Identification and sizing of the GAA trinucleotide repeat expansion of Friedreich's ataxia in 56 patients. Clinical and genetic correlates

Abstract

Fifty-six patients with a clinical diagnosis of Friedreich's ataxia were investigated for the GAA trinucleotide repeat expansion recently found within the gene X25 on chromosome 9. All 56 were found to be homozygous for the expansion, with all but two patients having alleles of differing sizes. The expansion size ranged from 2 to 5 kb, with normal alleles around 1.5 kb. Sizing of the single copy of the expansion in eight sets of parents revealed marked instability in the transmission of the expansion, with both increases and decreases in allele size seen. In Friedreich's ataxia patients there was a significant inverse correlation seen between the average of the two expansion sizes and age of onset of symptoms. The GAA repeat expansion was found in the homozygous state in atypical cases of Friedreich's ataxia, such as older age of onset, preservation of lower limb reflexes and cardiac presentations. In three families the father had onset of a spinocerebellar ataxia as an adult, and in two the possibility of partial expression in heterozygote carrier fathers has been raised. More importantly, the,history of an ataxic syndrome in a parent does not exclude the diagnosis of Friedreich's ataxia in the offspring, and tests for the expansion should be carried out. The third family with an affected father conforms to previously described 'pseudodominant' inheritance.