Congenital muscular dystrophy

With thanks to Dr.Richard Appleton and Dr.P.Nicolaides for their help in producing this Fact Sheet for the Muscular Dystrophy Campaign

The congenital muscular dystrophies are a group of the lesser known neuromuscular disorders. Diagnosis and recognition of this group of conditions has improved over the past few years following work done by a number of researchers around the world on the identification of the protein involved in CMD in a group of patients.

This protein is called ‘merosin’ (otherwise known as laminin -m) and it is missing in the muscles of roughly half the patients diagnosed as having ‘classical’ congenital md. Work is presently under way to try and further identify the genetic fault responsible for CMDs, with a view to providing effective prenatal diagnosis and ultimately offering a treatment for the disorder. In the meantime, much can be done to assist a child who has CMD.

What is congenital md?

Congenital means ‘from birth’ and, indeed, one of the signs of congenital md is that symptoms show as soon as the baby is born or in the first sixth months of life. Sometimes, however, a child is not diagnosed with congenital md until much later.

These symptoms are likely to be hypotonia (‘floppiness’) poor head control, muscle weakness, delayed motor milestones (e.g. when a baby first stands holding on to something, or learns to crawl or walk), and contractures (or tightness) in the ankles, hips, knees and elbows. The baby’s hips may be dislocated (out of joint) at birth. The contractures can sometimes be severe and affect several joints (known as arthrogryposis). They happen because the baby has not had the muscle strength to move freely enough in the womb.

There seem to be three main types of congenital md

1. Children who only have muscle weakness (dystrophy) involving all the muscles.

2. Children who have muscle weakness and learning difficulties, with or without epilepsy.

3. Children who have muscle weakness, learning difficulties and abnormalities of the eye. Learning difficulties may be subtle, moderate or severe.

How many people are affected by congenital md?

At a very rough estimate 1 in 50,000 babies may be born with congenital md in the UK. Not all of these will be correctly diagnosed and it is possible that some, with mild forms of the condition, remain undetected. As diagnosis becomes more accurate and we begin to understand the condition better, we will have a clearer idea of how many people really are affected in this country. 1 in 50,000, therefore may be an under-estimate.

Is congenital md inherited?

Yes. The pattern of inheritance is known as ‘autosomal recessive’. This means that both parents are carriers of the condition (although clinically unaffected) and they have a risk of 25%, or 1 in 4 in each pregnancy, of passing the condition on to their children (see diagram). Occasionally a case may be ‘sporadic’ which means it is a one-off with little risk of recurrence in other children. There is no accurate way of predicting who is and who is not a carrier.

How is congenital md diagnosed?

A baby with congenital md is usually first diagnosed as a ‘floppy baby’. Doctors can see the symptoms described above, but as these could be due to a number of different conditions, they have to conduct a series of tests to try and make an accurate diagnosis.

Firstly a blood test is taken and the level of a muscle enzyme assessed (the creatine kinase or CK level). In over 75% of cases of congenital md this level is 5 – 20 times higher than normal. However, at this stage, the diagnosis still needs to be backed up with a muscle biopsy. When the muscle is studied through a microscope there are three tell-tale signs which indicate that the child has congenital md.The muscle fibres, instead of being evenly sized, show great variation in size.

1. Some of the muscle fibres have been replaced by fat and fibrous tissue. Although some fat and fibrous tissue is found in normal muscle, in the case of congenital muscular dystrophy, the amount is greatly increased.

Some fibres are degenerating (breaking down).

In the merosin deficient cases a skin biopsy rather than a muscle biopsy may be used to diagnose this type of CMD. This followed the discovery that the protein merosin was present in both skin and muscle and was absent from both tissues in these patients. A skin biopsy means only having to remove a very small skin sample from the patient and may be done under a local anaesthetic. In addition skin cells can easily be grown in tissue culture and it is thought that in the future the cells which have been grown in the tissue culture might be used to discover exactly where the gene fault lies within the gene of an individual patient.

An electromyography (EMG) test may also be taken before a muscle biopsy is done. Here, a needle is inserted into muscle and the electrical activity recorded. An unusual level of activity could be either due to a myopathic (muscle related) or neuropathic (nerve related) condition.

An electromyogram, therefore, gives a broad indication of a muscle problem but a muscle biopsy must also be taken to pin-point the precise diagnosis. An abnormal EMG cannot show any difference between a congenital myopathy and congenital muscular dystrophy; only a muscle biopsy can do this.

Is there a treatment or a cure?

At the moment there is no cure for congenital md, but there are ways, described below, of helping to alleviate the effects of the condition.

Is congenital md progressive and is it life threatening?

Sometimes the condition is fairly stable and the child even appears to gain strength as he or she gets older although this is really a result of growing and developing rather than the muscle fibres regenerating and strengthening. If the condition is not progressive, there is no reason why a person should not live a normal lifespan. Sometimes the muscle weakness progresses quite rapidly and can lead to respiratory failure because the muscles which assist breathing are affected. This may happen in children of any age.

Can a child with congenital md learn to walk?

The severity of this condition varies greatly from person to person. Some children will walk although this can be delayed until five years of age or older. Leg splints (calipers) are often used to assist a child to walk. Children who have successfully walked may lose the ability later on because as they grow older and heavier, the muscles are unable to cope with the greater strain. Other children never achieve walking. As the severity of congenital md varies so much from child to child it is important not to assume that certain developments will or will not take place, but to work with the child to achieve the goals which are in his or her power.

What other physical effects might congenital md have on a child?

As the muscles are weak and mobility is limited, the child may develop or be born with ‘contractures’, this means that the muscle tendons tighten up and the child is unable to move the limbs or joints as freely as a healthy child. Physiotherapy can help prevent this and a programme of exercises should be worked out with a physiotherapist very soon after diagnosis. Even a very young baby can be helped to maintain suppleness. Hips are commonly affected and if they are dislocated this may require treatment with a splint or sometimes surgery.

If the child sits awkwardly or has to twist his or her body in order to balance when walking, then the spine may start to curve. This is called scoliosis. Passive and active stretching exercises help to keep the muscles flexible, prevent contractures and stop the spine from curving.

Standing in standing frames and/or using night splints and calipers can also help the child to stand symmetrically, and prevents or delays the onset of contractures and scoliosis. It is possible that a small operation which releases the Achilles tendon can help the child with congenital md to stand more easily using calipers or to continue walking after they would otherwise have had to start using a wheelchair. An operation on the spine is also sometimes advisable to help the child sit up straight.

Constipation, possibly due to the fact that a child is not very active or mobile, or possibly due to muscle weakness, is often an associated problem. This can be treated by a high fibre diet, drinking plenty of fluids and very occasionally by laxatives.

Update

What’s new in CMD?

Congenital muscular dystrophy is thought to be due to an abnormality in the muscle protein framework caused be deficiency in merosin (or laminin) a protein which normally helps connect the muscle framework to supportive structures outside the muscle membrane. Each laminin molecule is composed of a2, b1, and y1 chains.

A major advance in the understanding of CMD was the finding that the laminin a2 (or merosin M-chain) was found to be missing in the muscles of about half the patients diagnosed as having ‘classical’ CMD. This led to the identification of a group of patients known as the merosin negative patients. These patients manifest a broad range of clinical symptoms and as a group are more severely affected than merosin positive patients. It is interesting to note that in the merosin negative CMD the nature of the genetic defect and the severity of the disorder do not always correlate.

The merosin protein (alpha 2 laminin chain) is composed of two protein fragments of different sizes (80kDa and 300kDa). It has been found that some people who have milder CMD than usual have minimal abnormality of the smallest fragment, but significantly reduced merosin levels in the larger fragment. This finding may help to explain the broad range of clinical symptoms associated with a merosin (alpha 2 laminin) deficiency, that is the type and severity of symptoms could be linked to which fragment is missing.

Genetic advances

Most patients who lack merosin were found to have a genetic fault on chromosome 6 causing their condition. A different gene defect was localised on chromosome 9 causing the Japanese type of CMD otherwise known as Fukuyama congenital muscular dystrophy. In these patients merosin is present but in reduced amounts and it may be that the protein that helps to link merosin to the muscle structure is missing. The merosin positive patients probably lack another protein related to merosin which causes their type of CMD. It is likely that in the future the gene abnormality causing the classical merosin positive CMD will be localised.

Prenatal diagnosis

Prenatal diagnosis is a promising development in the diagnosis of inherited conditions. It is based on being able to detect the abnormality in the developing fetus. This is useful in conditions associated with a specific protein deficiency or a recognised genetic defect. Unfortunately at present no such test is available for the diagnosis of the merosin positive patients (no known protein deficiency or genetic fault). This picture is different in the merosin negatve families. Merosin is normally expressed in fetal tissue, it is therefore theoretically feasible to detect its presence in chorionic villus samples (CVS) of at-risk pregnancies. The advent of a number of new genetic tests has enabled the experimental use of prenatal diagnosis in merosin negative families. Such tests include linkage analysis (a way of tracking genes inherited by different family members) and immunocytochemistry (examining tissue using specific ‘tags’ which allow merosin to be detected visually). At present these tests may be suitable for some merosin negative families but it is likely that they will become more widely available in the future. There may also be an option in merosin positive families if either the genetic fault or the ‘protein’ abnormality is defined. It is advised that any merosin negative families who are interested in this service should contact the Cambridge Office in the first instance (details available from Head Office).

Future areas of research

At present although there is no curative treatment for CMD the recent major genetic advances offer a number of possible treatments for the future. Some of these treatment possibilities include gene therapy and myoblast (muscle cell) transfer. Myoblast transplantations have been shown to restore the production of the extracellular merosin (alpha 2 laminin) chain, at least partially, in experiments done using the dy/dy mouse (mouse model for human congenital muscular dystrophy). However at the moment it is unlikely that myoblast transfer will be helpful for children or adults with CMD.

Finally, following the recent identification of merosin deficiency it may be possible to try to compensate for this deficiency, particularly when the precise chemical consequences of merosin deficiency become clearer.