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Publication Detail
A clinical and genetic study of the skeletal muscle channelopathies
  • Publication Type:
    Thesis/Dissertation
  • Authors:
    Raja Rayan DL
  • Date awarded:
    2016
  • Supervisors:
    Hanna MG,Kullmann D
  • Status:
    Unpublished
  • Awarding institution:
    UCL (University College London)
  • Language:
    English
  • Keywords:
    myotonia, myotonia congenita, periodic paralysis, ion channels, skeletal muscle channelopathy
Abstract
The skeletal muscle channelopathies are a group of inherited muscle diseases characterised by the abnormal functioning of voltage-gated ion channels expressed in skeletal muscle. They manifest as the non-dystrophic myotonias and the periodic paralyses. This thesis increases the current understanding of the clinical and genetic basis of this group of diseases. It identifies the overall prevalence in England as 1.12/100,000 and determines the individual minimum prevalence of each disease, which has not previously been documented. It presents a detailed phenotype study of periodic paralysis (PP), paramyotonia congenita (PMC) and sodium channel myotonia (SCM), which is the first comparative study of these diseases. In the process it uncovers the marked similarity between PMC and SCM and suggests that these may be a spectrum of one disease, rather than two distinct diseases as traditionally thought. It provides the first systematic study of pregnancy and anaesthetics in a large number of channelopathy patients, identifying a marked increase in severity of symptoms during pregnancy that has not previously been documented. To widen the spectrum of genetic diagnosis and techniques in this group of diseases, this thesis describes the first cases of large scale rearrangements in CLCN1 causing myotonia congenita. It demonstrates how, using whole exome sequencing, the genetic diagnosis rate can be improved and illustrates two cases that may be explained by variations in RYR1 and another case in which a genetic diagnosis of Liddle’s syndrome may underlie secondary PP. This suggests that RYR1 variations may account for some unconfirmed cases and others may be explained by genetic causes of secondary PP. Finally this thesis presents convincing evidence of the efficacy of mexiletine in non-dystrophic myotonia in a double-blind placebo-controlled trial. It demonstrates improvement of the primary outcome measure of patient-reported stiffness and the majority of secondary outcome measures assessed.
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