Journal
NEUROLOGY
Volume 75, Issue 13, Pages 1181-1188Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0b013e3181f4d86c
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Funding
- University of Antwerp
- Fund for Scientific Research (FWO-Flanders)
- Medical Foundation Queen Elisabeth (GSKE)
- Association Belge contre les Maladies Neuromusculaires (ABMM)
- Belgian Federal Science Policy Office (BELSPO)
- Flemish Government
- E. von Behring Chair in Neuromuscular and Neurodegenerative Disorders
- NeuroNova
- Trophos
- Teva Pharmaceutical Industries Ltd.
- Packard Center for ALS Research
- Thierry Latran Foundation
- Fund for Scientific Research Flanders
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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. Neurology (R) 2010; 75: 1181-1188
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