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This thesis examines clinical characteristics, molecular genetic aspects and electrophysiological features of two muscle channelopathies - myotonia congenita (MC) and Andersen-Tawil syndrome (ATS). MC is a muscle stiffness disorder caused by mutations in the skeletal muscle chloride channel gene CLCN1. A detailed genotype-phenotype analysis was undertaken in an initial MC cohort (22 families). A screening strategy for genetic testing was developed and applied to a larger cohort (303 cases). Twenty-three novel mutations and a high proportion of dominant MC predominantly due to four novel mutations clustered in exon 8 were observed. These four mutations were studied in vitro using two-electrode voltage-clamp methods in Xenopus laevis oocytes. Loss of function and clear dominant-negative effect in CO-expression experiments were demonstrated. The Xenopus oocyte expression system was also used to study the non-genomic effect of sex hormones on CLC-1 channels. It is shown that both testosterone and progesterone rapidly and reversibly inhibit wild-type CIC-1 channels by causing a prominent rightward shift in the voltage dependence of their open probability. In contrast, 17 β-estradiol causes only a small shift. These results suggest a possible mechanism to explain how the severity of myotonia congenita may be modulated by sex hormones. The potential modifying effect of the myotonic dystrophy genes DMPK and ZNF9 on the phenotype of MC was investigated. Allele sizes for these genes were measured in more than 400 patients with suspected non-dystrophic myotonia. Four individuals were identified with an intermediate size allele of DMPK and ten individuals tested positive for myotonic dystrophy type 2. ATS is characterised by the triad of periodic paralysis, cardiac arrhythmias and dysmorphic features. A UK cohort with ATS is presented with detailed phenotype-genotype correlation. Novel mutations were found and unusual clinical features including renal tubular defect, CNS involvement, dental and phonation abnormalities were observed.

Translational research is the process that transfers knowledge from basic sciences to the clinical setting. This PhD thesis translates knowledge gained from animal model research in hypokalaemic periodic paralysis (HypoPP) and McArdle disease to humans affected by these conditions to identify new treatment options for both diseases. The efficacy of two compounds, sodium valproate and bumetanide, were assessed for the first time in humans with McArdle disease and HypoPP, respectively. For HypoPP, the role of the McManis test as an outcome measure was explored in a randomised, double-blind, placebo-controlled phase II clinical trial with a cross-over design. For McArdle disease, several outcome measures were explored in an open-label proof-of-concept phase II study. 2 mg bumetanide was not effective to abort a focal attack of weakness in an immobilised hand in the majority of the trial participants with HypoPP, but data presented here supports further studies of bumetanide in this population of patients. Extending the isometric exercise period to 10 minutes increased the sensitivity of the McManis test, and frequent compound muscle action potential (CMAP) amplitude assessments were shown to be useful in assessing both efficacy and safety. 20 mg/kg/day sodium valproate was ineffective in stimulating the expression of the brain glycogen phosphorylase enzyme in skeletal muscle of people with McArdle disease. Based on these results, further research into VPA as a treatment for McArdle disease is discouraged. The combination of several outcome measures contributed to data interpretation and should be considered in future studies exploring treatment efficacy in McArdle disease. The results of this research should contribute to future clinical trials in the field of exercise-related muscle disorders and provide valuable insights for translational research.