Charcot-Marie-Tooth disease is named after the three neurologists who first described the condition in 1886. Many different names have been used to describe Charcot-Marie-Tooth disease but the other commonly used name is hereditary motor and sensory neuropathy. This is an accurate term as it refers to the two primary features of this condition i.e. the condition is hereditary and it affects the motor and sensory peripheral nerves.
Charcot-Marie-Tooth disease, or hereditary motor and sensory neuropathy, is therefore is used to describe a group of conditions that give rise to weakness and wasting of the muscles below the knees and often those of the hands. Many affected people also have loss of feeling in the hands and feet, and this is the ‘sensory’ component. The term 'neuropathy' refers to the fact that it is the peripheral nerves (which connect the spinal cord to the muscles, joints and skin, carrying messages in both directions), which do not function normally. As the name implies, these are inherited disorders.
Charcot-Marie-Tooth disease is also referred to as peroneal muscular atrophy because the peroneal muscles on the outer side of the calves are particularly affected. Other names include Dejerine-Sottas disease and hereditary hypertrophic neuropathy. However, the term Charcot-Marie-Tooth disease is now the favoured term and is most commonly used in the literature.
Charcot-Marie-Tooth disease does not describe a single disorder, but a group of conditions that are superficially similar. It is important to determine exactly what kind of Charcot-Marie-Tooth disease someone has and this can be achieved by careful examination, taking a family history, electrical tests (nerve conduction studies) and genetic studies on blood samples.
This sort of assessment also serves to distinguish Charcot-Marie-Tooth disease from other non-genetic causes of neuropathy, and this is particularly important in people who do not have affected relatives.
Different types of Charcot-Marie-Tooth disease
Peripheral nerves can be thought of as being electrical cables: the fibres (like wires) run down the middle and are wrapped in insulating material (myelin). If the myelin is damaged the nerve impulses tend to be conducted more slowly than usual. If the fibres (also known as axons) are damaged, the speed of conduction is normal but the size of the signal is reduced. These changes can be detected by electrical tests.
Traditionally, the commonest forms of Charcot-Marie-Tooth disease have been divided into two types:
Type 1 - in type 1 the damage is to the myelin resulting in slow conduction, and this is referred to as the 'demyelinating type of Charcot-Marie-Tooth disease'
Type 2 - in type 2 it is the nerve fibres that are at fault and the term 'axonal type Charcot-Marie-Tooth disease' is used
Although major advances have been made in the last decade in the identification of the genes responsible for Charcot-Marie-Tooth disease, not all of the genes associated with the group of conditions have yet been identified. This means that the electrical test (nerve conduction studies) is still often very useful in making the diagnosis. An exception is when there is a clear family history of autosomal dominant inheritance (see below), when DNA testing for the commonest form of Charcot-Marie-Tooth disease (type 1A) might be performed as a first investigation.
Although the electrical tests are usually clearcut, allowing a diagnosis of Charcot-Marie-Tooth disease type 1 or type 2, in some cases it may be difficult to decide from the electrical test which type a patient has and the term 'intermediate Charcot-Marie-Tooth disease' is used. Although this can be confusing for patients it is useful for doctors in deciding which genes to screen. In the future, when all the causative genes are identified, a comprehensive classification of Charcot-Marie-Tooth disease will be available but in view of the fact that there are likely to be numerous genes involved it is probable that electrical tests will remain important in the initial assessment of patients.
Previously, the term 'hereditary motor and sensory neuropathy III' was applied to patients with a particularly severe form of the conditon starting in very early life. Hereditary motor and sensory neuropathy III is also called 'Dejerine Sottas disease' and 'congenital hypomyelinating neuropathy' and both these terms are commonly used clinically.
Hereditary motor and sensory neuropathy III was thought to be inherited in an autosomal recessive pattern, unlike the autosomal dominant pattern of inheritance of the common types of Charcot-Marie-Tooth disease types 1 and 2. We now know that hereditary motor and sensory neuropathy III is usually associated with a defect in the genes that cause Charcot-Marie-Tooth disease type I and that most cases are a result of a new mutation in the gene, which explains why neither parent was affected. Therfore the term 'hereditary motor and sensory neuropathy III' is no longer commonly used, having been replaced by the terms:
• Charcot-Marie-Tooth disease type 1
• Dejerine Sottas disease
• congenital hypomyelinating neuropathy
Occasionally Dejerine Sottas disease and congenital hypomyelinating neuropathy can be inherited in an autosomal recessive manner.
There are other more complex forms of Charcot-Marie-Tooth disease in which the neuropathy is combined with other features such as deafness, visual problems, vocal cord paralysis and breathing difficulties but these are all very rare.
How does Charcot-Marie-Tooth disease affect people?
The first evidence of Charcot-Marie-Tooth disease is usually between the ages of five and 15 but sometimes may not be until very much later, even into middle-age.
Usually the first symptom is a slight difficulty in walking because of problems with picking up the feet, and this may well be noted by parents first. Many people, particularly those with Charcot-Marie-Tooth disease type I, have high arched feet (referred to as 'pes cavus') and this may be obvious from a very early age. It tends to become particularly noticeable at the time of the growth spurt associated with puberty. Weakness of the hands occurs in some people, but this does not usually cause symptoms until after the age of 20.
Patients can experience numbness of the feet and hands (usually noticed in the feet first) which is not often troublesome, but the tendency to have cold feet is frequent. Very rarely the numbness can be severe, and it is then easy for affected individuals to injure themselves without knowing it; painless ulcers of the feet may develop as a result of poorly fitting shoes, or burns on the hand from hot cups etc. Pain is not a common feature of Charcot-Marie-Tooth disease and if present may be due to secondary effects on the joints or muscles.
The reflexes (such as the knee jerk) are commonly lost. This does not cause any trouble for the individual, but is often noted early on by doctors. A few people with Charcot-Marie-Tooth disease 1 have shakiness of the hands (tremor) and the combination of tremor and Charcot-Marie-Tooth disease is sometimes referred to as the Roussy-Levy Syndrome.
Mild curvature of the spine (scoliosis) occurs in some people and tends to be more severe in those with early onset of limb problems.
The types of Charcot-Marie-Tooth disease that run through the generations in families (see the section on 'dominant inheritance') are not usually severely disabling disorders and often do not change a great deal after people have finished growing. It is unusual for people with Charcot-Marie-Tooth disease to lose the ability to walk, although some older people need a stick or other walking aids. It is important to stress that the disorder often varies enormously in severity, even in members of the same family. In fact, 10 to 20% of affected individuals have no symptoms at all but are found to have evidence of the condition on examination or using electrical tests.
How is Charcot-Marie-Tooth disease inherited?
The commonest forms of Charcot-Marie-Tooth disease are inherited in a way that is referred to as autosomal dominant. This type of inheritance is the most common in Charcot-Marie-Tooth disease type 1 and type 2.
We all have two copies of every gene and in autosomal dominant inheritance, the affected person has one abnormal gene and one normal gene. Each child will only inherit one gene from an affected parent (the other gene will come from the other parent) and therefore each child of an affected parent has a 50% chance of inheriting the abnormal gene and being affected. People of either sex can have the condition.
However in occasional families with Charcot-Marie-Tooth disease type 1 and type 2, the inheritance is autosomal recessive. In autosomal recessive inheritance a person needs two abnormal copies of the gene to be affected - unlike autosomal dominant inheritance where the person only needs one copy of the abnormal gene to be affected.
Autosomal recessive inheritance is only seen if both parents are ‘carriers' of the faulty gene but these parents do not themselves have any symptoms. Both parents therefore have one abnormal and one normal copy of the gene. The condition develops only if a child inherits the abnormal gene in a double dose, i.e. one from each parent. Each child of such parents has a 25% chance of inheriting an abnormal copy form both parents (double dose) and being affected. Each child of such parents will have a 50% chance of inheriting one abnormal copy of the gene from either parent and be a “carrier” of the condition and each child will have a 25% chance of inheriting two normal genes (one from each parent). Males and females can be affected.
Many people with autosomal recessive Charcot-Marie-Tooth disease do not have affected relatives as each child has only a one in four chance of being affected and most families are quite small. It is therefore common for only one child to be affected.
In some families, Charcot-Marie-Tooth disease is caused by an X-linked gene (X-linked inheritance) which is carried on the X chromosome, one of the so-called sex chromosomes which determine the sex of the child (females are XX, males are XY). The result is that boys inherit the disease from their mothers who are known as carriers. Carriers may show no sign of disease, although sometimes they are mildly affected, but each of their sons has a 50% chance of having Charcot-Marie-Tooth disease and each of their daughters has a 50% chance of being a carrier. Affected males cannot transmit the disease to their sons. In these families therefore, males are more severely affected than females and males cannot pass on the disease to their sons.
It is very important to establish exactly what type of Charcot-Marie-Tooth disease someone has, and to investigate family members as advice given in genetic counselling will vary depending on the type and its mode of inheritance. This may require detailed family investigations, as some mildly affected family members may not have any symptoms.
What is the cause of Charcot-Marie-Tooth disease?
There have been major advances in the last decade in the identification of the causative genes for Charcot-Marie-Tooth disease. To date there have been 16 causative genes identified and at least eight other loci (location on a chromosome where a causative gene is but where the causative gene has not been identified).
Most of these genes have been identified for Charcot-Marie-Tooth disease type 1. At the moment patients with Charcot-Marie-Tooth disease are more likely to have the causative gene identified if they have type 1 rather than type 2.
In most families with dominantly inherited Charcot-Marie-Tooth disease type 1, the abnormal gene is located on chromosome number 17. This variety of Charcot-Marie-Tooth disease is called Charcot-Marie-Tooth disease 1A and is due to abnormalities in a protein found in myelin called peripheral myelin protein 22 (PMP-22). The commonest genetic abnormality of the PMP-22 gene in patients with Charcot-Marie-Tooth disease 1A is unusual; affected people have an extra copy (three copies) of the gene because they have an extra copy of a small part of chromosome 17 containing the PMP-22 gene.
Although this genetic abnormality, commonly called the chromosome 17 duplication, is usually inherited in an autosomal dominant manner, it has been found in some individuals with normal parents (and thus represents a new mutation). Rarely patients with Charcot-Marie-Tooth disease 1A have a different abnormality (a mutation) of the PMP-22 gene. About three-quarters of patients with Charcot-Marie-Tooth disease 1 have type 1A.
The second commonest form of Charcot-Marie-Tooth disease 1 is Charcot-Marie-Tooth disease 1X, where patients have a mutation of the connexin 32 gene on the X chromosome. In recent years this form of Charcot-Marie-Tooth disease has been diagnosed more commonly as doctors recognise X-linked inheritance in families.
The third well recognised type of autosomal dominant Charcot-Marie-Tooth disease 1 is Charcot-Marie-Tooth disease 1B where patients have a mutation in a gene (myelin protein zero, P0) on chromosome 1.
Recently mutations in five genes have been described in autosomal dominant Charcot-Marie-Tooth disease 2. Unlike Charcot-Marie-Tooth disease 1, there is no one gene that affects most patients and it has yet to be determined how common mutations in these five genes will be as a cause of Charcot-Marie-Tooth disease 2. Interestingly, occasionally mutations in myelin protein zero (P0), which usually causes Charcot-Marie-Tooth disease 1B, can cause Charcot-Marie-Tooth disease 2. The exact reason for this is not known yet.
Mutations have now been described in seven genes causing autosomal recessive Charcot-Marie-Tooth disease 1 and 2 (excluding the rare cases of Dejerine Sottas disease and congenital hypomyelinating neuropathy that can be autosomal recessive). Most of these have been described very recently and it remains to be seen how commonly mutations in these genes will cause autosomal recessive Charcot-Marie-Tooth disease type 1 and autosomal recessive type 2.
It is important for patients with Charcot-Marie-Tooth disease to know which genes are currently available for testing in the UK. Testing for the chromosome 17 duplication referred to above, which causes most cases of Charcot-Marie-Tooth disease 1A, is widely available in most regional genetic laboratories. Testing is also easily obtained for Charcot-Marie-Tooth disease 1X (connexin 32), PMP-22 mutations (Charcot-Marie-Tooth disease 1A) and P0 (Charcot-Marie-Tooth disease 1B and 2). Testing for all of the other autosomal dominant Charcot-Marie-Tooth disease 2 genes and all of the autosomal recessive Charcot-Marie-Tooth disease 1 and autosomal recessive Charcot-Marie-Tooth disease 2 genes is not yet routinely available but for individual genes testing may be available on a research basis.
Problems and management
There is no specific treatment at present for the underlying genetic defect in Charcot-Marie-Tooth disease even in those patients in whom a genetic diagnosis has been made although there are many groups researching this area.
This does not mean that patients with Charcot-Marie-Tooth disease cannot be treated or helped in many other ways. It is very important that problems patients experience, such as foot problems, are addressed appropriately as this may greatly improve a patient’s quality of life. Accurate genetic diagnosis and genetic counselling is the other area of management in which there has been rapid development in recent years.
One of the most common problems in Charcot-Marie-Tooth disease is difficulty in getting well-fitting shoes because of arched feet. It is important to wear shoes with good support, and arch supports or other devices within the shoes may be needed. In people who have quite a lot of weakness of the leg muscles splints are often very helpful to reduce the tendency of the foot to drop. New types of splints are continually being developed and patients should discuss the options with their physiotherapist.
Ideally children and teenagers with Charcot-Marie-Tooth disease should be seen annually by a neurologist or a paediatrician to ensure that severe problems with the feet do not develop. Surgery may be helpful for very highly arched feet, either to reduce the arch and the curling of the toes which often goes with it, or to fuse together some of the foot bones. After procedures of this sort, and any other operation, it is essential to minimise periods spent in bed as increased difficulties in walking are often noticed afterwards.
Just as rest may enhance difficulty in walking, active exercise and maintaining fitness help to maintain mobility. Surgery is not usually needed for scoliosis but may have to be considered in the very few cases in which this is severe. In those patients with a lot of numbness of the feet, it is important to take great care of the feet, washing and drying them carefully, and inspecting the skin for small ulcers. The inside of the shoes should be shaken out to remove small stones etc., and the insides felt for irregularities that could damage the skin.
Accurate genetic counselling is one of the mainstays of management and typically involves detailed assessment, including blood and electrical tests of close relatives. Despite the major advances in understanding the genetic abnormalities in Charcot-Marie-Tooth disease, the electrical studies remain the initial and most important tool in the diagnosis of most patients.
In Charcot-Marie-Tooth disease type 1A, affected children will show the typical electrical abnormality from about the age of five. Once a genetic diagnosis is made in a patient with Charcot-Marie-Tooth disease, the blood test can then be used to diagnose other affected members of a family. Occasionally members of a family with Charcot-Marie-Tooth disease but without signs of the disease or electrical abnormalities request a genetic test to see if they are likely to develop the disease in the future (predictive testing).
This is not usually done in unaffected children, the preference being to wait until they are adult and can make their own decision about testing. The interpetation of predictive testing can be difficult in rare causes of Charcot-Marie-Tooth disease as the information is not always available about whether having an abnormal gene means that a person will always develop the disease. Predictive testing needs to be discussed on an individual basis for each patient. In some families blood tests can be used for pre-natal diagnosis by analysing a small sample of the placenta taken at about 10 weeks of pregnancy. Couples wishing to consider this option should make enquiries through their regional clinical genetics centre before embarking on a pregnancy.
