Charcot-Marie-Tooth Disease Type 1 (CMT1)

What is CMT1?

Charcot-Marie-Tooth disease type 1 (CMT1) is the most common type of CMT, accounting for about two-thirds of all cases of CMT.


The characteristic symptoms of CMT1 include muscle weakness and atrophy, 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 the nerve extensions called axons that transmit nerve signals. 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 is sufficient to cause the disease and an affected parent has a 50 percent chance of passing the disease to their children.


The different subtypes of CMT1 are divided on the basis of specific genes that are mutated.


CMT1 subtype A (CMT1A) is the most common subtype of CMT1, accounting for about 60 percent of CMT1 cases.

CMT1A is caused by duplication (an extra copy) of the PMP22 gene situated on chromosome 17, which encodes 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 overexpression of PMP22 protein. Too much PMP22 protein cannot be processed correctly and the end result is reduced amounts of functional protein. This disrupts the structure and function of the myelin sheath.

CMT1A begins with typical CMT symptoms during adolescence with muscle weakness and atrophy of the lower legs, followed by hand weakness and decreased sensations later in life. However, the patients remain able to walk and have a normal life expectancy.


CMT1 subtype B (CMT1B) is the second-most common subtype of CMT1, accounting for 10 percent 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 (P0), which is another critical component of the myelin sheath. About 120 different single site mutations in the MPZ gene have been associated with CMT1B.

It is speculated that the defective myelin protein zero is unable to interact with other myelin components, which may disrupt the formation and maintenance of myelin. Thus, the peripheral nerve cells cannot relay signals for movement or sensation.

The onset and symptoms of CMT1B are similar to those of CMT1A, although severity levels vary from very severe with early childhood onset, to mild with onset later in adulthood.

Infantile onset

About 40 percent of patients with CMT1B have infantile onset disease with delayed walking (after 15 months). The symptoms usually develop before five years of age. CMT1B patients with early-onset disease also may experience hip dysplasia (misalignment of the hip joint during development), optic nerve atrophy (damage to the nerve that connects the eyes to the brain) and scoliosis (curvature of the spine). The nerve conduction velocity (the speed at which signals are transmitted through a nerve) is very slow with less than 15 m/sec in the arms in CMT1B patients with early-onset disease. (The normal nerve conduction velocity ranges between 50 to 60 meters per sec).

Childhood onset

About 7 percent of CM1B patients have a childhood onset disease, with symptoms appearing between ages six to 20 years. The nerve conduction velocity is slow and ranges between 15 and 25 m/sec.

Adult onset

The rest of CMT1B patients have a late-onset disease that develops during adulthood. The symptoms are relatively mild and begin after the age of 40. The nerve conduction velocity is intermediate, ranging between 35 and 45 m/sec.


CMT1 subtype C (CMT1C) is rare, affecting less than 1 percent of people with CMT. It is caused by mutations in the LITAF gene (also known as SIMPLE), which is situated on chromosome 16. It encodes for a protein called lipopolysaccharide-induced tumor necrosis factor-alpha factor or LITAF. The function of the LITAF protein is not clear.

The symptoms of CMT1C are similar to CMT1A, with onset between 10-20 years of age. There is muscle atrophy, weakness, and reduced sensation in the feet and hands. The nerve conduction velocity is slow, ranging between 16-25 m/sec.


CMT1 subtype D (CMT1D) is very rare, accounting for less than 1 percent of CMT cases.

It is caused by defects in the EGR2 gene, located on chromosome 10, which encodes for the early growth response 2 protein. This protein binds to the DNA and activates the expression of several other genes involved in the formation and maintenance of myelin. The defective EGR2 protein is unable to bind to the DNA, resulting in the loss of myelin and impaired nerve signal transmission. A particular mutation is the EGR2 gene causes loss of hearing in addition to the typical symptoms of CMT.

Most patients with CMT1D show severe symptoms, including delayed motor milestones and nerve conduction velocities of 10 m/sec or less, which begin during infancy or early childhood. This is referred to as Dejerine Sottas syndrome.

Some people with CMT1D have milder symptoms that appear later in life. Other symptoms include problems with facial nerves and breathing difficulties.


CMT1 subtype E (CMT1E) is rare, accounting for about 1 percent of people with genetically confirmed CMT.

CMT1E is caused by single site mutations (point mutations) in the coding sequence of the PMP22 gene, rather than a duplication of the normal PMP22 gene as in the case of CMT1A.

People with CMT1E have early-onset disease with more severe symptoms than those with CMT1A. A specific mutation in the PMP22 gene causes hearing loss in addition to the typical symptoms of CMT.

Conduction velocity is significantly low with less than 10 m/sec. Children often show symptoms within the first two years of life, with delayed walking. Many patients need aids, such as walkers or wheelchairs, earlier than those with CMT1A.

Some mutations in the PMP22 gene cause a severe, early-onset form of CMT also called Dejerine Sottas syndrome. It begins in infancy, causing muscle weakness and atrophy, and delayed development of motor skills such as walking.


CMT1 subtype F (CMT1F) accounts for a very small percentage of cases. It is caused by defects in the NEFL gene, located on chromosome 8, which encodes 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 axon, and subsequently impairing the transmission of nerve impulses.

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