Charcot-Marie-Tooth disease (CMT) is a group of conditions of the peripheral nervous system, the network of nerves that supply movement and sensation to the arms and legs.
Symptoms usually begin progressively in adolescence and include sensory loss, muscle weakness, and atrophy (wasting).
CMT is one of the most common inherited disorders, affecting around 126,000 individuals in the U.S. and 2.6 million people worldwide.
Causes
Mutations that cause CMT may directly damage a nerve cell (neuron) or may interfere with the formation of myelin, an insulating material around axons (nerve fibers) that ensures efficient signal transmission.
Damage to nerve fibers or myelin impairs the transmission of these nerve signals, resulting in weaker messages between the limbs and the brain.
More than 40 genes have been linked with CMT. Each gene is linked to one or more disease types.
Types
The disease can be classified into several types based on the genes that are mutated, the inheritance pattern, and the speed of nerve conduction, or how fast electrical impulses move through the nerves. Age of disease onset, disease severity, and whether nerve fibers or myelin are damaged also factor into CMT’s classifications.
CMT1 also is known as demyelinating CMT, as it is caused by genetic defects that damage the myelin sheath. This is the most common type of CMT and is inherited in an autosomal dominant pattern, meaning one mutated gene copy is enough to cause disease.
A second type, CMT2, is caused by mutations in genes important for the structure and function of nerve fibers. For this reason, CMT2 is commonly referred to as axonal CMT. This type of CMT is typically inherited in an autosomal dominant manner, but some cases have autosomal recessive inheritance, as two copies of the mutated gene — one from each biological parent — must be present for the disease to develop.
CMT3, also known as Dejerine-Sottas disease, is a rare early onset, severe type of CMT. It has been used to label markedly demyelinating cases, with both autosomal dominant and autosomal recessive inheritance. This disease type can be caused by mutations in multiple genes, and symptoms may progress to severe disability, loss of sensation, and spine curvature, known as scoliosis, a common symptom of CMT.
Another type is CMT4, which can affect myelin or nerve fibers, depending on the specific subtype. Symptoms begin in childhood, and patients may progressively lose the ability to walk. CMT4 is inherited in an autosomal recessive pattern.
CMTX gets its name because people with this disease type carry genetic defects on their X chromosome. It, therefore, is inherited in an X-linked dominant manner. As such, a male with the mutation will be affected more severely than a female, as he does not have another unaffected copy of the gene. CMTX also can be due to a spontaneous mutation, in which case the patient is the first in a family to have the mutation and can pass it down to any offspring.
In the most common subtype, CMTX1, a mutation affects a protein that forms channels between the specialized cells that form myelin in peripheral nerves, called connexin-32.
Finally, dominant intermediate CMT is characterized by both nerve fiber degeneration and demyelination, as well as by an intermediate speed of nerve conduction considered axonal and demyelinating forms of the disease. This type is inherited in an autosomal dominant manner.
Symptoms
The abnormal transmission of nerve signals in CMT causes muscle weakness, loss of muscle tissue, and, if sensory nerves are affected, a diminished sensation of heat, cold, or pain. Symptoms usually begin in the feet and legs, later spreading to the hands and arms.
Although the inherited defects of CMT are present from birth, symptoms may not appear until late adolescence or early adulthood. Symptoms gradually get worse with age and include walking difficulties, hearing loss, breathing problems, and fatigue.
Diagnosis
Symptoms alone are not enough to confirm the diagnosis of CMT, and therefore doctors may recommend several tests.
Among them are genetic tests, which help establish the diagnosis and type of CMT. Such tests also can help determine the risk of passing a CMT-causing mutation to the offspring.
Nerve conduction studies, along with electromyography, by measuring the speed of electrical signals, are used to detect changes in nerve fibers and muscles.
In rare cases, a nerve biopsy — usually from the calf of the lower leg — is used when the results of all other diagnostic tools are inconclusive.
Treatment
Pharmacological and nonpharmacological approaches are available to help manage the disease and maintain patients’ quality of life. These include physical and occupational therapies, which can help strengthen and stretch muscles and help people perform daily activities.
Orthopedic devices, such as braces or special shoes, can help with walking. Surgery is sometimes needed to correct foot deformities, which often occur in CMT.
Last updated: Dec. 2, 2021
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