MGA News April 2000

Figure 1 Family tree of our first patient with MG and AMC babies studied by Drs Philip Barnes and David Hilton-Jones.  The first four babies had AMC and only one survived.  After diagnosis of MG and appropriate treatment, a baby boy was born and is doing well.

Our interest in AMC began when Dr Hilton-Jones (at the MGA/MDC centre at the Radcliffe Infirmary) sent serum to our laboratory from a woman who had some muscle weakness and a very tragic history. She had one healthy child, but three other babies had died from AMC either in the womb or shortly after birth. The mother's weakness, and by implication the babies' too, had been thought to be a form of muscular dystrophy (which is a genetic disorder) until Dr Hilton-Jones recognised the signs of MG. Her serum was strongly positive for anti-acetylcholine receptor (AChR) antibodies, confirming a diagnosis of MG, and she was treated with thymectomy and immunosuppression resulting in substantial improvement in her symptoms. Moreover, she has since had a baby who is doing well (see Fig 1).

We might have thought no more about it, if the clinical geneticists at Oxford and Northwick Park had not talked to their colleagues about the case. Within a few months we were told about a similar story - a woman with one normal child and five subsequent pregnancies with fatal AMC- and she also had high levels of anti-AChR antibodies, even though she herself had no symptoms or signs of MG. One case is an anecdote, but two cases looks like a new research project! So we decided to find out what was special about the anti-AChR antibodies in these two women that produced such dreadful effects on their babies.
 

Figure 2  The fetal and adult forms of the acetylcholine receptor (AChR).  The fetal form (left) is present at the time when the muscles are first developing in the womb (and also in the thymus - but that's another story).  The adult form (right) only takes over when the nerve-muscle junction (NMJ)  is formed.  Antibodies in most MG patients bind to the 'main site for antibodies' and do not interfere with AChR function.  Antibodies that cause AMC bind very strongly to the same site as acetylcholine on the fetal AChR and prevent it working.

It has been known for many years that the AChR comes in two forms (Fig 2). During development the 'fetal' AChR has a gamma subunit, but as the muscle matures the gamma subunit is replaced by an epsilon subunit to form the 'adult' AChR at the neuromuscular junction (NMG; Fig 2). We used the full power of our MGA/MDG supported research to ask what was special about the antibodies. David Beeson injected toad eggs with genetic material so that they would make either the fetal or the adult form of the AChR. Then Claire Newland measured the function of the AChRs with her electrophysiological techniques before and after applying the antibodies from our two mothers of AMC babies. The results were dramatic (see Fig 3). The serum strongly inhibited the fetal AChR but had no effect on the adult AChR (published in The Lancet 1995). This proved that the antibodies were bound to the fetal AChR and in such a manner that they prevented it working (see Fig 2) . This would lead to paralysis of the baby during the time when the muscles and joints are developing, and explains why the babies were so badly affected. The fact that the antibodies did not prevent the adult AChR from working also explains, at least partly, why one of the mothers had no symptoms.
 

Figure 3  Toad eggs were engineered to make either fetal (top) or adult (bottom) AChRs.  When ACh is added to these eggs (black arrows), ionic currents can be recorded.  When AMC antibodies are added to the eggs, the 'fetal' AChR currents almost disappear, whereas the 'adult' ones are not affected.  These antibodies paralyse the baby but have no effect on the mother.

Although antibodies are only one of many causes of this distressing condition, we have since come across several other women with similar histories of AMC and high levels of anti-AChR antibodies. In order to prove that the antibodies were causing the condition, we injected them into pregnant mice and found that the mouse babies developed AMC (work done by Leslie Jacobson (MGA supported) and published in Journal of Clinical Investigation 1999). Now we have obtained funding from Action Research, a charity that is particularly interested in the study of childhood disorders, to see how many women with AMC babies have antibodies to AChR, and whether some have antibodies to other fetal muscle proteins. AMC can be fatal, but in other cases the child is born with severe deformities which need extensive surgery and physiotherapy throughout childhood and even into adult life. So it would be really helpful if we can recognise those cases that are caused by maternal antibodies, and then treat the mother during pregnancy so that the child is not deformed (we know of at least one other MG patient who successfully received treatment during pregnancy and has had a healthy baby). Sometimes babies with inherited forms of myasthenia also have AMC, so at the same time David Beeson and Rebecca Croxen (MGA/MDC supported) are going to screen for mutations in the gamma subunit that could be responsible for the inherited cases of AMC.

These results also raise some interesting questions. Why do these mothers make these particular antibodies? Is it only after the first pregnancy, as is suggested by the fact that several of the cases had a normal first child? Ian Matthews, partly supported by the French Association Francaise contre les Myopathies, has managed to clone the antibodies from the thymus of two thymectomised mothers of AMC babies, and to show clearly that they are different from the anti-AChR antibodies in typical MG patients which mainly bind to the 'main immunogenic region' (see Fig 2). To reassure young women who might want to have babies in due course, we have found the 'AMC' antibodies in very few of their sera but occasionally in women who have had several babies already.

So, if you are a woman with MG and thinking of becoming pregnant don't worry. These antibodies are very unusual, and your chances of having them are remote. But our work in this field has opened up the possibility of other fetal problems being caused by maternal antibodies, and we are beginning to test this hypothesis by looking for maternal antibodies to other proteins in disorders like dyslexia and autism. So investigating the cause of AMC in a few very unusual cases, may eventually throw light on more common conditions.

MGA NEWS April 2000

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