Mutations in SACS cause atypical and late-onset forms of ARSACS.
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.
Baets
J
J
Neurogenetics Group, University Hospital Antwerpen (UZA), Antwerpen, Belgium.
Deconinck
T
T
Smets
K
K
Goossens
D
D
Van den Bergh
P
P
Dahan
K
K
Schmedding
E
E
Santens
P
P
Rasic
V Milic
VM
Van Damme
P
P
Robberecht
W
W
De Meirleir
L
L
Michielsens
B
B
Del-Favero
J
J
Jordanova
A
A
De Jonghe
P
P
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
D006360:Heat-Shock Proteins; C404403:SACS protein, human