Frequency of rare recessive mutations in unexplained late onset cerebellar ataxia.

M J Keogh,J Duff,K Douroudis,H Steele,M Santibanez-Koref,T Smertenko,A Pyle,P F Chinnery,R Hussain,R Horvath,H Griffin

doi:10.1007/s00415-015-7772-x

M J Keogh, J Duff + Show 9 more

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https://doi.org/10.1007/s00415-015-7772-x

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Abstract

Sporadic late onset cerebellar ataxia is a well-described clinical presentation with a broad differential diagnosis that adult neurologists should be familiar with. However, despite extensive clinical investigations, an acquired cause is identified in only a minority of cases. Thereafter, an underlying genetic basis is often considered, even in those without a family history. Here we apply whole exome sequencing to a cohort of 12 patients with late onset cerebellar ataxia. We show that 33 % of ‘idiopathic’ cases harbor compound heterozygous mutations in known ataxia genes, including genes not included on multi-gene panels, or primarily associated with an ataxic presentation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00415-015-7772-x) contains supplementary material, which is available to authorized users.

Highlights

Adult onset cerebellar ataxia poses a considerable diagnostic challenge
Current molecular investigations for sporadic cases echo that of familial forms, beginning with testing for trinucleotide repeat disorders, such as the spinocerebellar ataxias (SCA1, 2, 3, 6, 7 and 17), dentatorubral pallidoluysian atrophy (DRPLA) and Friedreich’s ataxia (FDR) in most centres [1]
We identified confirmed or probable pathogenic variants causing sporadic late onset ataxia in four patients (33 %) in our cohort

Summary

Introduction

Adult onset cerebellar ataxia poses a considerable diagnostic challenge. Initial investigations focus on detecting degenerative, toxic, structural and inflammatory etiologies. Current molecular investigations for sporadic cases echo that of familial forms, beginning with testing for trinucleotide repeat disorders, such as the spinocerebellar ataxias (SCA1, 2, 3, 6, 7 and 17), dentatorubral pallidoluysian atrophy (DRPLA) and Friedreich’s ataxia (FDR) in most centres [1]. This approach fails to identify a molecular diagnosis in 87–98 % of late onset sporadic cases [1, 3], and subsequent investigations are undertaken on a gene-by-gene basis, often at considerable time and expense. We applied whole exome sequencing to a cohort of individuals with sporadic late onset ataxia

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