Vivekanandam, Vinojini; (2024) Defining Phenotypes and Treatment responses in Muscle Channelopathies. Doctoral thesis (Ph.D), UCL (University College London).

Text Thesis Vino Vivekanandam.pdf - Accepted Version Access restricted to UCL open access staff until 1 May 2025. Download (2MB)

Abstract

The skeletal muscle channelopathies are rare genetic conditions that cause episodic symptoms across a spectrum from myotonia (delayed muscle relaxation) to paralysis. This thesis provides an update of the prevalence of skeletal muscle channelopathies. In the era of next generation sequencing (NGS), the minimum point prevalence of skeletal muscle channelopathies is 1.99/100 000 (95% CI 1.981-1.999). We compare in silico predictive tools to more accurate electrophysiological tools. We show, that in silico predictive tools, that are currently part of the American College of Medical Genetics and Genomics algorithm used to assess novel variants in skeletal muscle channelopathies, have poor specificity in particular. The full phenotype of the periodic paralysis conditions requires in depth phenotyping in order to build towards clinical trial readiness. In Andersen-Tawil syndrome (caused by variants in KCNJ2), we demonstrate significant neuromuscular morbidity with fixed myopathy seen in a quarter of our cohort. 13.5% require a wheelchair or gait aid. 13% of patients required cardiac defibrillator or pacemaker insertion and an additional 23% reported syncope. Muscle MRI cross-sectional phenotyping across all the periodic paralyses reveals significant neuromuscular morbidity corresponding to fat accumulation. This MRI study additionally builds the foundation for further research to develop MRI as a biomarker. In myotonia, a clearer clinical phenotypic understanding exists and this thesis moves to assess treatment response. The current gold standard is mexiletine, but lamotrigine has recently been shown to also be an effective symptomatic treatment. We undertake a head-to-head clinical trial showing that lamotrigine is comparable to mexiletine in treating myotonia across all primary and secondary outcome measures with no serious adverse events. This thesis illustrates the breadth of translational clinical research, including understanding genetics, phenotyping, and exploring a biomarker. In a more trial ready cohort, this thesis, includes a clinical trial to asses treatment response.

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