Perry, Luke; (2025) Deep phenotyping and genotyping of rare and ultra-rare paediatric neuromuscular disorders; defining natural history and identifying novel biomarkers with implications for diagnostic and translational purposes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Knowledge of natural history, genotype-phenotype correlations and biomarkers are integral for the diagnosis, management, and study of neuromuscular disorders (NMD). This thesis aims to expand knowledge in these areas. I developed the largest reported cohort of genotyped nemaline myopathy (NM) patients and identified differences in disease trajectories and comorbidities as well as prognostic biomarkers. Qualitative analysis of lower-limb MRI alongside phenotypic information identified genotype-specific imaging patterns with utility as diagnostic and prognostic biomarkers. Secondly, I collected lower-limb MRI, phenotypic and genotypic data from 48 patients carrying recessive TTN variants. Through qualitative MRI scoring and applying a machine learning approach, I defined an MRI pattern with diagnostic biomarker utility, along-side genotype-imaging and imaging-phenotype correlations. I also demonstrated the similarity between MRI patterns of patients with missense and truncating TTN variants, aiding variant interpretation. Finally, I identified muscle specific correlations between disease duration and muscle involvement severity, with potential as outcome measures for clinical trials. Thirdly, I analysed whole exome data from genetically uncharacterised NMD patients. I discovered two novel GGPS1 variants, causing an ultra-rare form of congenital muscular dystrophy, implicating impaired substrate and co-factor binding as pathogenic mechanisms. Analysis of exome data from >340 NMD patients from low and middle-income countries resulted in a diagnostic yield of 58%, identified 1 in 3.5 variants as novel and demonstrated differences between the genetic composition of South African and Indian Duchenne and Becker muscular dystrophy patients. This work expands our understanding of the genetic architecture of understudied populations and can assist in genetic variant interpretation. Finally, I designed and implemented a protocol to prospectively assess the utility of salbutamol and pyridostigmine therapy in genetically characterised congenital myopathy patients with evidence of neuromuscular junction transmission dysfunction. This work highlights the feasibility of utilising these treatments in children and provides early results on efficacy and tolerability.

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