Friedreich's ataxia is the most frequent inherited ataxia in Caucasians. It is 
caused by deficiency of frataxin, a highly conserved nuclear-encoded protein 
localized in mitochondria. The DNA abnormality found in 98% of Friedreich's 
ataxia chromosomes is the unstable hyperexpansion of a GAA triplet repeat in the 
first intron of the frataxin gene. Most patients are homozygous for this repeat 
expansion. The expanded GAA repeat causes frataxin deficiency because it 
interferes with the transcription of the gene by adopting a non-B (probably 
triple helical) structure. Longer repeats cause a more profound frataxin 
deficiency and are associated with earlier onset and increased 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 fulfill the Friedreich's 
ataxia diagnostic criteria are homozygous for expanded alleles at the 
Friedreich's ataxia locus. Late age of onset, retained tendon reflexes, and lack 
of pyramidal signs are among the atypical features observed in some patients 
with a positive molecular test. Yeast cells deficient in the frataxin homologue 
accumulate iron in mitochondria and show increased sensitivity to oxidative 
stress. This suggests that Friedreich's ataxia is caused by mitochondrial 
dysfunction and free radical toxicity, with consequent mitochondrial damage, 
axonal degeneration, and cell death.