Charcot-Marie-Tooth disease

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

Charcot-Marie-Tooth disease usually becomes apparent in adolescence or early adulthood, but onset may occur anytime from early childhood through late adulthood. 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 flex 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. Affected individuals may also develop 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 feel aching or burning sensations in the feet and lower legs, or they may experience a decreased sensitivity to touch, heat, and cold. In rare cases, sensory loss can include gradual hearing loss, deafness, or loss of vision.

Symptoms of Charcot-Marie-Tooth disease vary in severity, even among members of the same family. Some people never realize they have the disorder, but most have a moderate amount of physical disability. A small percentage of people experience severe weakness or other problems which, in rare cases, can be life-threatening. In most affected individuals, however, Charcot-Marie-Tooth disease does not affect life expectancy.

No universal system is used to classify types of Charcot-Marie-Tooth disease. Different types of Charcot-Marie-Tooth disease can be distinguished by the details of their signs and symptoms, the abnormality that disrupts nerve function, the genetic cause, and how the condition is inherited. 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. Type 4 Charcot-Marie-Tooth disease affects either the axon or myelin and is distinguished by its pattern of inheritance. In intermediate forms of Charcot-Marie-Tooth disease, abnormalities occur in both axons and myelin. Type X Charcot-Marie-Tooth disease is caused by mutations in a gene on the X chromosome, one of the two sex chromosomes. Within the various types of Charcot-Marie-Tooth disease, subtypes (such as 1A, 2A, 4A, and X1) are distinguished by the specific gene that is altered.

Sometimes other, more historical names are used to describe this disorder. For example, Roussy-Levy syndrome is a form of type 1 Charcot-Marie-Tooth disease associated with rhythmic shaking (tremors). Dejerine-Sottas syndrome is a term sometimes used to describe a severe, early childhood form of Charcot-Marie-Tooth disease that has also been called type 3. Depending on the specific gene that is altered, this severe, early onset form of the disorder may also be classified as type 1 or type 4. Charcot-Marie-Tooth syndrome type X5 is also known as Rosenberg-Chutorian syndrome. Some researchers believe that this condition is not actually a form of Charcot-Marie-Tooth disease. Instead, they classify it as a separate disorder characterized by peripheral nerve problems, deafness and vision loss.

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 2,500 people.

Charcot-Marie-Tooth disease can be caused by changes in many different genes that are essential to the function of peripheral 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.

Charcot-Marie-Tooth disease is usually categorized by the specific gene that is altered. The list of these genes continues to grow as researchers identify additional mutations associated with the various types of the disorder. 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).

Type 2 Charcot-Marie-Tooth disease results from alterations in the following genes: MFN2 and, rarely, KIF1B (subtype 2A), RAB7A (subtype 2B), LMNA (subtype 2B1), TRPV4 (subtype 2C), BSCL2 and GARS (subtype 2D), NEFL (subtype 2E), HSPB1 (subtype 2F), MPZ (subtypes 2I and 2J), GDAP1 (subtype 2K), and HSPB8 (subtype 2L). Certain DNM2 gene mutations also cause a form of type 2 Charcot-Marie-Tooth disease.

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), PRX (subtype 4F), FGD4 (subtype 4H), and FIG4 (subtype 4J).

Intermediate forms of the disorder are caused by an altered DNM2 or YARS gene. Type X Charcot-Marie-Tooth disease is caused by mutations in the GJB1 (subtype X1) and PRPS1 (subtype X5) genes. Mutations in additional genes that have not been identified also cause Type X (subtypes X2, X3, and X4) and intermediate forms of Charcot-Marie-Tooth disease.

Read more about the BSCL2, DNM2, EGR2, FGD4, FIG4, GARS, GDAP1, GJB1, HSPB1, HSPB8, KIF1B, LITAF, LMNA, MFN2, MPZ, MTMR2, NDRG1, NEFL, PMP22, PRPS1, PRX, RAB7A, SBF2, SH3TC2, TRPV4, 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 Charcot-Marie-Tooth disease and a few forms of Type 2 are inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition.

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, affected males, who have the alteration on their only copy of the X chromosome, experience more severe symptoms of the disorder than females, who have two X chromosomes. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. All daughters of affected men will have one altered X chromosome, but may only have mild symptoms of the disorder.

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.