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MGA News

Summer 2003

New Progress on the Inherited Myasthenias

Dr David Beeson

Weatherall Institute of Molecular Medicine
Oxford

A new National Diagnostic and Advisory Service for Congenital Myasthenias

Your long-standing – and greatly appreciated – support for research into the inherited (‘congenital’) myasthenias has been rewarded by the Department of Health. It is now funding our new diagnostic service (in Oxford) for these rare forms of myasthenia through NSCAG (National Specialist Commissioning Advisory Service). Previously, this work was funded out of MGA/Muscular Dystrophy Campaign research grants.

The funding from NSCAG pays for:- (a) assessment of suspected inherited myasthenia patients at the Oxford Myasthenia Clinic (unfortunately this does not cover travelling expenses): (b) the considerable costs of screening their DNA to identify the exact genetic change that is to blame. If / when faults are identified, the families are invited back for further counselling and advice on treatments. It is already clear that faults in at least seven different genes can cause inherited myasthenias. At present, we screen only the most commonly affected gene in the NSCAG lab (the one for the ‘epsilon’ chain in the acetylcholine receptor [AChR]), and the other six genes in my research lab in the Neurosciences Group (Weatherall Institute of Molecular Medicine, Oxford). Over the next few years, we plan gradually to transfer all this work to the NSCAG-funded service. That should free-up all our research funds for searching for faults in new genes, for understanding how they cause weakness and for devising and testing new treatments

A New Gene Involved in Inherited Myasthenia The seventh gene was added to the list only in the last year. In most cases of inherited myasthenia, there are simply too few AChRs on the muscle surface, and triggering is inefficient. In about 3/4 of these, that is caused by small but crucial changes in the structure of the AChR itself. Many of the remaining 1/4 now turn out to have faults in a separate gene for an ‘anchoring’ protein called Rapsyn. The human version of this gene was first cloned in my lab; together with MuSK, it helps to cluster the AChRs tightly right opposite the nerve ending

Special signals from the nerve stimulate MuSK and Rapsyn (red) to cluster the ‘ignition locks’ (AChRs) opposite the nerve endings. They keep them tightly packed there, ready to trigger the muscle whenever electrical impulses (from the brain) release showers of ‘ignition keys’ (ACh) from their stores (green bubbles) in the nerve endings, ‘keys’ that home into the AChRs to ‘start the engine’.

Because of the Rapsyn gene faults, there are again too few AChRs in the right place. However, detailed scrutiny of these patients has revealed some interesting differences from those with AChR defects. If the Rapsyn is faulty, the myasthenia often gets gradually less severe by the age of about 8, and is usually only mildly disabling in adults. However, these same patients may previously have had serious trouble at birth and during their early years. Some even have bouts when their breathing is feeble; they are often brought on by throat or chest infections. Parents and other carers can be trained to cope with these potentially dangerous episodes quite easily.

Whereas the weakness is usually rather stable if the AChR loss is due to faults in the AChR itself, it can be quite mild and come on only in adulthood in a few other cases with Rapsyn defects, even when their faults seem identical to those in the severely affected infants. That strongly hints that there must be other influences at play; if only we could identify them, we might be able to turn them to some patients’ advantage. Finally, the late-onset weakness in the mild cases can easily be mistaken for autoimmune ‘antibody-negative’ MG – which underlines the importance of specialist assessment and clear diagnostic tests.

MGA NEWS Summer 2003
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