The clinical and genetic characteristics of congenital myasthenic syndromes

PhD ThesisCongenital myasthenic syndromes (CMS) are inherited disorders in which the safety margin of the neuromuscular transmission is compromised. The clinical hallmark of CMS is fatigable weakness. To date, nineteen genes have been implicated in causing this disorder, with most mutations located in postsynaptic proteins. Nevertheless, a great proportion of patients remains with no molecular diagnosis and cannot therefore access optimum therapy. In this thesis, each topic is summarized in one chapter that corresponds to one or part of a selected journal publication, or a book chapter. Chapter 1 is dedicated to the review of our current understanding of the different CMS subgroups based on their underlying molecular defects. Chapter 2 focuses on the methodology used to acquire the data described in the subsequent chapters. Chapter 3 reports on the mutation distribution, clinical features and genotype phenotype correlation of CMS patients referred to one of the largest CMS diagnostic centres worldwide. The phenotype genotype correlation and response to treatment in specific CMS subgroups are refined in chapters 4 and 5, including slow channel CMS and GFPT1 associated CMS respectively. Chapter 6 focuses on the selection strategy of an undiagnosed CMS cohort for whole exome sequencing and reports on the candidate variants identified. Finally, in chapter 7 and 8, detailed clinical and biological data are shown to demonstrate the pathogenicity of novel AGRN and SLC25A1 mutations identified using next generation sequencing