A NovelGBA2Gene Missense Mutation in Spastic Ataxia

Abstract

SummaryAutosomal recessive cerebellar ataxias (ARCA) encompass a heterogeneous group of rare diseases that affect the cerebellum, the spinocerebellar tract and/or the sensory tracts of the spinal cord. We investigated a consanguineous Cypriot family with spastic ataxia, aiming towards identification of the causative mutation. Family members were clinically evaluated and studied at the genetic level. Linkage analysis at marker loci spanning known ARCA genes/loci revealed linkage to the APTX locus. Thorough investigation of the APTX gene excluded any possible mutation. Whole genome linkage screening using microsatellite markers and whole genome SNP homozygosity mapping using the Affymetrix GenomeWide Human SNP Array 6.0 enabled mapping of the disease gene/mutation in this family to Chromosome 9p21.1-p13.2. Due to the large number of candidate genes within this region, whole-exome sequencing of the proband was performed and further analysis of the obtained data focused on the mapped interval. Further investigation of the candidate variants resulted in the identification of a novel missense mutation in the GBA2 gene. GBA2 mutations have recently been associated with hereditary spastic paraplegia and ARCA with spasticity. We hereby report a novel GBA2 mutation associated with spastic ataxia and suggest that GBA2 mutations may be a relatively frequent cause of ARCA.

Inhibition of β-Glucocerebrosidase Activity Preserves Motor Unit Integrity in a Mouse Model of Amyotrophic Lateral Sclerosis

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GBA2 Mutations Cause a Marinesco-Sjögren-Like Syndrome: Genetic and Biochemical Studies

“…The clinical syndrome associated with GBA2 mutations was characterized either as an autosomal recessive cerebellar ataxia (ARCA) with spasticity or complicated hereditary spastic paraplegia (HSP) with ataxia: the latter is also known as spastic paraplegia 46 [ SPG46 (MIM #614409)] [2,3]. Additional features include cataracts, peripheral neuropathy, skeletal deformities, mild to moderate mental impairment and hearing loss [1,2,4,5]. …”

Transition of Thalassaemia and Friedreich ataxia from fatal to chronic diseases

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