The nosology of hereditary cerebellar ataxias : development of a classification for recessive ataxias and phenotypical description of Spinocerebellar ataxia 34

Authors: Beaudin, Marie
Advisor: Dupré, NicolasLaurin, Danielle
Abstract: Hereditary cerebellar ataxias are neurodegenerative disorders associated with progressive motor incoordination and gait imbalance. Despite significant progress in the availability and performance of genetic tests, around half of patients remain without a molecular diagnosis, which has major counselling and management consequences. In this master thesis, we address the issue of underdiagnosis in patients with hereditary ataxias through the development of a novel classification system for recessive cerebellar ataxias and the in-depth characterization Spinocerebellar ataxia 34. The first chapter is a systematic review of the literature regarding recessive cerebellar ataxias. We revised 2354 references and 130 full-text articles to identify a group of 45 recessive disorders in which cerebellar ataxia is at the core of the clinical phenotype and 29 additional complex or multisystem disorders where ataxia is a secondary feature and which should be included in the differential diagnosis of ataxia. The second chapter presents the work of a dedicated task force on the classification of recessive cerebellar ataxias. Based on the results of the systematic review, 12 international ataxia experts agreed on revised inclusion criteria and on classifications based on clinical symptoms and pathogenic cellular mechanisms. We also propose a general clinical approach to the ataxic patient. The third chapter shows the clinical and biochemical characterization of a rare dominant ataxia, Spinocerebellar ataxia 34 caused by ELOVL4 mutations. We studied a multi-generational family with a late-onset cerebellar syndrome associated with executive deficits, and apparent visuospatial, attention, and psychiatric dysfunction. Immunohistochemistry of dermal fibroblasts showed the first evidence of ELOVL4 protein pathology in this disorder with mislocalization and aggregation of the protein. Classification systems based on detailed phenotypic descriptions are essential for both clinicians and researchers to understand complex groups of disorders. The work presented here advances our understanding of hereditary ataxias and constitutes a pragmatic diagnostic tool for clinicians.
Document Type: Mémoire de maîtrise
Issue Date: 2019
Open Access Date: 19 September 2019
Grantor: Université Laval
Collection:Thèses et mémoires

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