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MGA News

Autumn 2006

Recent Progress in Congenital Myasthenias

Professor Nick Willcox

As most of you know, Prof David Beeson, together with our President John Newsom- Davis and Dr Jackie Palace (at Oxford), are world authorities on these uncommon inherited myasthenias. You will also remember that inherited faults occur almost randomly and can affect any of our genes. Very often, in such diseases as the muscular dystrophies, identifying the exact fault helps to explain subtle differences between subsets of patients, eg, in the age at onset, the severity, the most suitable treatment and the outcome.

With loyal support from the MGA and MDC over the last 20 years, David has identified the exact faults in around two thirds of our ‘congenital’ myasthenia patients (and has recently set up a diagnostic service for routine testing). Many of these ‘mutations’ affect your old friend the acetyl-choline receptor (AChR), the target of the immune attack in typical MG patients.

As David and the rival team at the Mayo Clinic (USA) find, some of these ‘experiments of nature’ help to explain both what goes wrong, eg, in the Slow Channel Syndrome, and how things work normally. Others will surely teach us further lessons. For example, with David, Dr Georgina Burke recently identified another patient subgroup with faults in a nearby ‘scaffolding’ protein called Rapsyn. Curiously, the myasthenia is obvious at birth in some of these patients, whereas, in others, it only starts in the 20s or even 40s and is much milder – even though the faults seem identical. Do the lucky ones have some other special modifying gene(s) that protect them? The answer to that might hold clues to better treatments for the unlucky ones.

A lucky break in another subset

We are in a phase where many research groups are using the human genome map to track down interesting new genes that haven’t previously been recognised. One such team in Tokyo (with Prof Yuji Yamanashi) has focussed on a family of ‘Dok’ proteins; they noticed that one of them (Dok-7) is turned on only at the nerve->muscle junction. Because of his expertise on muscle, they got in touch with a Neurologist, Dr Masakatsu Motomura. He is an old friend of the Oxford team’s; working here with Dr Bethan Lang about 10 years ago, ‘Masa’ helped to develop the excellent blood test she still uses for diagnosing the LEMS.

Masa soon confirmed that the Dok-7 protein really is present at the junction. It is entirely inside the muscle cells, so it seemed an unlikely target for the mystery (immune) antibodies in the puzzling ‘antibody-negative’ MG patients. Instead, he suggested that it just might be affected in some of the inherited myasthenias. So, in the summer of last year, he asked David to try to check that out in his panel of DNA samples from around 50 ‘un-mapped’ patients.

With Hayley Spearman (funded by MDC/MGA) and Susan Maxwell, David soon began to find faults in the Dok-7 gene; together, they now account for around 25 of those 50 patients, including some very old friends known to us (and maybe to you) since the 1970s.

When John and Jackie started putting names to those mutations, they began to realise that they were picking out a subgroup with ‘limbgirdle’ myasthenia – ie affecting movements around the shoulders and hips more than the eyes, face or throat. They organised 2 or 3 reunions in the clinic where they reviewed as many of these particular patients as they could. That told them that, unlike in many other inherited myasthenias, their weakness is usually not obvious at birth; typically, the first signs are difficulties in walking and/or unexpected falls from the age of 2-5 years. The ‘recessive’ inheritance means that the patient’s parents are not usually affected; also that the faulty genes have something ‘missing’ rather than anything actively harmful (like Slow Channels are). In fact, there is an excellent description of the very first family to be reported (in the 1960s), on pages 146-153 of “You, Me and Myasthenia Gravis” by Deborah Cavel-Greant (the book we reviewed in the Summer Edition).

What’s going wrong in these patients?

When the nerve->muscle junction is first put together in developing babies, the nerve endings send signals across that tell the muscle to form an ‘endplate’. Acting with our new friend MuSK, Dok-7 helps to switch on the scaffolding protein Rapsyn that then assembles the AChRs into densely packed clusters. David thinks that the faulty Dok-7 just doesn’t attract enough AChRs to the endplates, which never reach the correct size and don’t trigger the muscles efficiently.

What use is it all?

This new finding will obviously help in diagnosing more congenital myasthenia patients. In some other subgroups, similar progress has, in turn, pointed patients towards more suitable treatments. For example, many of them find Mestinon® a big help, but, in some others, it can actually make things worse, especially in those with Slow Channels, who may benefit from Prozac® instead. Most Dok-7 patients seem not to respond very well to long-term Mestinon®. Further studies are needed to understand exactly what is going wrong at the nerve->muscle junction and so find more clues about which other drugs to try.

MGA NEWS Autumn 2006
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