[Clinical feature and molecular genetics of hereditary spinocerebellar ataxia]

Hereditary spinocerebellar ataxia (SCA) is a cluster of heterogeneous disorders. At now, 29 dominant loci have been assigned. Responsible genes and mutations are determined in at least 14 of them. In recessive and X-linked SCAs, 15 loci have been mapped, and mutation in each gene is determined by 6 disorders. Molecular mechanism of those SCAs are variable. Generally, deletion, insertion, or substitution in a gene modifies the primary structure of mRNA, subsequently resulting in disturbance of transcription or in translation of mutant proteins showing loss-of-function or dominant negative effect. Large expansion of tandem repeat in promotor region or intron suppress translation of the gene, thus causing similar effect. Expansion of (CAG)n in coding exon is translated into proteins containing elongated poly-Q. Since the poly-Q fragment is cytotoxic, this kind of mutation causes protein toxic gain-of-function. In addition, RNA toxic gain-of-function mechanism recently gains attention as a new molecular mechanism of SCA8 and SCA10. Clinically, dominant SCA with dynamic mutation shows variable onset of age, severity, and variation of clinical phenotypes. Among this clinical complexity, vocal cord abductor paralysis in SCA1, familial parkinsonism in SCA2, vestibular dysfunction and axonal neuropathy in MJD, and axial myoclonus in SCA14, are reviewed for potential usefulness in clinical practice.