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Molecular Genetics and Inherited Ataxias: Redefining Phenotypes and Pathogenesis

Department of Neurology, Neurogenetics Program, University of California, Los Angeles, School of Medicine, Los Angeles, California

Daniel H. Geschwind

Department of Neurology, Neurogenetics Program, University of California, Los Angeles, School of Medicine, Los Angeles, California, dhg{at}ucla.edu

Genetic research on inherited ataxias has transformed our understanding of these conditions. The availability of genetic testing has shown that a classification based solely on clinical and pathologic findings is not adequate, and molecular genetic analysis is now mandatory for diagnostic accuracy and prognostic purposes. The epidemiology of these disorders is also being rewritten under the light of molecular genetic analysis. In this review, we discuss some of the recent advances on the hereditary cerebellar degenerations without a known metabolic defect, focusing on genotype-phenotype correlations in the spinocerebellar ataxias (SCAs) and Friedreich’s ataxia (FRDA). Three main biochemical pathways seem to be involved in the pathogenesis of inherited ataxias: 1) expansion of (CAG)n repeats within genes coding for polyglutamine-containing proteins (SCAs); 2) impairment of mitochondrial function (FRDA); and 3) dysfunction of ion channels (episodic ataxias, EA1, EA2). It is likely that many neurodegenerative conditions will prove to share basic molecular mechanisms, and therefore, data provided by the investigation of a particular disease is likely to be relevant to our global understanding of spinocerebellar degenerations and other degenerative disorders of the nervous system. A better knowledge of the molecular and cellular routes leading to neurodegeneration will provide a key to the design of rational therapies.

Key Words: Spinocerebellar ataxia • Friedreich’s ataxia • Genetics • Pathogenesis • Trinucleotide repeats

The Neuroscientist, Vol. 6, No. 6, 465-474 (2000)
DOI: 10.1177/107385840000600609


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