Spinocerebellar ataxia type 15: diagnostic assessment, frequency, and phenotypic features

Abstract

International audienceBackground: To guide time- and cost-efficient analyses of the increasing number of autosomal-dominant spinocerebellar ataxia genes (SCAs), more information about frequency distributions, phenotypic characteristics and optimal diagnostic strategies is warranted. Objective: To assess the prevalence and phenotypic spectrum of SCA15 and to confirm multiplex ligation-dependent probe amplification (MLPA) as a robust and efficient strategy for routine molecular diagnosis. Methods: Fifty-six German SCA families negative for common repeat expansions were screened for ITPR1 deletions by MLPA. Samples with conspicuous MLPA data were additionally assessed by high-density SNP-array to confirm MLPA results and further determine the size of deletions. The phenotype of patients harbouring ITPR1 deletions was characterized by standardized clinical, electrophysiological and imaging assessment. Results: SCA15 accounted for 8.9% (5/56) of SCA families negative for common SCA repeat expansions. All deletions detected by MLPA were confirmed by SNP-array. One of the ITPR1 deletions preserved exons 1 and 2 in the 5' prime UTR of the ITPR1 gene. All SCA15 patients (n=10) presented with slowly progressive cerebellar ataxia and vermal cerebellar atrophy, while clinical and electrophysiological signs of extra-cerebellar affection were mild and more variable. Conclusions: SCA15 is the most common non-trinucleotide repeat SCA in Central Europe. Screening for ITPR1 deletions should be considered in patients with slowly progressive SCA, vermal cerebellar atrophy and prominent tremor after excluding common SCA repeat expansions. Promotor and exon 2 of ITPR1 may be preserved from the deletion in some cases of SCA15