BACKGROUND- Since the recognition of the inherited nature of many progressive ataxic syndromes by Friedreich and Marie in the last century, clinicians and pathologists have tried to understand the complexity of the clinical features and the underlying pathogenesis of these disorders. However, it has taken the power of reverse genetics within the last decade to identify the numerous genetic abnormalities that underlie such syndromes and point a way toward true understanding of the causes of neuronal death. There is increasing hope for useful therapeutic measures.
REVIEW SUMMARY- An orderly approach to patients with progressive ataxic syndromes can result in the identification of the specific disorder involved in many instances and the exclusion of disorders that can mimic inherited ataxias as well as treatable diseases. Within the last decade, various inherited ataxias have been linked to more than a dozen different chromosomal loci and, in most, the gene mutation itself has been identified, allowing simple molecular tests for precise genotypic diagnosis. Although the clinical features of these illnesses overlap to such a degree that the identification of the underlying genotype from clinical or pathological features alone may be often difficult, the broad genotype-phenotype correlations summarized in this article will allow a more rational approach to the genetic tests available. The management of these disorders remains supportive and symptomatic, but the identification of the genotype allows better genetic counseling and the possibility of predictive testing. There is also increasing understanding of the possible pathogenesis of selective neuronal degeneration in the inherited ataxias.
CONCLUSIONS- There has been a virtual explosion in our knowledge regarding the gene mutations responsible for the inherited ataxias. However, a number of additional genotypes remain unidentified. Understanding of the molecular pathogenesis of these disorders may rapidly lead to useful treatment options.