Research Update February 2017 Congenital myasthenias Congenital myasthenic syndromes (CMS) are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in the acetylcholine receptor genes and their associated proteins have been known for many years, there are at least 20 different genes known to be affected in CMS. Mutations in two novel groups of genes have recently been described. In order to work correctly, many of the proteins present at the neuromuscular junction need to be "glycosylated", that is to say that there need to have sugar residues added to their surface. There are special proteins to do this called glycosylation enzymes. Mutations in genes responsible for adding these sugar residues have recently been detected in a small number of CMS patients. Why mutations in genes responsible for this process result in the specific muscle weakness associated with CMS is as yet unknown. A second novel group of recently described mutations have been found in a series of proteins that are located on the presynaptic or the nerve side of the synapse. These mutations in the choline reuptake transporter and the vesicular acetylcholine transporter have a phenotype very similar to patients previously described with CHAT mutations. Identification of the exact mutation involved in CMS, allows clinicians to ascribe the correct treatment for the patients involved. New treatments: Salbutamol Salbutamol, often marketed as Ventolin, is a well-tolerated anti-asthma drug which has now been shown to be effective in treating certain forms of congenital myasthenia. Several studies have shown that treatment with oral salbutamol and ephedrine show a functional benefit within one month of initiation of treatment, with a progressive improvement in 12 - 18 months. These treatments are well tolerated and improvement in strength can be dramatic in many cases. Acquired myasthenia gravis Antibody Testing Myasthenia gravis (MG) is an autoimmune condition in which over 90% of patients have autoantibodies against the muscle nicotinic acetylcholine receptor (AChR), with a further 5% of cases having muscle-specific tyrosine kinase (MuSK) autoantibodies. Recent reports have suggested the presence of two further antibody targets: low-density lipoprotein receptor-related protein 4 (LRP4) and cortactin. The relevance as disease causing antibodies is as yet to be fully assessed as these antibodies have also been found in the serum of patients with other conditions and in some healthy controls too. Thymectomy Trial The results of the ten year thymectomy trial in MG have now been published in the very prestigious journal, New England Journal of Medicine. The study looked at 126 patients at 67 centres in 18 different countries and was initiated by the late Professor John Newson-Davis, who was a former Trustee of myaware. The results showed that patients who underwent thymectomy had a better prognosis than patients on prednisolone alone and following thymectomy also required a lower average requirement for alternate-day prednisolone. These results demonstrated that thymectomy improved clinical outcomes over a 3-year period in patients with non-thymomatous myasthenia gravis. (New England Journal of Medicine, August 2016) Treatment White blood cells, called B cells are the cells in the circulation that make antibodies, both good, and in the case of patients with MG, bad. Rituximab is a chimaeric (mouse / human) monoclonal antibody that has been made against a particular protein (CD20) on the surface of these B-cells. These drugs, therefore, work by knocking out (ablating) the B cells that make the antibodies in patients with autoimmune conditions. Rituximab and other anti-CD10 drugs are now being used in MG and in other autoimmune conditions. It is hoped to be especially helpful in patients with refractory / difficult to treat MG. In a similar study, new research is going into producing a class of drug called "Abdegs" which will work by making the body degrade antibodies faster, and so decreasing the levels of antibodies in the patients' body, in a more "natural" way. Another treatment trial, but at an even earlier stage is being developed by CuraVac. This biopharmaceutical company is developing a new class of immunotherapies (or vaccines) for use in different autoimmune conditions. They have set up a consortium in the Netherlands to initiate a clinical trial, which it is hoped will advance a therapeutic vaccine candidate for myasthenia gravis; this trial hoped to show a clinical proof of concept. Although there is some evidence that this vaccine works in rats with an experimentally-induced form of MG, there is obviously a long way to go to show it will be effective in patients with MG. Although this trial is in its infancy, it is hoped that trials like this, will one day prove beneficial for patients with MG in the future. Lambert-Eaton myasthenic syndrome (LEMS) A recent large study of the medical records (12.5 million) for all patients in the USA Veterans health system, demonstrated the prevalence of LEMS to be approximately 3 patients per 1,000,000. This makes LEMS far less prevalent than MG in the United States, where there is estimated at 140 to 200 MG patients per 1,000,000; with approximately 36,000 to 60,000 MG cases diagnosed. How these statistics relate to levels in the UK is uncertain, however, myaware is planning some work on prevalence of myasthenia in the near future.