In reply

Stevanin et al.1 and Worth et al.2 suggest that the reduced penetrance of SCA8 in ataxia families and the large alleles found in controls indicate that the CTG expansion may be a non-pathogenic polymorphism tightly linked to an ataxia locus. Because we isolated the CTG expansion from a single ataxia patient using RAPID cloning3,4, the likelihood that the expansion would be tightly linked to an ataxia locus by chance can be conservatively estimated as 3×10−4 to 1.5×10−5, the product of the frequency of alleles with more than 50 CTG repeats in the general population (1/100–1/500) multiplied by the portion of the human genome in a 10-cM interval (1/300, assuming 1 Mb=1 cM). To put these data1,2 in perspective, it is important to realize that whereas all affected individuals in our large family had 107–127 CTG repeats, 20 asymptomatic family members had shorter alleles of 74–101 CTG repeats3. The only inconsistency between our data and that of Stevanin et al.1 is that one of their control individuals had 107 CTG repeats. Worth et al.2 found 2 alleles among their controls with more than 107 CTG repeats. Although we did not detect alleles in this size range among our control population, we reported two asymptomatic men with alleles (260 and 300 repeats) larger than those of their four ataxic offspring. This reduced penetrance causes small families to appear to have recessive or sporadic ataxia. The presence of the adjacent (CTA)1–21 tract or sequence interruptions within the CTG tract may explain the reduced penetrance of SCA8 (refs 1,3,5).

We presented3 five lines of evidence supporting the hypothesis that the SCA8 CTG expansion causes ataxia: (i) linkage data in a single family (lod=6.8, θ=0); (ii) the biological relationship between repeat length and disease, with affected family members having longer CTG repeat tracts (mean=117) than asymptomatic carriers (mean=92 , P<10−6); (iii) the absence of alleles in the pathogenic range (107–127 CTG repeats) on 1,200 control chromosomes; (iv) a high frequency of expansions among apparently unrelated ataxia patients (8/102); and (v) the expression of SCA8 transcripts mainly in central nervous system tissue3. We believe all available data support the hypothesis that this CTG expansion is directly associated with ataxia, but that a number of issues, including reduced penetrance, gender effects, and normal and pathogenic exapnsion ranges, will require further investigation.