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.

Epidemiology

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

Clinical presentation

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 degree⁵.

Pathology

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

Classification

• CMT type 1​
  • this form of CMT disease is a disorderMost common^4,5
  • Autosomal dominant inheritance, most commonly due to over-expression of peripheral myelinationmyelin protein 22 (PMP22)⁵
  • repeatedRepeated cycles of demyelination and remyelination result in a thick layer of abnormal myelin around the peripheral axons
  • theseThis form of CMT disease is a disorder of peripheral myelination
  • These changes cause what is referred to as an onion bulb appearance
• CMT type 24
  • this primarily is a neuronal (i.e. axonalAutosomal recessive inheritance ⁵

Axonal forms

Preserved or mildly affected nerve conduction velocity (>38 m/s) disorder, not a demyelinating disorderand nerve biopsy evidence of degeneration and regeneration ⁵.

• CMT type 2 results in peripheral
  • 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

Other forms

• 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)
  • characterizedCharacterised by infantile onset, this condition resultsresulting 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 X(CMTX) (X-linked
  • Second most common form of CMT overall  ⁵
  • Most commonly due to a mutation in the gap-junction B1 (GJB1) and CMT 4: these are also demyelinating neuropathiesgene  ⁵

Radiographic features

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.

History and etymology

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