Dominant ataxias and Friedreich ataxia: an update

Purpose of review: The present review covers recent developments in inherited ataxias. The discovery of new loci and genes has led to improved understanding of the breadth and epidemiology of inherited ataxias. This has resulted also in more rational classification schemes. Research on identified loci has begun to yield insights into the pathogenesis of neuronal dysfunction and neurodegeneration in these diseases.

Recent findings: There are a plethora of inherited ataxias due to a variety of mutational mechanisms involving numerous loci. While ataxia and other aspects of cerebellar dysfunction are the core features of these diseases, rational classification has been impeded by the simultaneous variety of associated clinical features and considerable overlap in clinical features among diseases involving different loci. Inherited ataxias can be classified according to mode of inheritance and mechanism of mutations. Dominantly inherited ataxias (spinocerebellar ataxias) are one major group of ataxias. Spinocerebellar ataxias can be subdivided into expanded exonic CAG repeat (polyglutamine; polyQ) disorders, dominantly inherited ataxias with mutations in non-coding regions, and dominantly inherited ataxias with chromosomal localizations but unidentified loci. Another group of dominantly inherited ataxias are episodic ataxias due to ion channel mutations. Recessive ataxias constitute a more heterogeneous group due to loss-of-function effects in numerous loci. A number of these loci have now been identified. Progress has been made in investigating the pathogenesis of neuronal dysfunction/neurodegeneration in several inherited ataxias. Convergent evidence suggests that transcriptional dysregulation is an important component of neurodegeneration in polyQ disorders. Mitochondrial dysfunction is central to pathogenesis of the most common recessive ataxia, Friedreich ataxia.

Summary: Mapping of additional ataxia loci and identification of novel ataxia genes continues unabated. Genetic classification enables typology of inherited ataxias. Identification of the affected loci and the mutational mechanisms has allowed the first glimmers of understanding of the pathogenesis of several inherited ataxias.