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. These are the nerves throughout the body that communicate motor and sensory information to and from the spinal cord. CMT causes 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 unknown as of 2004, 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 increased dramatically shortly thereafter.

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 loss causes symptoms such as not being able to tell if something is hot or cold or having 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 by which part of the nerve is affected. Children who have problems with the myelin have CMT type 1 and children 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 CMT1 or CMT2 is present. 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

Charcot-Marie-Tooth is the most common inherited neurological disorder, affecting approximately 150,000 Americans. It is the most common type of inherited neurological condition, occurring in approximately one in 2,500 people worldwide, in all races and ethnic groups.

Genetic causes

CMT is caused by changes (mutations) in any one of a number of genes that carry the instructions on how 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 2004, not all had been identified.

CMT types 1 and 2 can be broken down into subtypes based upon the gene that causes 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 the one that causes CMT1B.

Types of CMT

CMT1A The most common type of CMT, called CMT1A, 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 they have a point mutation in the gene. A point mutation is like a typo in the gene that causes it to work incorrectly.

HEREDITY 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 when they develop weakness and problems with sensation after compression of certain pressure points such as at the elbows or knee. Often these symptoms 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 as of 2004 for most types. In the early 2000s, the gene for CMT2E was 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 known as of 2004 that this is not a separate type of CMT; in fact, people who have onset in infancy or early childhood often have mutations in the PMP22 or MPZ genes. Children with type 3 CMT may not develop early motor skills such as walking until they are three or four years old.

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 as of 2004 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.