Novel SACS Mutations Identified by Whole Exome Sequencing in a Norwegian Family with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Charalampos Tzoulis,Bjørn Ivar Haukanes,Stefan Johansson,Per Morten Knappskog,Laurence A Bindoff,Helge Boman,Mathias Toft

doi:10.1371/journal.pone.0066145

Abstract

We employed whole exome sequencing to investigate three Norwegian siblings with an autosomal recessive spastic ataxia and epilepsy. All patients were compound heterozygous (c.13352T>C, p.Leu4451Pro; c.6890T>G, p.Leu2297Trp) for mutations in the SACS gene establishing the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The clinical features shown by our patients were typical of this disorder with the exception of epilepsy, which is a rare manifestation. This is the first report of ARSACS in Scandinavian patients and our findings expand the genetic and clinical spectrum of this rare disorder. Moreover, we show that exome sequencing is a powerful and cost-effective tool for the diagnosis of genetically heterogeneous disorders such as the hereditary ataxias.

Highlights

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations of the SACS gene, encoding sacsin, a protein that is highly expressed in neurons throughout the central nervous system [1] and apparently involved in mitochondrial fission [2]
We found that all three affected siblings had the same two novel heterozygous mutations in the SACS gene establishing them as the first cases of ARSACS in Scandinavia
Clinical Features All three patients were born after normal pregnancies and uncomplicated deliveries

Summary

Introduction

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations of the SACS gene, encoding sacsin, a protein that is highly expressed in neurons throughout the central nervous system [1] and apparently involved in mitochondrial fission [2]. The disease was first identified in individuals from the Quebec province in Canada where most cases are caused by two founder mutations (c.6594delT and c.5254C.T) [3], other mutations have been identified in this population [4]. Disease onset is commonly in early childhood, but may be later in life especially in patients originating outside Quebec. Patients may have retinal hypermyelinated fibres appearing as yellowish retinal streaks on fundoscopy, these are less common in individuals originating outside the province of Quebec [7,16]. Cerebral atrophy may occur later in life [18,19]

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