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Clinical, genetic and electrophysiological study of skeletal muscle channelopathies - new insights into Myotonia congenita and Andersen-Tawil syndrome

Fialho, D.; (2009) Clinical, genetic and electrophysiological study of skeletal muscle channelopathies - new insights into Myotonia congenita and Andersen-Tawil syndrome. Doctoral thesis, UCL (University College London).

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Abstract

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.

Type:Thesis (Doctoral)
Title:Clinical, genetic and electrophysiological study of skeletal muscle channelopathies - new insights into Myotonia congenita and Andersen-Tawil syndrome
Language:English
Additional information:Authorisation for digitisation not received
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Molecular Neuroscience

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