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Late-onset hereditary dominant episodic ataxia in French Canadians

Late-onset hereditary dominant episodic ataxia in French Canadians

Dr David Pellerin 1, Dr. Mathilde Renaud 2, Mrs. Karine Choquet 1, Prof. Martine Tétreault 3, Mrs. Sylvie

Provost 3, Mrs. Marie-Josée Dicaire 1, Dr Roberta La Piana 1, Dr Rami Massie 1, Dr Colin Chalk 1, Dr.

Anne-Louise Lafontaine 1, Prof. Marie-Pierre Dubé 3, Dr Antoine Duquette 3, Dr Bernard Brais 1

  1. McGill University, 2. Centre Hospitalier Régional Universitaire de Nancy, 3. Université de Montréal

 

The episodic ataxias (EA) are a heterogeneous group of dominantly inherited disorders. Eight different forms of EA have been described based on identified causative genetic variants or clinical features. Mutations in KCNA1(EA1) and CACNA1A (EA2) have been reported in multiple kindred and account for the majority of reported EA cases worldwide. We recruited a cohort of 65 French Canadian patients from 37 families with an undetermined EA phenotype. Mutations in known EA genes were excluded. All patients presented with recurrent attacks of ataxia that were often triggered by alcohol or physical activity, 75% of whom developed progressive ataxia. The mean age at onset was 54.4 years (range: 30-72) for the first episode, and 60 years (45-72) for the progression of ataxia. Ataxia was of mild to moderate severity with a mean SARA score of 8.9/40 (1-18). Interictal downbeat nystagmus was observed in more than 90% of patients, while diminished vibration sense was present in 50% of cases on clinical examination. Migraines were comorbid in half the patients. Acetazolamide was effective for reducing the frequency of attacks in 9% of patients. Brain MRI showed mild to moderate cerebellar atrophy in more than 50% of permanently ataxic cases. Variable expressivity in the severity of episodic attacks and ataxia progression was observed across all families. Whole exome sequencing and whole genome sequencing in the three largest families failed to reveal a shared potentially pathogenic rare genetic variant. Approximately 640,000 SNPs were genotyped in the largest family which included 8 affected and 11 unaffected members. Linkage analysis uncovered a segregated locus on chromosome 16, which was further supported by genotyping of 9 more polymorphic sequence-tagged sites markers. Copy number variation and loss of heterozygosity analyses did not reveal major rearrangements that segregated with the disease on chromosome 16. Efforts are ongoing to uncover the underlying causative mutation. In conclusion, we report a new form of late-onset progressive EA in French Canadians likely related to a locus on

chromosome 16.

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