Charcot Marie Tooth Disease Health Article

Definition

Charcot Marie Tooth disease (CMT) is the name of a group of inherited disorders of the nerves in the peripheral nervous system (nerves throughout the body that communicate motor and sensory information to and from the spinal cord) causing weakness and loss of sensation in the limbs.

Description

CMT is named for the three neurologists who first described the condition in the late 1800s. It is also known as hereditary motor and sensory neuropathy, and is sometimes called peroneal muscular atrophy, referring to the muscles in the leg that are often affected. The age of onset of CMT can vary anywhere from young childhood to the 50s or 60s. Symptoms typically begin by the age of 20. For reasons yet unknown, the severity in symptoms can also vary greatly, even among members of the same family.

Although CMT has been described for many years, it is only since the early 1990s that the genetic cause of many of the types of CMT have become known. Therefore, knowledge about CMT has increased dramatically within a short time.

The peripheral nerves

CMT affects the peripheral nerves, those groups of nerve cells carrying information to and from the spinal cord. CMT decreases the ability of these nerves to carry motor commands to muscles, especially those furthest from the spinal cord located in the feet and hands. As a result, the muscles connected to these nerves eventually weaken. CMT also affects the sensory nerves that carry information from the limbs to the brain. Therefore people with CMT also have sensory loss. This causes symptoms such as not being able to tell if something is hot or cold or difficulties with balance.

There are two parts of the nerve that can be affected in CMT. A nerve can be likened to an electrical wire, in which the wire part is the axon of the nerve and the insulation surrounding it is the myelin sheath. The job of the myelin is to help messages travel very fast through the nerves. CMT is usually classified depending on which part of the nerve is affected. People who have problems with the myelin have CMT type 1 and people who have abnormalities of the axon have CMT type 2.

Specialized testing of the nerves, called nerve conduction testing (NCV), can be performed to determine if a person has CMT1 or CMT2. These tests measure the speed at which messages travel through the nerves. In CMT1, the messages move too slowly, but in CMT2 the messages travel at the normal speed.

Demographics

CMT has been diagnosed in people from all over the world. It occurs in approximately one in 2,500 people, which is about the same incidence as multiple sclerosis. It is the most common type of inherited neurologic condition.

Signs and symptoms

CMT is caused by changes (mutations) in any one of a number of genes that carry the instructions to make the peripheral nerves. Genes contain the instructions for how the body grows and develops before and after a person is born. There are probably at least 15 different genes that can cause CMT. However, as of early 2001, many have not yet been identified.

CMT types 1 and 2 can be broken down into subtypes based upon the gene that is causing CMT. The subtypes are labeled by letters, so there is CMT1A, CMT1B, etc. Therefore, the gene with a mutation that causes CMT1A is different from that that causes CMT1B.

Types of CMT

CMT1A. The most common type of CMT is called CMT1A. It is caused by a mutation in a gene called peripheral myelin protein 22 (PMP22) located on chromosome 17. The job of this gene is to make a protein (PMP22) that makes up part of the myelin. In most people who have CMT, the mutation that causes the condition is a duplication (doubling) of the PMP22 gene. Instead of having two copies of the PMP22 gene (one on each chromosome) there are three copies. It is not known how this extra copy of the PMP22 gene causes the observed symptoms. A small percentage of people with CMT1A do not have a duplication of the PMP22 gene, but rather have a point mutation in the gene. A point mutation is like a typo in the gene that causes it to work incorrectly.

HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSIES (HNPP). HNPP is a condition that is also caused by a mutation in the PMP22 gene. The mutation is a deletion. Therefore, there is only one copy of the PMP22 gene instead of two. People who have HNPP may have some of the signs of CMT. However, they also have episodes where they develop weakness and problems with sensation after compression of certain pressure points such as the elbows or knee. Often these symptoms will resolve after a few days or weeks, but sometimes they are permanent.

CMT1B. Another type of CMT, called CMT1B, is caused by a mutation in a gene called myelin protein zero (MPZ) located on chromosome 1. The job of this gene is to make the layers of myelin stick together as they are wrapped around the axon. The mutations in this gene are point mutations because they involve a change (either deletion, substitution, or insertion) at one specific component of a gene.

CMTX. Another type of CMT, called CMTX, is usually considered a subtype of CMT1 because it affects the myelin, but it has a different type of inheritance than type 1 or type 2. In CMTX, the CMT-causing gene is located on the X chromosome and is called connexin 32 (Cx32). The job of this gene is to code for a class of protein called connexins that form tunnels between the layers of myelin.

CMT2. There are at least five different genes that can cause CMT type 2. Therefore, CMT2 has subtypes A, B, C, D and E. As of early 2001, scientists have narrowed in on the location of most of the CMT2 causing genes. However, the specific genes and the mutations have not yet been found for most types. Very recently, the gene for CMT2E has been found. The gene is called neurofilament-light (NF-L). Because it has just been discovered, not much is known about how mutations in this gene cause CMT.

CMT3. In the past a condition called Dejerine-Sottas disease was referred to as CMT3. This is a severe type of CMT in which symptoms begin in infancy or early childhood. It is now known that this is not a separate type of CMT and in fact people who have onset in infancy or early childhood often have mutations in the PMP22 or MPZ genes.

CMT4. CMT4 is a rare type of CMT in which the nerve conduction tests have slow response results. However, it is classified differently from CMT1 because it is passed through families by a different pattern of inheritance. There are five different subtypes and each has only been described in a few families. The symptoms in CMT4 are often severe and other symptoms such as deafness may be present. There are three different genes that have been associated with CMT4 as of early 2001. They are called MTMR2, EGR2, and NDRG1. More research is required to understand how mutations in these genes cause CMT.