Molecular Genetics of Hereditary Spinocerebellar Ataxia

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Abstract
The autosomal dominant cerebellar ataxias are a heterogeneous group of neurodegenerative disorders, characterized by progressive ataxia variably associated with other neurological signs and caused by a progressive degeneration of the cerebellum and brainstem.1 Advances in the genetic understanding of these diseases have identified at least 21 genetically distinct subtypes of spinocerebellar ataxias (SCAs): SCA1 through SCA8, SCA10 through SCA19, SCA21, SCA22 (SCA9 and SCA20 symbols have been reserved but not yet assigned), and fibroblast growth factor 14–SCA (FGF14-SCA). In addition, the group includes an ataxia with a complex phenotype—dentatorubral-pallidoluysian atrophy (DRPLA)—and 2 types of episodic ataxia (EA1 and EA2) (available at: http://www.geneclinics.org and http://www.neuro.wustl.edu/neuromuscular/ataxia). In 12 genetic variants of familial ataxias (SCA1-SCA3, SCA6-SCA8, SCA10, SCA12, SCA14, SCA17, FGF14-SCA, and DRPLA), the disease gene has been identified.2-8 In most cases (SCA1-SCA3, SCA6, SCA7, SCA17, and DRPLA), the disorder is caused by expanded CAG repeats that are translated into polyglutamines, or by expanded trinucleotide/pentanucleotide repeats occurring in the promoter (CAG in SCA12), in the intron (ATTCT in SCA10), or in a noncoding RNA (CTG in SCA8).

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