Matthews, EL; (2014) The skeletal muscle channelopathies: phenotype, genotype and pathogenesis. Doctoral thesis , UCL (University College London).

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Abstract

The skeletal muscle channelopathies are a group of inherited disorders due to the dysfunction of voltage gated channels in the sarcolemma resulting in abnormal membrane excitability. Simplistically they are broadly divided into those that result froman “over excited” membrane (the non-dystrophic myotonias) and those due to an inexcitable one (the periodic paralyses). Skeletal muscle channelopathies were describedclinically long before they were genotyped or hypotheses regarding pathogenesis fullyevolved. This thesis explores all three, the phenotype, the genotype and recent insightsinto the pathogenesis. Detailed clinical and neurophysiologic examination of a large group of patients identifiednew aspects of the phenotype including neonatal presentations with importantimplications for early life care. Morphological findings are also expanded with thepresence of inflammatory infiltrates, not previously described in the channelopathies. Extensive DNA sequencing of causative genes was undertaken in a carefully genotypedcohort. In hypokalaemic periodic paralysis an exclusive relationship between mutationsand the channel voltage sensor emerged which relates closely to recentelectrophysiological evidence of a “gating pore” disease mechanism. A small butsignificant minority of cases remain however where no mutation is found. The implication of other potential genetic mechanisms or even undescribed genes in thesecases is discussed. Current drug therapies are also examined in three separate cohorts and evidence suggests acetazolamide, a commonly prescribed treatment, may only be effective in 50-60% of those with hypokalaemic periodic paralysis. A tentative relationship between efficacy and genotype also emerges. Patch clamp studies show significant loss of function of the main alpha pore of the sodium channel in periodic paralysis but the implications of this in light of the “gating pore” hypothesis are discussed. Tentative explorations are made as to the viability of performing future studies in myoctes as opposed to the traditional HEK cell model with early experiments illustrating limitations.

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