Clinical, biochemical and molecular genetic correlations in Friedreich's ataxia

Friedreich's ataxia (FRDA) is an autosomal recessive disorder with a freque ncy of 1 in 50 000 live births. In 97% of patients it is caused by the abno rmal expansion of a GAA repeat in intron 1 of the FRDA gene on chromosome 9 , which encodes a 210 amino acid protein called frataxin, Frataxin is widel y expressed and has been localized to mitochondria although its function is unknown. We have investigated mitochondrial function, mitochondrial DNA le vels, aconitase activity and iron content in tissues from FRDA patients. Th ere were significant reductions in the activities of complex I, complex II/ III and aconitase in FRDA heart. Respiratory chain and aconitase activities were decreased although not significantly in skeletal muscle, but were nor mal in FRDA cerebellum and dorsal root ganglia, although there was a mild d ecrease in aconitase activity in the latter. Mitochondrial DNA levels were reduced in FRDA heart and skeletal muscle, although in skeletal muscle this was paralleled by a decline in citrate synthase activity. Increased iron d eposition was seen in FRDA heart, liver and spleen in a pattern consistent with a mitochondrial location. The iron accumulation, mitochondrial respira tory chain and aconitase dysfunction and mitochondrial DNA depletion in FRD A heart samples largely paralleled those in the yeast YFH1 knockout model, suggesting that frataxin may be involved in mitochondrial iron regulation o r iron sulphur centre synthesis. However, the severe deficiency in aconitas e activity also suggests that oxidant stress may induce a self-amplifying c ycle of oxidative damage and mitochondrial dysfunction, which may contribut e to cellular toxicity.