Novel, complex interruptions of the GAA repeat in small, expanded alleles of two affected siblings with late-onset Friedreich ataxia

Abstract

Friedreich ataxia (FA) is an autosomal recessive disorder associated with expanded GAA repeats in intron 1 of the FRDA gene. Two siblings presented with a mild form of FA at >60 years of age. Both had a large expansion (>600 repeats) and a small expansion (120 repeats) by long-range PCR. Sequence analysis of the small allele revealed multiple, complex interruptions in the GAA repeat. These 2 patients presented later than predicted from their allele size alone, when compared with a large cohort of FA patients. Accounting for the interruptions in the GAA repeat, though, did not make the age of onset consistent with that noted in other patients. Three additional patients with late onset FA and small expanded alleles also exhibited interrupted GAA repeats that were not associated with inappropriately late onset. Our observations suggest that interrupted GAA repeats do not clearly impact the age of onset in FA.