08 July 2021

Charcot Marie Tooth Disease


Charcot-Marie-Tooth (CMT) disease is one of the most common inherited neuromuscular disorders that affect the peripheral nerves. The disease is named for the three physicians who first identified it in 1886 – Jean-Martin Charcot and Pierre Marie in Paris, France, and Howard Henry Tooth in Cambridge, England. It’s also known as hereditary motor and sensory neuropathy (HMSN) or peroneal muscular atrophy. 

Nerve tissue outside the brain and spinal cord is known as the peripheral nervous system. This system causes body movements by contracting and relaxing the muscles under instruction from the brain. The peripheral nervous system also relays sensory information from the sense organs of the skin, tendons and muscles back to the spinal cord. CMT either interferes with the production of proteins that make up the myelin sheath (insulating material protecting axons), or else affects the structure or function of the axon. Neuropathies that affect myelin are known as ‘demyelinating’ neuropathies. Those that affect primarily the nerve fibres are called ‘axonal’ neuropathies. The result of both is that affected nerves cannot work properly to control movement or sensation. Specific gene mutations are responsible for the abnormal function of the peripheral nerves.  

The symptoms of CMT usually start to appear between the ages of five and 15, although they sometimes don’t develop until well into middle age or later. CMT is a progressive condition. This means the symptoms slowly get worse, making everyday tasks increasingly difficult. Signs and symptoms of Charcot-Marie-Tooth disease may include: 

  • Weakness in your legs, ankles and feet 
  • Loss of muscle bulk in legs and feet 
  • High foot arches 
  • Curled toes (hammertoes) 
  • Decreased ability to run 
  • Difficulty lifting your foot at the ankle (footdrop) 
  • Awkward or higher than normal step (gait) 
  • Frequent tripping or falling 
  • Decreased sensation or a loss of feeling in your legs and feet 

As Charcot-Marie-Tooth disease progresses, symptoms may spread from the feet and legs to the hands and arms. The disease is slowly progressive and variable and those affected may remain active for years and live a normal life span. In the most severe cases, breathing difficulties can hasten death. The severity of symptoms can vary greatly from person to person, even among family members. 

Most inherited disorders can only be passed on by one or two patterns of inheritance. However, CMT can be inherited via most known patterns of inheritance and is the most common inherited disorder of the peripheral nervous system. Patterns of inheritance for CMT include: 

  • Autosomal dominant – the parent has one abnormal gene and one normal gene in the pair. Each child of this parent has a 50 per cent chance of inheriting the abnormal gene and a 50 per cent chance of developing CMT. 
  • Autosomal recessive – the child can only inherit the disorder if both parents are carriers (carriers show no signs of CMT), and both pass on the abnormal gene.  
  • X-linked – the abnormal gene is carried on the X-chromosome, which is involved in determining the baby’s sex. Each child, male or female, of a mother carrying the CMT type X-linked gene has a 50 per cent chance of inheriting the disorder. Males are more affected than females. Females may be carriers without showing any obvious effects. All daughters of an affected man would inherit the gene, but none of his sons. (There is no ‘male-to-male transmission’ in these families.) 

CMT disease is divided into several types, as follows: 

CMT1 – the dominant form of the condition in which nerve conduction velocities are slow, and is much more common than CMT2. CMT1 is caused by abnormal genes involved in the structure and function of myelin. CMT1 is further divided into: 

  • CMT Type 1A – a duplicated gene on chromosome 17 
  • CMT Type 1B – a genetic defect on chromosome 1 
  • CMT Type 1C – a genetic defect on chromosome 16 

CMT2 is an autosomal dominant form of the condition in which nerve conduction velocities are usually normal or slightly slower than normal. CMT2 is caused by abnormal genes involved in the structure and function of axons. CMT2 has been further subdivided into: 

  • CMT Type 2A – a genetic defect on chromosome 1 
  • CMT Type 2B – a genetic defect on chromosome 3 
  • CMT Type 2C – a genetic defect on chromosome 12 
  • CMT Type 2D – a genetic defect on chromosome 7 

CMT4 – a rare subtype of CMT. It comprises several different subtypes of autosomal recessive demyelinating motor and sensory neuropathies. Each neuropathy subtype is caused by a different genetic mutation. 

CMTX – caused by a point mutation in the connexin-32 gene on the X chromosome. It is also a demyelinating neuropathy. 

A diagnosis of CMT is established through a thorough neurological evaluation by an expert in neuropathy, including a complete family history, physical exam, and nerve conduction tests, and appropriate genetic testing. Clinical tests include nerve conduction velocity (NCV) which measures the speed at which impulses travel along the nerves and electromyogram (EMG) which records the electrical activity of muscle cell. . Molecular genetic testing is currently available for CMT1A, CMT1B, CMT1D, CMT2E, CMT4A, CMT4E, CMT4F and CMTX. 

Treatment of CMT is supportive. Ambulation aids, such as foot orthotics and braces (ankle-foot-orthotics, AFOs) are commonly needed to help with foot deformity and foot drop. Surgery to correct foot alignment or to lengthen or transfer tendons is often performed. Physical and occupational therapies are instrumental in providing long lasting quality of life. There is no cure for CMT nor any drug or vitamin known at this time to improve CMT symptoms. However, considering the slow progression, a normal life span may be achieved. 





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