From an original written by the late Prof Anita Harding MD, FRCP and revised by Dr D.Hilton-Jones MD, FRCP, for the Muscular Dystrophy Campaign.
What are hereditary motor and sensory neuropathies?
The term hereditary and sensory neuropathy (HMSN) 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 a 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.
Many different names have been used to describe HMSN in the past, and this is rather confusing. They are often referred to as peroneal muscular atrophy, because the peroneal muscle on the outside of the calves are particularly affected. Another commonly used name is Charcot-Marie-Tooth disease, after the three neurologists who first described the condition in 1886. Other names include Dejerine-Sottas disease and hereditary hypertrophic neuropathy. HMSN is now the preferred term, largely because Charcot-Marie-Tooth disease and peroneal muscular atrophy are more general terms used to describe a wider group of conditions including one form of spinal muscular atrophy.
Even HMSN does not describe a single disorder, but a group of conditions that are superficially similar. It is important to determine exactly what kind of HMSN 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 HMSN from other non-genetic causes of neuropathy, and this is particularly important in people who do not have affected relatives.
The different types of HMSN
Peripheral nerves can be thought of as being electrical cable: 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 called axons) are damaged, the speed of conduction is normal but the size of signal reduced.
These changes can be detected by electrical tests. Traditionally, the commonest forms of HMSN have been divided into two types: type 1 the conduction is slow, and this is sometimes referred to as the demyelinating-type of HMSN, whereas in type 11 it is the nerve fibres that are at fault and the term axonal-type HMSN may be used.
We now know that different abnormalities in various genes responsible for the formation of myelin do not always cause slowing of nerve conduction. Thus, some people previously categorised as being type 11,on the basis of electrical test, and therefore assumed to have a disease affecting the axons actually have a myelin problem! This causes some patients a great deal of confusion. We do not yet know all of the genes associated with HMSN, but when we do it will be possible to devise a comprehensive genetic classification and the results of electrical tests will be less important.
Previously, the term HMSN 111 was applied to patients with a particularly severe form of HMSN starting in very early life. It was though to be inherited as an autosomal recessive, unlike the autosomal dominant pattern of inheritance of HMSN type 1 and 11 (see below). We now know that HMSN 111 is usually associated with a defect in the genes that are also involved in some forms of type 1 and that most cases are a result of a new mutation in the gene, which explains why neither parent was affected.
There are other more complex forms of HMSN 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 HMSN affect people?
The first evidence of HMSN is usually between the ages of 5 and 15 but sometimes may not be until much later, even into middle-age. Usually the first symptom is 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 HMSN 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. The same applies to numbness of the feet and hands, 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.
The reflexes (such as the knee jerk) are commonly lost particularly in HMSN type I. This does not cause any trouble for the individual, but is often noted early on by doctors. A few people with HMSN I have shakiness of the hands (tremor). This combination 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 HMSN which run through the generations in families (see 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 HMSN 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, and 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 HMSN inherited?
The commonest forms of HMSN are inherited in a way that is referred to as autosomal-dominant. The affected person has one abnormal gene and each child of an affected parent has a 50% chance of being affected. People of either sex can have the condition. At present, there is considerable confusion because of the attempt to re-classify HMSN in terms of the genetic defect rather than simply on the basis of electrical tests. Most specialists now consider that all conditions put within the categories HMSN I and II are inherited by this mechanism. As noted below, HMSN IV is a separate category in which the inheritance is autosomal recessive.
In some families, HMSN is caused by an X-linked gene, which is carried on 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 very mildly affected, but each of their sons has a 50% chance of having HMSN and each of their daughters has a 50% chance of being a carrier. Unaffected boys cannot transmit the disease to their sons.
However in occasional families with HMSN the inheritance is autosomal recessive. These conditions become apparent only if both parents are ‘carriers’ of the faulty gene but these parents do not themselves have any symptoms. The condition develops only if a child inherits the abnormal gene in a double dose, i.e. one from each parent, and each child of such parents has a 25% chance of being affected. Males and females can be affected. Many people with autosomal recessive HMSN do not have affected relatives because the disorder only comes out in one set of brothers and sisters; as only 1 in 4 of these brothers and sisters will be affected, and most families are quite small, it is most likely that only one child will be affected. Autosomal recessive forms of HMSN are currently classified as HMSN type IV.
It is very important to establish exactly what type of HMSN someone has, and to investigate family members, as advice given in genetic counselling will vary depending on the type of HMSN 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 HMSN?
Recent research has shown that in most families with dominantly inherited HMSN I, the abnormal gene is located on chromosome number 17. This variety is called HMSN Ia. The genetic abnormality on chromosome 17 is unusual; affected people have an extra copy of a small part of the chromosome, which includes a gene (the peripheral myelin protein 22, or PM22 gene) involved in myelin formation. This genetic abnormality has been found in some individuals with normal parents (and thus represents a new mutation) and it seems to be a common cause of HMSN in such individuals. About three-quarters of patients with HMSN I have a type Ia.
Probably the second commonest form is type Ix. Type Ib involves a defect in a gene (myelin protein zero, or Mpo, gene) on chromosome one. Other types remain to be identified. For HMSN types II and IV the chromosomal location of some forms is known but the genes have not yet been identified and cannot be tested in the laboratory.
Problems and management
One of the most common problems in HMSN is difficulty in getting well fitting shoes because of the 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, plastic splints are often very helpful to reduce the tendency of the foot to drop. Ideally children and teenagers with HMSN 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 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. Over the next few years blood tests will gradually replace the less reliable electrical tests. However, in those disorders which cause a marked slowing of nerve conduction electrical tests are still a very valuable tool. In such families, affected children will show the typical electrical abnormality from about the age of 5 years. 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.