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Blood, 1 July 2007, Vol. 110, No. 1, pp. 1-2.
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RED CELLS
Comment on Boddaert et al, page 401
Ironing out a therapy for Friedreich ataxia
Grazia Isaya
MAYO CLINIC COLLEGE OF MEDICINE
Boddaert and colleagues show the positive effects of selective iron chelation in young patients with Friedreich ataxia, a devastating inborn error of mitochondrial iron metabolism.
Never before has a therapy for Friedreich ataxia (FA) seemed more within reach. The FA gene (FRDA) was identified in 1996 and found to encode a conserved mitochondrial protein of unknown function, frataxin. In most patients, large trinucleotide repeat expansions in the first intron of the FRDA gene were further found to result in a drastic reduction in frataxin levels.1 The studies that followed led to the current understanding of the roles played by frataxin in mitochondrial iron metabolism and the main biochemical sequelae of frataxin deficiency, namely the inability to efficiently incorporate iron into iron-sulfur clusters and heme and the failure to detoxify labile iron, which together result in impaired oxidative phosphorylation and increased oxidative damage (see figure). It became clear early on that until ways to restore normal levels of frataxin were identified, the next best option for treating the disease rested upon the ability to limit the consequences of frataxin deficiency by use of mitochondria-targeted antioxidants and iron chelators. Antioxidants were first tested in FA patients in 19992 and currently represent a standard treatment for the disease, albeit with overall limited benefits. On the other end, the use of iron chelators was hampered by the potential risks of causing systemic iron depletion in a disease where iron overload and/or toxicity were seemingly limited to the mitochondria of only a few tissues (spinal cord, cerebellum, heart, endocrine pancreas). Boddaert and colleagues have now made a critical stride toward solving this conundrum by use of a membrane-permeable chelator apparently capable of shuttling excess labile iron from the mitochondria to transferrin. When administered to adolescent FA patients, this compound resulted in reduced iron accumulation in the nucleus dentatus of the cerebellum. Remarkably, in the youngest patients, iron removal was associated with improvement of neurological symptoms without obvious systemic effects. Although limited to a small group of patients, these results are extremely exciting and warrant further testing with larger clinical trials. In fact, this study reaches beyond the issue of effectiveness of selective brain iron chelation in FA and prompts the reader to ask at what time it would be most beneficial to begin such treatment. Assuming that it could be confirmed that the greatest benefit is achieved by beginning treatment as soon as possible, an argument could be made for providing newborn screening for FA. A recently published report has issued recommendations for the creation and, when appropriate, expansion of a uniform panel of conditions for which all newborns should be tested.3 Based on a series of specific criteria related to the natural history of the condition, the effectiveness of treatment, and the availability of a high-throughput screening method, a case could be made to include FA in the uniform panel once a suitable screening method has been developed and validated. Nucleic-acid–based and protein-based methods using a variety of platforms are currently under intense development and evaluation, showing great promise that cost barriers could be overcome by the introduction of new technology.4 Therefore, it is tempting to speculate that in the relatively near future there could be a suitable method to detect the FRDA repeat expansion or measure frataxin levels in the traditional blood spots collected from newborns on filter paper. The availability of an effective treatment is likely to give a strong impetus for the development of such methods.
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A reduction in the levels of frataxin leads to (1) a decrease in the biosyntheses of iron-sulfur clusters (ISC) and heme, (2) an increase in "free" iron levels, (3) a reduction in ISC repair, and (4) an inability to detoxify redox-active iron and store it in a stable form. These primary effects result in a cascade of secondary events including impaired oxidative phosphorylation (OXPHOS) and widespread oxidative damage to mitochondrial DNA, proteins, and membranes. Boddaert and colleagues have used a compound that can remove excess "free" iron from the mitochondrial matrix, thereby preventing iron toxicity without causing iron depletion. Professional illustration by Kenneth Probst.
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Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests. 
REFERENCES
- Campuzano V, Montermini L, Molto MD, et al. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996; 271:1423–1427.[Abstract]
- Rustin P, von Kleist-Retzow JC, Chantrel-Groussard K, Sidi D, Munnich A, Rotig A. Effect of idebenone on cardiomyopathy in Friedreich's ataxia: a preliminary study. Lancet 1999; 354:477–479.[CrossRef][Medline]
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- Watson MS, Mann MY, Lloyd-Puryear MA, Rinaldo P, Howell RR. Newborn screening: toward a uniform screening panel and system. Genet Med 2006; 8:1S–11S.[Medline]
[Order article via Infotrieve]
- Green NS and Pass KA. Neonatal screening by DNA microarray: spots and chips. Nat Rev Genet 2005; 6:147–151.[CrossRef][Medline]
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Related Article in Blood Online:
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Selective iron chelation in Friedreich ataxia: biologic and clinical implications
- Nathalie Boddaert, Kim Hanh Le Quan Sang, Agnès Rötig, Anne Leroy-Willig, Serge Gallet, Francis Brunelle, Daniel Sidi, Jean-Christophe Thalabard, Arnold Munnich, and Z. Ioav Cabantchik
Blood 2007 110: 401-408.
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