Friedreich's ataxia: Clinical aspects and pathogenesis

Friedreich's ataxia is the most frequent inherited ataxia in Caucasians, It is caused by deficiency of frataxin, a highly conserved nuclear-encoded pr otein localized in mitochondria. The DNA abnormality found in 98% of Friedr eich's ataxia chromosomes is the unstable hyperexpansion of a GAA triplet r epeat in the first intron of the frataxin gene. Most patients are homozygou s for this repeat expansion. The expanded GAA repeat causes frataxin defici ency because it interferes with the transcription of the gene by adopting a non-B (probably triple helical) structure. Longer repeats cause a more pro found frataxin deficiency and are associated with earlier onset and increas ed severity of the disease. Molecular testing has shown that the phenotypic spectrum of Friedreich's ataxia is wider than previously thought. Up to 10 % of patients with recessive or sporadic degenerative ataxia who do not ful fill the Friedreich's ataxia diagnostic criteria are homozygous for expande d alleles at the Friedreich's ataxia locus. Late age of onset, retained ten don reflexes, and lack of pyramidal signs are among the atypical features o bserved in some patients with a positive molecular test. Yeast cells defici ent in the frataxin homologue accumulate iron in mitochondria and show incr eased sensitivity to oxidative stress. This suggests that Friedreich's atax ia is caused by mitochondrial dysfunction and free radical toxicity, with c onsequent mitochondrial damage, axonal degeneration, and cell death.