CHARCOT MARIE TOOTH DISEASE

Also known as Peroneal Muscular Atrophy and Hereditary Motor and Sensory Neuropathy

What is CMT?

CMT is the name for a group of muscle-wasting diseases affecting mainly the legs and arms. The disease was discovered by Professor Charcot and his student Dr. Marie in Paris, and, quite separately, by Dr. Tooth in England during the 19th century.

PMA (Peroneal Muscular Atrophy)

It was Tooth who first mentioned that one of the shin muscles of the leg, medically known as the peroneus muscle, which lifts the foot (without it there is foot drop and severe turning out) was affected by the disease. Therefore, Tooth called the disease Peroneal Muscular Atrophy, a term which means the same as CMT disease. CMT disease is, in fact, a group of many diseases, including HMSN (Hereditary Motor And Sensory Neuropathy).

In the beginning, Charcot and Tooth could not agree what was affected by the disease; Charcot said muscle, Tooth said nerve and was later proved correct. The disease was therefore called a neuropathy. The nerves affected were "motor" (those carrying messages to the muscles) and "sensory" (those carrying messages from the extremities). As the disease runs in families, it is therefore called hereditary.

With increased medical knowledge and more sophisticated methods of diagnosis, a wider range of symptoms became apparent, and the name changed to keep up with this trend. The disease did not change, but doctors have become able to group people according to the new techniques. This means a patient can be classified according to type. HMSN type 1A and IB and H are the commonest. In addition there are at least six other types of CMT, with extremely complicated names, and it is obvious that this is a complex group of diseases.

What benefit is there is knowing what type I am?

An accurate diagnosis which allows the specialist or expert to decide which type of CMT a patient may have is most useful for family planning, or perhaps career planning. This is no easy task because HMSN is highly variable even within one family.

The function of the nerve

Motor function is the passing of a message from the brain or spinal cord, down nerves to muscles, to bring about a particular movement. The message is passed in the form of an electrical signal. A nerve consists of a long thread of fibre which is insulated by a fatty substance, like any electrical wire. The greater the damage to the nerve, the slower the speed of passage of the message, even to the point where signals fail to reach their destination.

This results in the muscles wasting away, since they are not being told to move, and because the problem is located in the nerves, exercising the muscles doe snot help a great deal. It should be noted that this disease only affects what are called skeletal muscles. For instance, the heart muscles and nerves are not affected, although the diaphragm is connected to this nerve system and so can, in rare cases, be affected (though not in a life-threatening way).

In the case of sensory function, electrical signals are passed along the nerve in the same way as motor nerves, but from joints or skin to the spinal cord and are interpreted as sensation or feelings. Abnormal sensory nerve function, therefore, causes loss of feeling, particularly in the hands and feet.

The basic problems

CMT will cause various sorts of damage to nerves depending on the type of disease. The loss of the insulating myelin reduces the speed at which signals pass along the nerve, or reduction of nerve conduction velocity, and this applies to CMT type 1.

When the nerve fibre itself (that is, not the insulating material but the "wire") is affected by disease, the signal will pass at normal speed but will be weaker than it should be, resulting in the same effect as slow speed, i.e. the muscle still does not move properly. CMT type 2 shows this feature and therefore the two types can be distinguished from each other.

It should be pointed out that these problems with the nerves cannot be repaired.

Genetics

This is the scientific way of describing how family features can be passed from one generation to another, a process known as heredity. Every child will inherit some of its parents features, some more obvious than others, like hair and eye colour. The mixture of mother/father features depends on the combination of chromosomes.

Chromosomes come in pairs and are packets of codes, called genes. The codes carry all the messages that are needed to create an individual (e.g. eye colour, hair colour and sex). This includes all the instructions for the nervous system, as well as all the other "mechanical" parts of the body. In CMT, the gene(s) which produce the message to create the nervous system are faulty, and therefore, cause the problem.

Because there are many different types of CMT, there is more than one faulty gene located on different chromosomes. Researchers hope to be able to locate the different genes on the chromosones, and eventually find out what is wrong with the those genes, since it is not known what all the genetic facts are.

As mentioned previously, all genes are in pairs, corresponding to the pairs of chromosomes. When eggs and sperm are created, the chromosomes split in half, so that each egg or sperm contains one gene out of the pair. When fertilisation takes place, the chromosomes from the mother and father form pairs again. Therefore, the offspring will have half the genes from the father and half from the mother.

CMT types 1 and 2, the most common types, are inherited in the vast majority of cases as a dominant gene, i.e. the faulty gene takes control of the pair of genes. Therefore, when the chromosome pairs split in half to create sperm or eggs, half contain the faulty gene, and half will be normal.

If a father has CMT type 1, then when his sperm fertilises a normal egg (from an unaffected mother), it is a fifty-fifty chance as to whether the egg has been fertilised by a sperm containing the faulty gene, or a normal one. Because the faulty gene is dominant, an egg fertilised by this gene produces a child with CMT type 1 as well.

CMT type 3, and very rarely, some cases of CMT 1 and 2, is inherited as a recessive gene. This means that the normal gene of the pair is dominant, and therefore the faulty gene is inactive. In order for a child to be affected, both parents must carry this inactive faulty gene on their chromosomes. When the chromosomes split, half the chromosomes in the sperm, and half in the egg, will contain this faulty gene. When fertilisation occurs, there are four possible combinations of genes:
a) the two normal genes will come together, giving a normal child who does not have a faulty gene at all
b) there are two chances that a normal gene will meet with a faulty one, still creating a normal child, because the normal gene takes precedence over the faulty one, but the child "carries" the disease
c) the two faulty genes will come together, creating a affected child, since there are no normal genes to suppress the faulty ones; in other words, in the recessive forms of CMT, there is a 1 in 4 chance of children being affected.

Even more rarely, the faulty gene is carried on the chromosomes which determine the sex of the child, called X-linked inheritance. Boys are more severely affected and they inherit the disease from mothers with the faulty gene; the mother is either not affected or very mildly affected. Each son will have a fifty-fifty chance of being affected, and each daughter will have a similar chance of being a carrier. The affected son cannot then pass the disease onto his sons, but each daughter will be a carrier.

Summary

HMSN is a group of inherited neurological diseases, referred to as a syndrome. HMSN is part of the CMT syndrome group. Damage to the nerves results in loss of muscle power and disability. Nerves are damaged in two different ways: in CMT type 1 the insulating sheath of the nerve is lost; in CMT type 2, the nerve fibre itself is damaged. Inheritance is usually dominant which means there is a 1 in 2 chance that a child will inherit the disease from an affected parent.