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Diagnosing congenital myasthenic syndrome

Research at the at the Nuffield Department of Clinical Neurosciences has had a profound effect on the diagnosis and treatment of patients with Congenital Myasthenic Syndrome.

Congenital myasthenic syndromes (CMS) are inherited diseases resulting in fatiguable muscle weakness. The onset of these disorders is often in infancy or childhood and the sufferer often ends up wheelchair bound. By the late early 2000s the genetic mutations giving rise to many cases had been discovered.  However, a relatively common group with weakness in the limb girdle (the muscles around the shoulder girdle and hips) remained a mystery.  Work by Professor David Beeson and his team at the Nuffield Department of Clinical Neurosciences has had a profound effect on the diagnosis and treatment of patients with this form of the disease.

Limb girdle myasthenic syndrome often becomes apparent around 18 months of age and does not respond to standard treatments for CMS.  In 2006 David Beeson’s team published a research paper reporting mutations in the gene encoding a crucial muscle protein called DOK7.  These mutations affect the size and structure of the connection, known as the synapse, between the nerve ending and muscle at the neuromuscular junction.  They also caused abnormal maturation and survival of these synapses. For the first time scientists understood the cause of the disease in this group and the mechanism by which these mutations lead to muscle weakness. DOK7 mutations were quickly confirmed in similar cases worldwide.  They are now recognised as one of the commonest causes of CMS in the UK, responsible for around 21% of cases. The team also defined the clinical spectrum of patients with this form of the disease and together with the ability to identify DOK7 mutations this provides the basis of reliable diagnosis.  Diagnostic testing for DOK7 mutations is now routine for patients with suspected CMS.  A diagnostic service handling samples from the UK and Europe is provided by the Churchill Hospital and the Weatherall Institute of Molecular Medicine.  In the UK approximately 100 samples a year are sent for DOK7 testing and prenatal testing is also provided if requested. Similar screening services have now been established across Europe and in the USA.

During their research the team also noticed that patients with DOK7 mutations either did not respond, or got worse when standard treatments for CMS were given.  However, they did respond to a class of drugs known as beta 2 adrenergic receptor agonists.  They subsequently found that giving patients this type of drug resulted in a dramatic improvement in their myasthenic weakness.  Other studies have confirmed these striking results. In one study all 9 children given the drug showed significant improvement and children who have been unable to walk for many years gained were able to walk independently.

As a result of the research by David Beeson and others in Oxford, the Department of Health set up a National Diagnostic and Advisory Service for CMS based at the John Radcliffe and Churchill Hospitals.  This is linked with Great Ormond Street Hospital, has been integrated into the NHS and forms part of a national ‘Rare Neuromuscular Diseases Service’. A national outpatient service is provided at which patients are advised about the genetic basis of the condition and offered the most appropriate treatment.  In a 2013 patient and family satisfaction survey, 89% reported they were completely satisfied with the service and 97% said that they felt involved in decisions about their care.