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MGA News

July 1998

Hereditary Myasthenia

Dr David Beeson

Neurosciences Group
Institute of Molecular Medicine
John Radcliffe Hospital, Oxford

Inherited or "congenital" myasthenic syndromes (CMS), have symptoms that are superficially similar to those in myasthenia gravis. However, unlike myasthenia gravis, inherited myasthenic syndromes have a definite underlying genetic cause and the symptoms are often apparent in early childhood. Over the years, and with the loyal support of the MGA,we have been laying the scientific groundwork necessary for defining the genetic basis of these syndromes. Now, at last, it has become possible to identify the precise faults in the genetic code for many cases.

Since muscle acetylcholine receptors (AChR) are the target for autoimmune attack in myasthenia gravis, the genes that encode the AChR protein were considered prime candidates for the DNA changes that might be responsible for CMS. Recently, Rebecca Croxen has been comparing the AChR genes of CMS patients and healthy individuals and has found changes in the DNA sequences of patients that are co-inherited with disease. Interestingly, however, different patients with the same mutation sometimes show quite different severities of weakness, as in many other genetic diseases. Thus, understanding how the DNA changes cause muscle weakness is proving to be a fascinating scientific jig-saw puzzle that we are only just beginning to put together.

Figure 1:
A Model picture of the two types of AChR molecules 
(fetal and adult) located within the muscle membrane

As Figure 1 illustrates, the AChR is made up of five pieces of protein, termed subunits, that assemble to form a doughnut structure in the surface of the muscle, with a central pore that acts as a very small channel through the membrane. In the middle of the channel is a closed gate. It is the brief opening and closing of this gate that relays the signal, initiated in the brain, that triggers muscle contraction. There are two types of AChR in muscle; one form is present on the muscle during the fetal stages of life (fetal AChR) and another in adult muscle (adult AChR). Figure 2 illustrates that the two forms differ in one of the five subunits. In fetal AChR there is a gamma subunit that is replaced by an epsilon subunit in adult AChR.


Figure 2:
A Model of the AChr subunit (wavy line) within the muscle membrane (in black), illustrating the positions of a few of the DNA changes (black circles) that we have detected.

With this image of the AChR in mind, let us consider a summary of the results we have obtained from studying patient DNA. First, the majority of patients with CMS have mutations in the genes that code for the subunits of the AChR. Secondly, most, but not all, of the mutations detected are in the gene that codes for the epsilon subunit present in adult AChR. Thirdly, there is no one common mutation, but rather there are many different DNA changes located along the length of the genes. Figure 1b illustrates the position of a few of the changes we have detected within the epsilon subunit.

Different mutations are likely to give rise to different disease severity. Working out how the AChR is affected by each mutation is highly complex, but this is what Claire Newland in our laboratory is attempting to achieve. In simple terms, with some DNA changes there are too few AChR in the muscle membrane, whereas with others the gate at the centre of the AChR could be open for too long or too short a period. Each of these would have subtly different effects on the transfer of signal from nerve to muscle, but nevertheless would cause serious muscle weakness. We also believe that, in certain cases, patients survive because the fetal form of the receptor is reactivated and takes over from the defective adult AChR.

What of the future? Much more work needs to be done, but once the results of the individual DNA changes are worked out then rational approaches to treatments and novel therapies can be devised. What is already apparent is that, as in the case of myasthenia gravis, the original estimate of the incidence of CMS (1 in 500,000) is likely to be too low, and there are many more DNA changes in AChR genes within the population at large that we, at Oxford, are keen to uncover.
MGA NEWS July 1998
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