Repeat Expansions in Movement Disorders: Disease Modification and New Horizon

Repeat expansion disorders are caused by repetition of a small stretch of DNA at specific loci, and movement disorders are the most common manifestations. The length of the expanded DNA tracks is a major determinant of disease onset and progression, but many genetic modifiers are unknown. In the first results chapter, I report the establishment of an international consortium for the investigation of genetic modifiers of trinucleotide repeat ataxias, and negative results from a study on the genetic modifying effect of a repeat variant in mismatch repair gene MSH3 in spinocerebellar ataxia type 3 and Friedreich’s ataxia. I also provide ancillary evidence to support that alteration of DNA repair may have genome-wide impact on short tandem repeats. With the discovery of more than 10 pathogenic repeat expansion loci in the last 2 years, the second results chapter outlines gene-specific screening in 3 genetic disorders—benign adult familial myoclonic epilepsy, cerebellar ataxia neuropathy and vestibular areflexia syndrome (CANVAS) and neuronal intranuclear inclusion disease (NIID). I describe their prevalence in various movement disorder cohorts and deep phenotyping of mutation-positive patients, which expand the clinical spectrum of CANVAS and NIID. Current approaches to establishing the molecular aetiology of repeat expansion disorders rely on single gene testing. Simultaneous interrogation of all pathogenic repeat expansion loci will greatly facilitate diagnostic efficiency. The last results chapter describes the study of short-read whole genome sequencing coupled with bioinformatic methods in the screening for known and 6 novel repeat expansions in 72 inherited ataxia patients. We achieved a genetic diagnosis in 22% of the cohort and identified 91 outlying repeat expansions that will require further investigation. The body of work in this thesis helps clinicians to better recognise and diagnose movement disorders with repeat expansions and supports future research in this field amidst the evolving technological landscapes