Friedreich's ataxia (FA) is an autosomal recessive disease characterized by progressive neurological disability, cardiomyopathy, and increased risk of diabetes mellitus (Pandolfo, 2003). The disease, which currently has no treatment, affects roughly 1 in 50,000 people. The first symptoms usually appear in childhood, but age of onset may vary from infancy to adulthood. Atrophy of sensory and cere-bellar pathways causes ataxia, dysarthria, fixation instability, deep sensory loss and loss of tendon reflexes. Corticospinal degeneration leads to muscular weakness and extensor plantar responses. A hypertrophic cardio-myopathy may contribute to disability and cause premature death. Kyphoscoliosis and pes cavus are common.

The FA gene (FRDA) encodes a small mitochondrial matrix protein, frataxin, that is highly conserved in evolution. FA is caused by a so far unique mutation mechanism: the expansion of an intronic GAA triplet repeat sequence. Most patients are homozygous for expanded GAA repeats, rare patients are heterozygous for an expanded repeat and a point mutation affecting the frataxin coding sequence. In all cases, FA patients have a profound but not complete frataxin deficiency, with a small residual amount of normal protein (Campuzano, 1996).

Most of our initial knowledge about the functional role of frataxin came from the investigation of yeast cells in which the frataxin homolog gene (YFH1) was deleted (Babcock, 1997). A mouse model of FA was difficult to generate because complete loss of frataxin causes early embryonic lethality. Viable mouse models have been so far obtained only through a conditional gene targeting approach (Puccio, 2001).

These investigation have unequivocally revealed that frataxin deficiency leads to loss of function of Fe-S center containing enzymes (in particular respiratory complexes

1, II and III, and aconitase), excessive free radical production in mitochondria and progressive iron accumulation in these organelles. Ongoing biochemical and structural studies are aimed to understand the specific function of the protein.

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