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Title: Congenital myasthenic syndromes and the therapeutic modulation of the neuromuscular junction
Authors: McMacken, Grace Maria
Issue Date: 2019
Publisher: Newcastle University
Abstract: Impairment of neuromuscular transmission at the neuromuscular junction is a primary pathomechanism of many human conditions. The congenital myasthenic syndromes (CMS) are caused by primary genetic defects which reduce the efficacy of neuromuscular transmission. CMS are increasingly diverse, both phenotypically and genetically, and the study of this group of disorders has improved our understanding of the role of neuromuscular junction proteins in health and disease. For most subtypes of CMS, symptomatic treatments are available. However, these are poorly understood and often limited by systemic side effects. In many CMS, sympathomimetics such as salbutamol and ephedrine lead to clinical benefit. However, the reason for this clinical benefit is unknown. Using animal models, this research aimed to explore the mechanisms underlying improved muscle strength from sympathomimetics in CMS. Experiments in zebrafish models revealed that salbutamol alters many aspects of neuromuscular junction development. Follow-up studies in the mouse model of end-plate acetylcholinesterase deficiency revealed that salbutamol leads to structural neuromuscular junction alterations which are primarily postsynaptic. The identification of novel CMS genes has been accelerated by the use of next generation sequencing. Genetic sequencing of undiagnosed patient cohorts lead to the identification of a novel presynaptic CMS subtype caused by mutations in SLC5A7, encoding the presynaptic choline transporter. Mutations in SLC5A7 were previously associated with an inherited motor neuropathy, and this finding expanded the overlap between disorders of the neuromuscular junction and of the motor nerve. In addition, through analysis of a patient cohort with CMS and episodic apnoea, I identified genetic, phenotypic and neurophysiological characteristics which provide mechanistic insights into this phenomenon. Understanding the mechanisms of neuromuscular junction dysfunction and of its therapeutic modulation are essential to facilitate earlier diagnosis and the development of targeted therapies for the wide range of disorders in which the neuromuscular junction is implicated.
Description: PhD Thesis
Appears in Collections:Institute of Genetic Medicine

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