Objective: We report on a family with ataxia due to mutations in the ANO10 gene to provide comprehensive clinical and cognitive data on the associated phenotype, expanding the knowledge of this rare ataxia and to communicate the response to a trial with CoQ10.

Background: Mutations in ANO10 have been identified as a cause of autosomal recessive spinocerebellar ataxia type 10 (SCAR10). A genetic diagnosis in this pedigree was obtained using next generation sequencing (NGS) more than 15 years after first presentation, following an expensive and fruitless diagnostic odyssey.

Methods: Three affected siblings from a sibship of 11, born to Irish non-consanguineous parents developed slowly progressive ataxia with onset between 31-42 years, associated with early dysarthria. One presented initially with loss of consciousness with incontinence, attributed to a seizure. The two older siblings had also bladder dysfunction and on examination downbeat nystagmus and conjunctival vessel tortuosity and teleangiectasias. All siblings had gait ataxia, lower limb spasticity and prominent dysarthria.

Results: Cognitively the affected siblings performed less well than unaffected siblings with prominent frontal/executive impairment. Brain MRI showed global cerebellar atrophy, most severe in the eldest and longest affected. Neurophysiology and OCT were normal. Genetic analysis with a targeted gene panel revealed homozygous ANO10 c.132dupA p.(Asp45fs) mutations in the eldest sibling, confirmed with a Sanger sequencing in other two. 300mg/day CoQ10 for 3 months resulted in subjective improvement in one of the siblings, although SARA and ICARS scores did not change significantly.

Conclusions: Our report provides useful data on this evolving phenotype, representing a slowly progressive spastic ataxia with prominent early dysarthria and frontal cortical involvement, paralleling what is known about ANO10 expression. The family are of interest as they span the divide between the traditional gene testing and more modern NGS methods. These advances are likely to change our past beliefs about the prevalence of certain recessive ataxias. ANO10 mutations (in 6 individuals) now outnumber AOA1, AOA2 and ataxia telangiectasia in our cohort, making it the second most common recessive ataxia. Further blinded randomised studies of CoQ10 supplementation may be feasible if larger numbers of patients can be identified earlier in the disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/autosomal-recessive-ataxia-due-to-ano10-mutations-full-and-novel-phenotypic-data-in-an-irish-pedigree/