PHENOTYPE CORRELATION AND INTERGENERATIONAL DYNAMICS OF THE FRIEDREICH ATAXIA GAA TRINUCLEOTIDE REPEAT

The Friedreich ataxia (FA) mutation has recently been identified as an unstable trinucleotide GAA repeat present 7-22 times in the normal po pulation but amplified as many as >1,000 times in FA. Since it is an a utosomal recessive disease, FA does not show typical features observed in other dynamic mutation disorders, such as genetic anticipation. We have analyzed the GAA repeat in 104 FA patients and 163 carrier relat ives previously defined by linkage analysis. The GAA expansion was det ected in all patients, most (94%) of them being homozygous for the mut ation. We have demonstrated that clinical variability in FA is related to the size of the expanded alleles: milder forms of the disease-late -onset FA and FA with retained reflexes-are associated with shorter ex pansions, especially with the smaller of the two expanded alleles. Abs ence of cardiomyopathy is also associated with shorter alleles. Dynami cs of the GAA repeat has been investigated in 212 parent-offspring pai rs. Meiotic instability showed a sex bias: paternally transmitted alle les tend to decrease in a linear way that depends on the paternal expa nsion size, whereas maternal alleles can either increase or decrease. A different pattern of intergenerational variation was also observed, depending on the genetic status of the sib: patients had shorter expan sions than were seen in heterozygous carriers. This finding has been i nterpreted as a postzygotic event. Finally, we have observed that the size of the expansion remains constant in the population through carri ers.