Collectively, CMT is a group of inherited disorders of the peripheral nervous system, the network of nerves that supply movement and sensation to the arms and legs.
The characteristic symptoms of CMT1 include muscle weakness and atrophy (wasting), and reduced sensation — touch, heat, cold — particularly in the feet, lower legs, hands, and forearms.
CMT1 is caused by genetic defects that damage the myelin sheath, the fat-rich layer covering nerve extensions. Demyelination (loss of myelin) results in a slow transmission of nerve signals from the brain to the muscles, and vice-versa. Consequently, the disease often is referred to as “demyelinating CMT.”
The defective genes causing CMT1 are inherited in an autosomal dominant manner, meaning that one copy of a faulty gene — passed to a child from either biological parent — is sufficient to cause the disease. An affected parent has a 50% chance of passing the disease to their children.
The different subtypes of CMT1 are divided on the basis of the specific genes that are mutated.
CMT1 subtype A (CMT1A) is the most common subtype of CMT1, accounting for up to 80% of CMT1 cases.
CMT1A is usually caused by duplication (an extra copy) of the PMP22 gene on chromosome 17, which codes for the peripheral myelin protein 22, a critical component of the myelin sheath produced by Schwann cells.
The duplication of the PMP22 gene results in the overproduction of PMP22 protein. Too much PMP22 cannot be processed correctly, and the end result is increased amounts of nonfunctional protein. This disrupts the structure and function of the myelin sheath.
Rarely, CMT1A may also be caused by point mutations in the PMP22 gene, in which a single nucleotide (DNA building blocks) is modified.
CMT1A begins with typical CMT symptoms, usually during adolescence. Patients experience muscle atrophy of the lower legs, along with hand weakness and decreased sensations, but remain able to walk and have a normal life expectancy.
CMT1B is the second-most common subtype of CMT1, accounting for about 10% of CMT1 cases.
It is caused by mutations in the MPZ gene, which is situated on chromosome 1. This gene encodes for the myelin protein zero, which is another critical component of the myelin sheath. About 120 different single site mutations in the MPZ gene have been associated with CMT1B.
The defective myelin protein zero is unable to interact with other myelin components, which can disrupt the formation and maintenance of myelin. As a result, the peripheral nerve cells cannot relay signals for movement or sensation.
The onset and symptoms of CMT1B are similar to those of CMT1A, although the clinical presentation of CMT1B — its severity — varies considerably.
About 40% of CMT1B patients have infantile-onset disease with delayed walking (after 15 months). The symptoms usually develop before 5 years of age. These patients also may experience hip dysplasia (misalignment of the hip joint), optic nerve atrophy (damage to the nerve that connects the eyes to the brain), and scoliosis (sideways curvature of the spine).
In CMT1B patients, the nerve conduction velocity (the speed at which signals are transmitted through a nerve) is very slow, at less than 15 meters per second (m/s) in the arms (normal values are higher than 50 m/s).
About 7% of CM1B patients have childhood onset disease, with symptoms appearing between ages 6 and 20. The nerve conduction velocity is slow, ranging between 15 and 25 m/sec.
Other CMT1B patients have a late-onset disease, one that develops during adulthood. Their symptoms are relatively mild and begin after age 40. Nerve conduction velocity is intermediate, ranging between 35 and 45 m/sec.
CMT1C is rare, affecting less than 1% of all cases. It is caused by mutations in the LITAF gene, which is situated on chromosome 16. It encodes a protein with the same name, which has a critical role in peripheral nerves function.
The symptoms of CMT1C are similar to CMT1A, with onset between 10 and 30 years of age. Nerve conduction velocity is slow, ranging between 16–25 m/sec.
This CMT form is similarly quite rare, also accounting for fewer than 1% of CMT cases.
It is caused by defects in the EGR2 gene located on chromosome 10, which codes for the early growth response protein 2. This protein binds to DNA and activates the activity of several other genes involved in the formation and maintenance of myelin. A defective EGR2 protein results in problems with myelin formation.
Most people with CMT1D show severe symptoms, including delayed motor milestones and nerve conduction velocities of 10 m/s or less, which begin during infancy or early childhood. Other symptoms include problems with facial nerves and breathing difficulties.
A few CMT1D patients will have milder symptoms that appear later in life.
CMT1E, accounting for about 1% of people with genetically confirmed CMT, is caused by point mutations in the PMP22 gene. People with CMT1E have early-onset disease and typically symptoms more severe than those with CMT1A.
Conduction velocity is less than 10 m/sec. Children often show symptoms within the first year or two of life, and walking is delayed. Needing walkers, wheelchairs or other walking aids is common and earlier in these patients than in people with CMT1A.
Of note, mutations in the PMP22 gene — and in the genes MPZ and EGR2 — may also cause CMT3, also known as Dejerine Sottas disease.
CMT1F accounts for a very small percentage of all cases. It is caused by defects in the NEFL gene located on chromosome 8, which codes for the neurofilament light chain protein. Neurofilaments form the structural framework that determines the shape and size of nerve cells.
The defective NEFL protein is thought to disrupt the assembly of neurofilaments, reducing the diameter of the nerve fiber, and subsequently impairing the transmission of nerve impulses.
Last updated: Nov. 18, 2021
Charcot-Marie-Tooth News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.