/s) and nerve biopsy evidence of degeneration and regeneration 5.

  • CMT type 2
    • Peripheral neuropathy through direct axonal death and Wallerian degeneration
    • Autosomal dominant inheritance 5
    • Most commonly due to a mutation in the mitofusin 2 gene (MFN2) 5
  • Pure motor neuropathy (dHMN) with sparing of sensory nerves
  • Pyramidal involvement (CMT type 5)
  • Optic nerve involvement (CMT type 6)
  • CMT type 3 (also known as Déjerine-Sottas disease)
    • Characterised by infantile onset, resulting in severe demyelination with delayed motor skills, it is much more severe than CMT type 1
    • Increased CSF protein and severe demyelination on nerve biopsy are features 5
  • X chromosome linked CMT (CMTX
    • Second most common form of CMT overall  5
    • Most commonly due to a mutation in the gap-junction B1 (GJB1) gene  5

The nerve roots are typically hypertrophic with onion bulb sign. This represents hypertrophic demyelination. Denervation changes in muscles are apparent.

Some enhancement may be seen on MRI, but it is not usually a prominent feature.

Soft tissue and skeletal abnormalities (e.g. scoliosis) may also be noticeable .

Unfortunately no effective drug for CMT exists. Treatment is largely supportive with rehabilitation therapy and surgery for skeletal deformities 5. Most patients with CMT1A (the most common form of CMT) will remain able to walk for their entire life. However, the disease has variable severity depending on the subtype 5.

It is named after Jean-Martin Charcot, Pierre Marie and Howard Henry Tooth.

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Article information

rID: 1099
Section: Syndromes
Synonyms or Alternate Spellings:
  • Hereditary motor and sensory neuropathy (HMSN)
  • Charcot-Marie-Tooth disease (CMT)
  • Hereditary motor and sensory neuropathy

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