I.2New genes and better treatment for congenital myasthenic syndromes

Abstract

The congenital myasthenic syndromes (CMS) are rare inherited disorders of neuromuscular transmission characterised by fatiguable muscle weakness. Their overall prevalence is uncertain but is thought to be in the order of 1 in 100 000 of the population in the UK. They are genetically determined (usually autosomal recessive - so a history of consanguinity is common), non-autoimmune disorders. Remarkable differences in severity occur even within families harboring the same mutation. Although impairment of neuromuscular transmission may often give rise to similar clinical presentation many distinct molecular and cellular mechanisms may be involved. It has become evident over the last ten years that impaired synaptic structure and stability are disease features of equal importance as defects in proteins directly involved in signal transmission. Understanding the molecular mechanisms that underlie impaired synaptic transmission helps guide appropriate and often life-transforming therapy. What has also become evident is that for forms of CMS in which synaptic structure is disrupted, treatment with β2-adrengic receptor agonists is highly effective. Cases where components of the AGRN-LRP4-MUSK-DOK7 AChR clustering pathway are mutated usually respond well to this form of medication. Moreover, in CMS patients and in animal models of CMS long term treatment with pyridostigmine may be detrimental to synaptic structure but can be partially alleviated by treatment with β2-adrengic receptor agonists. The benefit of β2-adrenergic agonists alone or combined with pyridostigmine or 3,4-Diaminopyridine is increasingly becoming an effective part of the repertoire for treating many different subtypes of CMS.