These authors contributed equally to this work.
A novel SACS mutation results in non-ataxic spastic paraplegia and peripheral neuropathy
Article first published online: 25 JUN 2013
© 2013 The Author(s) European Journal of Neurology © 2013 EFNS
European Journal of Neurology
Volume 20, Issue 11, pages 1486–1491, November 2013
How to Cite
Gregianin, E., Vazza, G., Scaramel, E., Boaretto, F., Vettori, A., Leonardi, E., Tosatto, S. C. E., Manara, R., Pegoraro, E. and Mostacciuolo, M. L. (2013), A novel SACS mutation results in non-ataxic spastic paraplegia and peripheral neuropathy. European Journal of Neurology, 20: 1486–1491. doi: 10.1111/ene.12220
- Issue published online: 10 OCT 2013
- Article first published online: 25 JUN 2013
- Manuscript Accepted: 16 MAY 2013
- Manuscript Received: 12 DEC 2012
- University of Padova. Grant Number: CPDA090313/09
- ARSACS ;
- linkage analysis;
- mutation identification;
- peripheral neuropathy;
- spastic paraplegia
Background and purpose
Mutations in the SACS gene are commonly associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a complex neurodegenerative disorder characterized by progressive degeneration of the cerebellum and spinal cord tracts. The aim of this study was to identify the genetic cause of the disease in an Italian family with spastic paraplegia and peripheral neuropathy.
Affected subjects were subjected to a comprehensive neurological examination including electromyography and brain magnetic resonance imaging. Genetic studies included exclusion of known disease genes, genome-wide linkage analysis using high density single nucleotide polymorphism genotyping and candidate gene sequencing.
Molecular analyses revealed a novel missense mutation in the SACS gene (c.11,104A>G) occurring in a homozygous state in patients and absent in 700 Italian control chromosomes. The mutation led to the amino acid substitution p.Thr3702Ala in the sacsin protein, in a possible protein−protein interaction site of UBE3A binding domain.
This study broadens the genetic spectrum of SACS mutations and expands the clinical ARSACS phenotype suggesting that the SACS gene can be considered in patients with non-canonical ARSACS clinical presentations.