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Charcot-Marie-Tooth disease

  • Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy (HMSN), is a term used to describe a group of differing inherited disorders affecting motor and sensory peripheral nerves (nerves outside of the brain and spinal cord).
  • CMT is the most common condition among inherited neuropathies (inherited disorders of nerves), occurring in about 1 in 3,300 people.
  • A peripheral nerve can be likened to an insulated electrical wire cable. CMT can be caused by loss of the insulating myelin sheath round a nerve (demyelinating forms), or deterioration of the nerve axon (equivalent to the wire) itself (axonal forms).
  • Symptoms in people with CMT predominantly involve weakness and wasting of distal limb muscles (those of the foot, lower leg, hand and forearm), accompanied by distal sensory loss, but also show variation in severity and progression.
  • There are many different forms of CMT owing to alterations in different genes. Inheritance can be autosomal dominant, X-linked, or autosomal recessive.

Clinical features

  • Clinical signs of CMT usually become apparent between the ages of 5 and 15 years, though some individuals do not experience symptoms until their 30s or 40s. The clinical presentation can vary widely in severity, both between different clinical forms, and between different people within families.
  • Typical clinical signs include weakness in the muscles of the feet, clawed toes, a high foot arch, and loss of muscle bulk in the lower calves. In most forms of CMT, weakness of the hands is unusual in the early stages of the disorder, but becomes more frequent later on. There is slow progression of muscle weakness, and the development of scoliosis (curvature of the spine) is not uncommon.
  • Painful muscle cramps can occur, while deterioration of sensory nerves leads to loss of sensation distally in the limbs, sometimes associated with a tendency to a ‘shooting’ pain sensation. 
  • Very rarely, or in rare forms of CMT, speaking, swallowing and breathing can become affected.  


  • A diagnosis of CMT can be suspected clinically from the combination of clinical symptoms and signs, usually together with a family history. Confirmation is usually by electrical testing of peripheral nerves (nerve conduction studies), which measures the velocity (speed) and properties of the electrical nerve impulse. The velocity helps in deciding which of the two broad types of HMSN a patient has (demyelinatiing or axonal). Very rarely, a nerve biopsy may be performed.
  • DNA testing now provides a definitive diagnostic test in most cases, and can often replace the need for electrical testing.

Genetic basis

  • There are more than 40 different genes known in which genetic alteration can give rise to CMT by causing changes to the proteins in nerves.
  • HMSN disorders that cause demyelination are classed as CMT1. A majority of CMT1 cases (70%-80%) are caused by a duplication of a small region of chromosome 17 which includes the PMP22 gene, encoding a major component of myelin (peripheral myelin protein 22). The duplication results in a person having two copies of the PMP22 gene on one of their chromosome 17s, and one copy on the other. The resulting condition (CMT1a) follows autosomal dominant inheritance.
  • About 10%-20% of CMT1 cases are caused by alterations in an X-linked gene (GJB1). Symptoms occur in males and most females, following an X-linked semi-dominant inheritance pattern (the severity of symptoms usually being greater in males, having no unaltered copy of the gene).
  • HMSN disorders that cause loss of axons are classed as CMT2. Inheritance pattern for CMT2, which is similarly due to alteration in any of several different genes, can be autosomal dominant or autosomal recessive.

Clinical management

  • There is currently no cure or specific management for CMT. Emphasis is placed on avoiding joint contractures by retaining as much ability of ankle movement and muscle strength as possible. Moderate physical and stretching exercise, as well as careful choice of supportive footwear and/or ankle braces, is advised.
  • Avoidance of neurotoxic drugs, particularly vincristine, is important in preventing progression.
  • Orthopaedic surgery is an option in the case of severe foot deformity.

Genetic testing

  • Testing for the location and nature of the gene alteration gives the ability to define the exact form of CMT in someone with the condition, establishing the nature of the disorder and its inheritance pattern. The DNA information allows for forecasting of progression and appropriate management, and enables other family members to find out whether they may also have inherited the disorder.
  • DNA testing in CMT has usually involved testing groups of genes depending on the electrical categorisation as CMT1 or CMT2 and on the likely mode of inheritance according to the pattern of people in the family with the condition. However, it is also considered reasonable to test for PMP22 gene duplication, as the most common genetic form of CMT, irrespective of whether there is electrical test information.
  • The recommended order for diagnostic investigation in CMT is now changing with the availability of gene panel tests. These use next-generation sequencing technology to search multiple genes simultaneously for a genetic alteration. The efficiency of this technique means that it is likely to become the first-line test in someone with clinical signs and symptoms suggestive for CMT, avoiding the need for electrical tests, which patients tend to find unpleasant.


This information is intended for educational use and was current in August 2013. For clinical management, it is recommended that local guidelines and protocols are used.