title: ARSACS in the Dutch population: a frequent cause of early-onset cerebellar ataxia.
abstract: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS: MIM 270550) is a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. This disorder, considered to be rare, was first described in the late seventies among French Canadians in the isolated Charlevoix-Saguenay region of Quebec. Nowadays, it is known that the disorder is not only limited to this region but occurs worldwide. Our objective was to identify cases of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) in Dutch patients with recessive early-onset cerebellar ataxia by sequencing the complete SACS gene. In a Dutch cohort of 43 index patients with ataxia onset before age 25, we identified 16 index patients (total 23 patients) with mutations in the SACS gene. Nine of them had homozygous mutations, and seven of them had compound heterozygous mutations. Retrospectively, the phenotype of patients carrying mutations was remarkably uniform: cerebellar ataxia with onset before age 13 years, lower limb spasticity and sensorimotor axonal neuropathy, and cerebellar (vermis) atrophy on magnetic resonance imaging, consistent with the core ARSACS phenotype previously described. The high rate of mutations (37%) identified in this cohort of Dutch patients suggests that ARSACS is substantially more frequent than previously estimated. We predict that the availability of SACS mutation analysis as well as an increasing awareness of the characteristic ARSACS phenotype will lead to the diagnosis of many additional patients, possibly even at a younger age.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. S.Vermeer@antrg.umcn.nl
authors.forename: Sascha
authors.initials: S
authors.lastname: Vermeer
authors.forename: Rowdy P P
authors.initials: RP
authors.lastname: Meijer
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Pijl
authors.forename: Janneke
authors.initials: J
authors.lastname: Timmermans
authors.forename: Johannes R M
authors.initials: JR
authors.lastname: Cruysberg
authors.forename: Maaike M
authors.initials: MM
authors.lastname: Bos
authors.forename: Helenius J
authors.initials: HJ
authors.lastname: Schelhaas
authors.forename: Bart P C
authors.initials: BP
authors.lastname: van de Warrenburg
authors.forename: Nine V A M
authors.initials: NV
authors.lastname: Knoers
authors.forename: Hans
authors.initials: H
authors.lastname: Scheffer
authors.forename: Berry
authors.initials: B
authors.lastname: Kremer
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005808:Genes, Recessive; D006360:Heat-Shock Proteins / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D009154:Mutation; D009426:Netherlands; D010641:Phenotype; D012189:Retrospective Studies; D020754:Spinocerebellar Ataxias / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D006360:Heat-Shock Proteins; C404403:SACS protein, human