A Novel Late-onset Dominant Episodic Ataxia in a Large French Canadian Kindred (1460)

Objective: To report a large French Canadian family with a novel form of late-onset episodic ataxia (EA) characterized by variable expressivity. Background: The EAs are a heterogenous group of dominantly inherited disorders. Eight subtypes have been described, among which a genetic cause has been established in EA1, EA2 and EA6 only. Other forms were defined according to mapped genetic loci or shared clinical features. A sizeable proportion of EA cases presenting in late adulthood still awaits mutation identification. Design/Methods: Phenotyping was performed through serial clinical evaluations, brain MRI and nerve conduction studies. Whole exome and genome sequencing were obtained in three patients. Linkage analysis was performed using SNP genotype data of 8 affected and 11 unaffected family members. Haplotype mapping using microsatellites and copy number variant analyses were performed on genomic regions of interest. Genome-wide screening for putative repeat expansions is currently underway. Results: Sixteen individuals belonging to a French Canadian family presented with recurrent attacks of ataxia often triggered by alcohol or physical activity. Attack frequency varied from once daily to weekly, while duration varied from 5–180min. More than 90% developed progressive ataxia. The mean age of onset was 58.2 years for the first episode, and 62.3 years for the progression of ataxia. The ataxia was of variable severity with SARA scores varying between 1 and 18. Interictal downbeat nystagmus was observed in 80% of individuals. Brain MRI showed mild-to-moderate cerebellar atrophy in permanently ataxic cases. Next generation sequencing failed to reveal a shared potentially pathogenic rare variant. Mutations in known EA genes, including in CACNB4, were excluded. Linkage analysis identified 4 candidate loci with LOD scores >2, one of which was excluded using microsatellite-based haplotype mapping. Conclusions: This study describes a novel and variable form of late-onset progressive EA in a French Canadian family. Efforts are underway to identify the underlying causative mutation. Disclosure: Dr. Pellerin has nothing to disclose. Dr. Renaud has nothing to disclose. Dr. Choquet has nothing to disclose. Dr. Tetreault has nothing to disclose. Dr. Provost has nothing to disclose. Dr. Dicaire has nothing to disclose. Dr. La Piana has nothing to disclose. Dr. Massie has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sanofi, CSL Behring. Dr. Massie has received research support from Octapharma.. Dr. Chalk has nothing to disclose. Dr. Lafontaine has nothing to disclose. Dr. Dube has nothing to disclose. Dr. Duquette has nothing to disclose. Dr. Brais has nothing to disclose.