title: Mutations in SACS cause atypical and late-onset forms of ARSACS.
abstract: BACKGROUND
  Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a complex neurodegenerative disorder caused by mutations in SACS. The phenotype consists of a childhood-onset triad of cerebellar ataxia, peripheral neuropathy, and pyramidal tract signs.
  
  
  OBJECTIVE
  To provide more insight into the prevalence of SACS mutations and the variability of the associated phenotype.
  
  
  METHODS
  Mutation screening of SACS by direct sequencing and multiplex amplicon quantification for detection of intragenic copy number variations in a cohort of 85 index patients with phenotypes suggestive for ARSACS. Additional short tandem repeat (STR) marker analysis was performed for haplotype sharing.
  
  
  RESULTS
  In 11 families,18 new SACS mutations were found (12.9% of total cohort). Five patients displayed onset ages in adulthood, a feature not known to be associated with ARSACS. The remaining index patients displayed a classic early onset phenotype. Initial phenotypic presentation was atypical in several patients, obscuring the clinical diagnosis. A founder mutation in SACS was identified in 3 Belgian families. In one isolated patient, an intragenic SACS deletion of exons 3-5 was detected. Partial SACS deletions were not previously described.
  
  
  CONCLUSIONS
  In this study, we enlarge the ARSACS phenotype and the underlying genetic spectrum of SACS mutations. Patients with ARSACS are more common than previously known and risk underdiagnosis due to late onset age and unusual presentation.
authors.affiliation: Neurogenetics Group, University Hospital Antwerpen (UZA), Antwerpen, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Baets
authors.forename: T
authors.initials: T
authors.lastname: Deconinck
authors.forename: K
authors.initials: K
authors.lastname: Smets
authors.forename: D
authors.initials: D
authors.lastname: Goossens
authors.forename: P
authors.initials: P
authors.lastname: Van den Bergh
authors.forename: K
authors.initials: K
authors.lastname: Dahan
authors.forename: E
authors.initials: E
authors.lastname: Schmedding
authors.forename: P
authors.initials: P
authors.lastname: Santens
authors.forename: V Milic
authors.initials: VM
authors.lastname: Rasic
authors.forename: P
authors.initials: P
authors.lastname: Van Damme
authors.forename: W
authors.initials: W
authors.lastname: Robberecht
authors.forename: L
authors.initials: L
authors.lastname: De Meirleir
authors.forename: B
authors.initials: B
authors.lastname: Michielsens
authors.forename: J
authors.initials: J
authors.lastname: Del-Favero
authors.forename: A
authors.initials: A
authors.lastname: Jordanova
authors.forename: P
authors.initials: P
authors.lastname: De Jonghe
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D006360:Heat-Shock Proteins; C404403:SACS protein, human