P1.25. MOLECULAR CHALLENGES IN HEREDITARY SPINOCEREBELLAR DEGENERATIONS
Jean-Loup Méreaux, Giulia Coarelli, Claire-Sophie Davoine, Léna Guillot-Noel, Anna Heinzmann, Claire Ewenczyk, Alexis Brice, Alexandra Durr
Sorbonne Université, Institut du Cerveau - Paris Brain Institute- ICM, Inserm, CNRS, APHP, University Hospital Pitié-Salpêtrière, Paris, France
INTRODUCTION: Hereditary spinocerebellar degenerations are neurodegenerative disorders affecting mainly the spinocerebellar tracts. They include hereditary cerebellar ataxias, spastic ataxias, and spastic paraplegias. They are caused by pathogenic genetic variants in hundreds of genes.
AIM(S): Our research aims to identify new genes and causal variants, as well as genetic factors modifying clinical variability. This work describes the clinical features and molecular causes of spinocerebellar degenerations in our cohort.
METHOD(S): Our cohort from Rare Disease Reference Center for Genetic Diseases of the Nervous System at Pitié Salpêtrière Hospital and Paris Brain Institute includes 3665 families with hereditary spinocerebellar degenerations (SPATAX and BIOMOV studies, NCT00140829 and NCT05034172 respectively). For one thousand of these families, we conducted large-scale genomic explorations (exome/genome sequencing).
RESULTS: We identified a pathogenic variant in a known gene in only half of the cases. Additionally, these diseases are characterized by high clinical variability, including age at onset (from birth to late age) and and severity (from mild symptoms to bedridden).
In each mode of inheritance and clinical form, there are a few main causal genes and many rare ones. Heterozygous CAG repeats expansions encoding polyglutamines in ATXN1,2,3,7 are the most frequent causes of autosomal dominant cerebellar ataxia, along with non-coding GAA expansion in FGF14. Bi-allelic non-coding GAA expansions in FXN are 58% of the known causes of autosomal recessive cerebellar ataxia. Then, SPG7, SACS, RFC1 and SETX are the other main genes in recessive forms.
CONCLUSIONS: The numerous molecular alterations and clinical heterogeneity present both challenges and clues for understanding the physiopathology of spinocerebellar ataxias. Data collection from large cohorts promotes collaborative studies and facilitates dialog between fundamental and clinical sciences.
FINANCIAL SUPPORT: APHP, Inserm, Paris Brain Institute, Fondation Médicale pour la Recherche (FRM)