genes and who were found to be negative. 1 In this group of 122 patients, we identified 5 patients with an FMR1 premutation and in 4 of them a definite diagnosis of fragile Xassociated tremor/ataxia syndrome (FXTAS) could be made, based on the proposed diagnostic criteria for FXTAS. We proposed based on these results to include FMR1 analysis in the molecular diagnostic workup in the group of older male ataxia patients.
Earlier this year, Hagerman and colleagues reported five female carriers of the FMR1 premutation who also presented with the cardinal symptoms of tremor and ataxia and thus proving the occurrence of FXTAS in the female population. 2 This prompted us to perform FMR1 premutation screening in female subjects, referred to us for testing of the spinocerebellar ataxia genes and who were found to be negative for the expansion (SCA1, 2, 3, 6, 7). We selected all female probands with ataxia who were 50 years or older at time of referral. In this group of 131 females, we did not detect a single ataxia patient with an FMR1 premutation. All repeat alleles were within the range of 10 to 49. Compared with our study in male subjects, with the same ascertainment and referral strategy, this result is significantly different but not surprising. Previous reports already suggested that FXTAS occurs less frequently in female subjects than in male subjects and that the phenotype is milder with older age at onset. 3,4 The presence of a second normal allele and random X-inactivation might explain this milder phenotype, that may not be severe enough to warrant clinical attention. 5 Moreover, it is likely that female premutation carriers are identified at an earlier age because of their risk of their premutation allele causing a full-mutation allele and an affected child and because of the increased occurrence of premature ovarian failure. Therefore, should one screen for the FMR1 premutation in the older females presenting with ataxia?
In a similar study, Zu Β¨hlke and colleagues recently identified in a group of 241 females, after exclusion of SCA expansions, a 73-year-old woman with 84 repeats and FXTAS. 6 Taking together their and our results, it is clear that the FMR1 premutation is not a major cause of late-onset ataxia in female subjects but should be excluded especially when additional FXTAS symptoms are present. Surprisingly, in their study none of the 269 male patients was found to be affected by FXTAS. These results probably reflect a difference in referral policy and ascertainment. Nevertheless, we believe that further FMR1 screening in the late-onset ataxia population is needed to obtain a better insight in the prevalence of this disorder, as well as to better delineate the differences in clinical course, age of onset, and allele sizes, in the female and the male FXTAS population. The important counseling aspects and the identification of several new, mostly female, fragile X patients in the families of the five identified FXTAS male subjects further justifies this screening.