Friedreich ataxia: 150 years of bench and bedside studies

Friedreich ataxia is the most frequent hereditary ataxia among Caucasians. Almost invariably, the disease is caused by homozygous GAA triplet repeat expansions in the first intron of the frataxin gene, FXN, whereas point mutations or deletions in conjunction with an expanded GAA tract account for the remaining cases. The expanded intronic alleles interfere with FXN transcription, decreasing the production of normally functioning frataxin protein to 5-20% of normal. Deficient frataxin levels result in excessive mitochondrial iron accumulation, reduced iron-sulfur clusters vital for mitochondrial energy production, and increased intracellular oxidative damage. To date, no cure has emerged and treatments remain largely supportive, despite extensive ongoing research and several rationale strategies have been attempted.