title: 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 membrane-permeant 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 age-matched 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 neuropathy and ataxic gait in the youngest patients. To our knowledge, this is the first clinical demonstration of chelation removing labile iron accumulated in a specific brain area implicated in a neurodegenerative disease. The use of moderate chelation for relocating iron from areas of deposition to areas of deprivation has clinical implications for various neurodegenerative and hematologic disorders.
authors: Pediatric Radiology Unit, Institut National de la Santé et de la Recherche Médicale, Hôpital Necker Enfants Malades, Université Paris V René Descartes, Paris, France.
authors: Nathalie
authors: N
authors: Boddaert
authors: Kim Hanh
authors: KH
authors: Le Quan Sang
authors: Agnès
authors: A
authors: Rötig
authors: Anne
authors: A
authors: Leroy-Willig
authors: Serge
authors: S
authors: Gallet
authors: Francis
authors: F
authors: Brunelle
authors: Daniel
authors: D
authors: Sidi
authors: Jean-Christophe
authors: JC
authors: Thalabard
authors: Arnold
authors: A
authors: Munnich
authors: Z Ioav
authors: ZI
authors: Cabantchik
mesh_terms: D000293:Adolescent; D000328:Adult; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects*; D016022:Case-Control Studies; D000077543:Deferiprone; D005260:Female; D005621:Friedreich Ataxia / Q000188:drug therapy*; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008297:Male; D011728:Pyridones / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D007502:Iron Chelating Agents; D011728:Pyridones; D000077543:Deferiprone; D007501:Iron