Selective iron chelation in Friedreich ataxia: biologic and clinical implications

Abstract

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...

Hemochromatosis

“…The signs and symptoms of the disorder (mainly due to neurological impairment) derive from decreased expression of the protein frataxin, which chaperones iron for iron-sulfur cluster biogenesis and detoxifies iron in the mitochondrial matrix. Because of the local accumulation of iron, iron chelators seem effective in removing and relocating iron, as suggested by a recent study 27 (Table 4).…”

The MCK mouse heart model of Friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation

“…Recently, a small clinical trial suggested that the chelator deferiprone may have favorable effects on preventing the neurological symptoms of FA (28). However, the role of Fe chelation in producing this outcome was difficult to ascertain, as de- There is increased TfR1 and decreased ferritin and ferroportin1 in the mutant relative to the WT mice.…”

Neuroimaging Features of Neurodegeneration with Brain Iron Accumulation

“…15 Deferiprone has been shown to reverse iron deposition in Friedreich ataxia, associated with an appreciable decrease in iron content as measured by MR imaging. 12 It remains to be seen whether this agent will have a similar effect in NBIA and whether decreasing the brain iron burden will affect patients' clinical courses.…”

“…MR imaging techniques that are not yet in widespread clinical use include quantitative T2 mapping sequences, which may be useful in quantifying iron content. 12 Most interesting, iron deposition detectable by MR imaging may precede the development of clinical symptoms, as evidenced by the identification of an "eye-of-the-tiger" in presymptomatic mutation-positive siblings of children affected by PKAN. 13 In contrast, children with INAD may develop iron deposition later in their disease course or not at all.…”