Incidence of dominant spinocerebellar and Friedreich triplet repeats among361 ataxia families

Objective: To determine the incidence of spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7 and Friedreich's ataxia (FA) among a large panel of atax ia families. Background. The ataxias are a clinically and genetically heter ogeneous group of neurodegenerative diseases that variably affect the cereb ellum, brainstem, and spinocerebellar tracts. Trinucleotide repeat expansio ns have been shown to be the mutational mechanism for five dominantly inher ited SCAs as well as FA. Methods: We collected DNA samples and clinical dat a from patients representing 361 families with adult-onset ataxia of unknow n etiology. Patients with a clinical diagnosis of FA were specifically excl uded from our collection. Results: Among the 178 dominant kindreds, we foun d SCA1 expansion at a frequency of 5.6%, SCA2 expansion at a frequency of 1 5.2%, SCA3 expansion at a frequency of 20.8%, SCA6 expansion at a frequency of 15.2%, and SCA7 expansion at a frequency of 4.5%. FA alleles were found in 11.4% of apparently recessive and 5.2% of apparently sporadic patients. Among these patients the repeat sizes for one or both FA alleles were rela tively small, with sizes for the smaller allele ranging from 90 to 600 GAA repeats. The clinical presentation for these patients is atypical for FA, w ith one or more of the following characteristics: adult onset of disease, r etained tendon reflexes, normal plantar response, and intact or partially i ntact sensory perceptions. Conclusions: Pathogenic trinucleotide repeat exp ansions were found among 61% of the dominant kindreds. Among patients with apparently recessive or negative family histories of ataxia, 6.8% and 4.4% tested positive for a CAG expansion at one of the dominant loci, and 11.4 a nd 5.2% of patients with apparently recessive or sporadic forms of ataxia h ad FA expansions. Because of the significant implications that a dominant v ersus recessive inheritance pattern has for future generations, it is impor tant to screen patients who do not have a clearly dominant inheritance patt ern for expansions at both the FA and the dominant ataxia loci.