Sailer, AME; (2014) Genetic Analysis of Multiple System Atrophy and Related Disorders. Doctoral thesis , UCL (University College London).

Abstract

Multiple system atrophy is a sporadic neurodegenerative disorder presenting clinically with parkinsonism, ataxia and autonomic dysfunction in variable combinations. It is clinically and pathologically heterogenous but unified by the key pathological finding of alpha-synuclein containing glial cytoplasmic inclusions. Little is known about the pathogenesis of this relatively newly defined sporadic disease. In this PhD I will present an analysis of different genetic risk factors as in many diseases, in particular neurodegenerative disorders, the study of genetics has revealed important knowledge about the biological mechanisms. As a basis for genetic studies the largest cohort of MSA samples with about 1000 MSA samples was collected as part of this PhD. These samples were then used to investigate common genetic risk factors by performing a genome wide association study (GWAS) and several candidate genes - namely MAPT, Pink1, Parkin and EIF4G1 - known to be involved in similar disorders were screened for mutations. I also collected DNA from one of the few described families with proposed autosomal dominant inheritance and performed exome sequencing, thus screening this family genome-wide for coding mutations. I then went on to study clinically or pathologically related disorders. In the genetically very heterogeneous group of hereditary ataxias new genomic technologies were shown to rapidly diagnose two families with SCA14 and SCA20, the latter being the second family of SCA20 described to date. Finally, genetic variants in the SNCA gene known to be involved in PD and MSA were investigated in a cohort of Dementia with Lewy Bodies cases.

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