CLINICOGENETIC CORRELATIONS IN RARE COMPLEX MOVEMENT DISORDERS Focus on combined and complex dystonia phenotypes

Movement disorders is relatively unique among neurology subspecialties in its reliance on clinical judgement to accurately define disease phenotypes which are often complex. Progress in genetics – particularly the advent of next-generation sequencing (NGS) – has enabled an unparalleled gene discovery and revealed unmatched intricacy of genotype-phenotype correlations in the field of movement disorders and neurodegeneration. “Deep phenotyping”, with detailed characterization and continual updating of movement disorder phenotypes, and the active involvement of movement disorder specialists in the multidisciplinary process to establish clinicogenetic correlations are the cornerstone of precision medicine and will have increasingly more crucial implications for the diagnosis, treatment and counseling of movement disorders in the advanced NGS era. This thesis summarizes the 18-month clinical and research experience of the PhD candidate in a hub center for the diagnosis and treatment of movement disorders (National Hospital for Neurology and Neurosurgery) and its neurogenetic research laboratory (UCL Queen Square Institute of Neurology) in the United Kingdom. It investigates clinicogenetic correlations of rare complex movement disorders, with particular focus on combined and complex dystonia phenotypes, including neurodegeneration with brain iron accumulation (NBIA) syndromes. General objectives of the projects herein reported were: 1) to characterize phenotypically a large cohort of patients with combined and complex dystonia syndromes; 2) to explore genetic causes of dystonia phenotypes through NGS techniques, including whole-exome (WES) and whole-genome sequencing (WGS); 3) to expand the phenotypic and genotypic spectrum of known genetic movement disorders; and 4) to investigate new possible candidate disease genes. This thesis consists of six chapters. After a general introduction (chapter I) and summary of aims (chapter II), chapter III reports on the retrospective clinical review and analysis of WES data of a large cohort of patients with complex movement disorder phenotypes, in particular dystonia and NBIA syndromes. Chapter IV describes preliminary results of an ongoing study on WGS to explore the genetic basis of dystonia, including the first association of a dystonia phenotype with the peroxisomal gene AMACR. Chapter V dissects the phenotype and genotype of PLA2G6-related parkinsonism based on data from 14 unpublished cases and a systematic literature review. Chapter VI provides final remarks and future directions.