Friedreich's ataxia and iron metabolism

The possible causes of abnormal iron metabolism in patients with Friedreich 's ataxia are considered. Reduced expression of a frataxin homologue in yea st is associated with mitochondrial iron accumulation at the expense of cyt osolic iron, and the same phenomenon can be demonstrated in these patients. A decrease in cytosolic iron causes the expression of a high-affinity iron -uptake protein, and therefore Friedreich's ataxia can be considered to be a disease of abnormal intracellular iron distribution. Friedreich's ataxia is of autosomal recessive inheritance, and the gene associated with it has been mapped to chromosome 9. This encodes the protein frataxin which regula tes mitochondrial iron transport. The commonest mutation causing this disor der is an expanded GAA repeat in the gene for this protein. Different point mutations may account for some of the variations in the phenotypic feature s that are often found, and these variations are discussed. These findings have raised therapeutic possibilities in a condition for which previously t here was no specific treatment. There are intracellular enzymes which are v ery sensitive to injury by oxygen-free radicals. Treatment has therefore be en tried with ibebenone which acts as a free-radical scavenger, with some e vidence of improvement. Iron chelating agents, such as deferoxamine, have a lso been given, but the finding of normal serum iron and ferritin casts dou bt on the rationale of this. However the finding that the accumulation of i ron in the mitochondria of the cells in patients with this form of ataxia w ill cause oxidative stress and cell death, gives hope for more effective tr eatment in the future, possibly with gene therapy. (C) 2000 Elsevier Scienc e B.V. All rights reserved.