Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease is a group of progressive disorders that affect the peripheral nerves. Peripheral nerves connect the brain and spinal cord to muscles as well as sensory cells that detect sensations such as touch, pain, heat, and sound.

Symptoms of Charcot-Marie-Tooth disease usually begin in adolescence or early adulthood, but onset may occur anytime from early childhood to mid-adulthood. Symptoms vary in severity. Some people never realize they have the disorder, but most have a moderate amount of physical disability, and a small percentage of people experience severe weakness. Many people with this disorder lead active lives and have normal life expectancies.

Typically, the earliest symptoms involve muscle weakness in the feet, which can cause foot abnormalities such as high arches (pes cavus) or curled toes (hammer toes). It may become difficult to hold up the foot or to walk on the heel of the foot. These difficulties may cause a higher than normal step (or gait) and can increase the chance of ankle injuries and tripping. As the disease progresses, muscles in the lower legs usually weaken, but leg and foot problems rarely require the use of a wheelchair.

Later symptoms may include muscle weakness in the hands, causing difficulty with daily activities such as writing, fastening buttons, and turning doorknobs. Because signals to sensory cells can be disrupted in Charcot-Marie-Tooth disease, people with this disorder may also notice some numbness, feel pain in the feet and lower legs, or experience a decreased sensitivity to heat and cold. In rare cases, sensory loss can include gradual hearing impairment and deafness.

Different types of Charcot-Marie-Tooth disease can be distinguished by the abnormality that disrupts nerve function and by the genetic cause. Type X Charcot-Marie-Tooth disease is caused by mutations in a gene on the X chromosome, one of the two sex chromosomes. Type 1 Charcot-Marie-Tooth disease is characterized by abnormalities in myelin, the protective substance that covers nerve cells. Type 2 Charcot-Marie-Tooth disease is characterized by abnormalities in the fiber, or axon, that extends from a nerve cell and transmits nerve impulses. In intermediate forms of Charcot-Marie-Tooth disease, abnormalities occur in axons and myelin. Type 4 Charcot-Marie-Tooth disease affects either the axon or myelin. Types 1, 2, 4, and intermediate forms are further categorized by subtypes (such as 1A, 2A, 4A). Subtypes are distinguished by the specific gene that is altered.

No universal system is used to classify types of Charcot-Marie-Tooth disease, and sometimes other names are used to describe this disorder. For example, Roussy-Levy syndrome is a form of type 1 Charcot-Marie-Tooth disease (type 1B). Dejerine-Sottas syndrome is a severe, early childhood form of Charcot-Marie-Tooth disease that may be type 1 or type 4 (depending on the specific gene that is altered).

Charcot-Marie-Tooth disease is the most common inherited disorder that involves the peripheral nerves, affecting an estimated 150,000 people in the United States. It occurs in all races and ethnic groups. Worldwide, this disorder affects about 1 in 3,300 people.

Mutations in the BSCL2, DNM2, EGR2, FGD4, GARS, GDAP1, GJB1, HSPB1, KIAA0274, KIF1B, LITAF, LMNA, MFN2, MPZ, MTMR2, NDRG1, NEFL, PMP22, PRX, RAB7A, SBF2, SH3TC2, and YARS genes cause Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease is caused by changes in one of several different genes that are essential to the function of nerves in the feet, legs, and hands. These changes impair axons that transmit nerve impulses or affect the specialized cells that produce myelin. As a result of these disrupted functions, nerve cells slowly lose the ability to stimulate the muscles and to transmit sensory signals.

Increasingly, Charcot-Marie-Tooth disease is categorized by the specific gene that is altered. Type 1 is caused by mutations in the following genes: PMP22 (subtypes 1A and 1E), MPZ (subtype 1B), LITAF (subtype 1C), EGR2 (subtype 1D), and NEFL (subtype 1F).

Alterations in the following genes cause type 2 Charcot-Marie-Tooth disease: KIF1B and MFN2 (subtype 2A), RAB7A (subtype 2B), LMNA (subtype 2B1), BSCL2 and GARS (subtype 2D), NEFL (subtype 2E), HSPB1 (subtype 2F), MPZ (subtypes 2I and 2J), and GDAP1 (subtype 2K).

Type 4 Charcot-Marie Tooth disease is caused by mutations in the following genes: GDAP1 (subtype 4A), MTMR2 (subtype 4B1), SBF2 (subtype 4B2), SH3TC2 (subtype 4C), NDRG1 (subtype 4D), EGR2 (subtype 4E), and PRX (subtype 4F).

Type X Charcot-Marie-Tooth disease is caused by a mutation in the GJB1 gene, and intermediate forms of the disorder are caused by an altered DNM2 or YARS gene.

Read more about the BSCL2, DNM2, EGR2, GARS, GDAP1, GJB1, HSPB1, KIF1B, LITAF, LMNA, MFN2, MPZ, MTMR2, NDRG1, NEFL, PMP22, PRX, RAB7A, SBF2, SH3TC2, and YARS genes.

The pattern of inheritance varies with the type of Charcot-Marie-Tooth disease. Type 1, most cases of type 2, and intermediate forms of Charcot-Marie-Tooth disease are inherited in an autosomal dominant pattern. This pattern of inheritance means that one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one affected parent.

Type 4 and subtypes 2B1 and 2K are inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder each carry one copy of the altered gene but do not have signs and symptoms of the disorder.

Type X is inherited in an X-linked dominant pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. The inheritance is dominant if one copy of the altered gene is sufficient to cause the condition. In most cases, males experience more severe symptoms of the disorder than females. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Some cases of Charcot-Marie-Tooth disease result from a new mutation and occur in people with no history of the disorder in their family.