Genetic disorders of iron metabolism and chronic inflammation often evoke local iron accumulation. In Friedreich ataxia, decreased iron-sulphur cluster and heme formation leads to mitochondrial iron accumulation and ensuing oxidative damage that primarily affects sensory neurons, the myocardium, and endocrine glands. We assessed the possibility of reducing brain iron accumulation in Friedreich ataxia patients with a membranepermeant chelator capable of shuttling chelated iron from cells to transferrin, using regimens suitable for patients with no systemic iron overload. Brain magnetic resonance imaging (MRI) of Friedreich ataxia patients compared with agematched controls revealed smaller and irregularly shaped dentate nuclei with significantly (P < .027) higher H-relaxation rates R2*, indicating regional iron accumulation. A 6-month treatment with 20 to 30 mg/kg/d deferiprone of 9 adolescent patients with no overt cardiomyopathy reduced R2* from 18.3 s ؊1 (؎ 1.6 s ؊1 ) to 15.7 s ؊1 (؎ 0.7 s ؊1 ; P < .002), specifically in dentate nuclei and proportionally to the initial R2* (r ‫؍‬ 0.90). Chelator treatment caused no apparent hematologic or neurologic side effects while reducing neu- IntroductionTissue iron overload and ensuing organ damage have generally been identified with transfusional hemosiderosis and genetic hemochromatosis. 1 Liver, heart, and endocrine glands are among the most affected organs in these forms of systemic iron overload. 1 The source of tissue iron overload has been traced to plasma iron originating from enteric hyperabsorption of the metal and/or enhanced red cell destruction. The labile forms of plasma iron (LPI) that appear as transferrin become saturated, permeate into particular cell types by unregulated mechanisms, and cause labile iron pools to raise and challenge cellular antioxidant capacities. 2 However, in chronic inflammation 3 and in various genetic disorders, 4 iron accumulates in particular cell types attaining toxic levels, even in the absence of circulating LPI and often even in iron-deficient plasma. In Friedreich ataxia (FA), an expansion of a GAA repeat in the first intron of the nuclear encoded frataxin gene 5,6 results in underexpression of a mitochondrial protein involved in the assembly of iron-sulphur cluster proteins (ISPs) and/or in protecting mitochondria from iron-mediated oxidative damage. 7 The defective ISP formation that causes a combined aconitase and respiratory chain deficiency (complex I-III) leads in turn to mitochondrial accumulation of labile iron 8,9 and ensuing oxidative damage in brain, heart, and endocrine glands. However, the pathophysiologic role of mitochondrial iron accumulation in oxidative damage found in FA 5,9 and other neurologic disorders [10][11][12][13] has not been resolved.In analogy to transfusional iron overload, histopathologic and magnetic resonance imaging (MRI) studies of FA patients have shown that iron accumulates not only in the heart but also in the spinocerebellar tracts (dentate nuclei) and spinal cord. 10 Those and othe...

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