The increasing number of SCA loci: Contributes from classical genetics and new genomics

Hereditary ataxias comprise a clinically and genetically heterogeneous group of rare neurological disorders (prevalence of ~6/100,000). Autosomal dominant forms, known as spinocerebellar ataxias (SCAs), will be the focus of this review. SCAs are characterized by progressive degeneration of the cerebellum and spinocerebellar tracts, associated with a variable combination of signs of central and peripheral nervous system dysfunction. Poor balance with falls, incoordination, postural or kinetic tremor, dysarthria and dysphagia, diplopia, among other clinical deficits, constitute typical signs of these presently incurable disorders. Due to clinical overlap, they cannot be distinguished solely by clinical criteria, thus demanding a subtype confirmation by molecular diagnosis. To date, about 35 SCA loci have been mapped and 22 genes have been identified, but this list is expected to rapidly grow, since the percentage of SCA cases of unknown cause is still enormous (up to ~50%). Different types of mutations and molecular mechanisms have been associated with SCAs. Expansions of coding CAG tracts in specific genes represent the most frequent cause (responsible for "polyglutamine" ataxias, e.g., SCA1-3), but non-coding repeat expansions and conventional mutations (namely deletions, missense, nonsense, and splice site mutations) also account for several SCA subtypes (e.g., SCA8 and SCA36, SCA5 and SCA35, respectively). On what concerns genotype-phenotype correlations, an inverse correlation between the size of the CAG tract and the age at onset is well known for "polyglutamine" ataxias. However, this kind of knowledge is very scarce for other the subtypes of SCAs. After reviewing all the above mentioned topics, we will also discuss contributes from classical gene mapping methods (e.g., linkage analysis) as well as promising but challenging results from new genomic approaches (e.g., whole-exome sequencing), to the discovery of SCA genes and to the decoding of unknown causes. © 2012 Nova Science Publishers, Inc. All rights reserved.