Genotype and phenotype analysis of Friedreich's ataxia compound heterozygous patients

Friedreich's ataxia is caused by mutations in the FRDA gene that encodes fr ataxin, a nuclear-encoded mitochondrial protein. Most patients are homozygo us for the expansion of a GAA tripler repeat within the FRDA gene, but a fe w patients show compound heterozygosity for a point mutation and the GAA-re peat expansion. We analyzed DNA samples from a cohort of 241 patients with autosomal recessive or isolated spinocerebellar ataxia for the GAA triplet expansion. Patients heterozygous for the GAA expansion were screened for po int mutations within the FRDA coding region. Molecular analyses included th e single-strand conformation polymorphism analysis, direct sequencing, and linkage analysis with FRDA locus flanking markers. Seven compound heterozyg ous patients were identified. In four patients, a point mutation that predi cts a truncated frataxin was detected. Three of them associated classic ear ly-onset Friedreich's ataxia with an expanded GAA allele greater than 800 r epeats. The other patient associated late-onset disease at the age of 29 ye ars with a 350-GAA repeat expansion. In two patients manifesting the classi cal phenotype, no changes were observed by single-strand conformation polym orphism (SSCP) analysis. Linkage analysis in a family with two children aff ected by an ataxic syndrome, one of them showing heterozygosity for the GAA expansion, confirmed no linkage to the FRDA locus. Most point mutations in compound heterozygous Friedreich's ataxia patients are null mutations. In the present patients, clinical phenotype seems to be related to the GAA rep eat number in the expanded allele. Complete molecular definition in these p atients is required fur clinical diagnosis and genetic counseling.