Recent advances in the molecular pathogenesis of Friedreich ataxia

Friedreich ataxia, the most frequent cause of recessive ataxia, is due in m ost cases to a homozygous intronic expansion resulting in the loss of funct ion of frataxin. Frataxin is a mitochondrial protein conserved through evol ution. Yeast knock-out models and histological data from patient heart auto psies have shown that frataxin defect causes mitochondrial iron accumulatio n. Biochemical data from patient heart biopsies or autopsies have revealed a specific deficiency in the activities of aconitases and of mitochondrial iron-sulfur proteins. These results suggest that frataxin may play a role e ither in mitochondrial iron transport or in iron-sulfur cluster assembly or transport. Iron abnormalities suggest a pathogenic mechanism involving fre e radical production and oxidative stress, a process that might be sensitiv e to antioxidant therapies.