title: Effect of idebenone on cardiomyopathy in Friedreich's ataxia: a preliminary study.
abstract: BACKGROUND
  Friedreich's ataxia is caused by a deficiency of frataxin, a protein involved in regulation of mitochondrial iron content. We have reported a combined deficiency of a Krebs-cycle enzyme, aconitase, and three mitochondrial respiratory-chain complexes in endomyocardial biopsy samples from patients with this disorder. All four enzymes share iron-sulphur cluster-containing proteins that are damaged by iron overload through generation of oxygen free radicals. We used an in-vitro system to elucidate the mechanism of iron-induced injury and to test the protective effects of various substances. On the basis of these results, we assessed the effect of idebenone (a free-radical scavenger) in three patients with Friedreich's ataxia.
  
  
  METHODS
  Heart homogenates from patients with valvular stenosis were tested for respiratory-chain complex II activity, lipoperoxidation, and aconitase activity by spectrophotometric assays, in the presence of reduced iron (Fe2+), oxidised iron (Fe3+), desferrioxamine, ascorbic acid, and idebenone. The Friedreich's ataxia patients (aged 11 years, 19 years, and 21 years) underwent ultrasonographic heart measurements at baseline and after 4-9 months of idebenone (5 mg/kg daily).
  
  
  RESULTS
  Fe2+ (but not Fe3+) decreased complex II activity and increased lipoperoxidation in heart homogenate. Addition of ascorbate or desferrioxamine increased some of the iron-induced adverse effects. Idebenone protected against these effects. In the three patients, left-ventricular mass index decreased from baseline to 4-9 months of idebenone treatment (patient 1, 145 g to 114 g; patient 2, 215 g to 151 g; patient 3, 408 g to 279 g).
  
  
  CONCLUSIONS
  Our in-vitro data suggest that both iron chelators and antioxidant drugs that may reduce iron are potentially harmful in patients with Friedreich's ataxia. Conversely, our preliminary findings in patients suggest that idebenone protects heart muscle from iron-induced injury.
authors.affiliation: Unité de Recherches sur les Handicaps Génétiques de l'Enfant (INSERM U393), Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Rustin
authors.forename: J C
authors.initials: JC
authors.lastname: von Kleist-Retzow
authors.forename: K
authors.initials: K
authors.lastname: Chantrel-Groussard
authors.forename: D
authors.initials: D
authors.lastname: Sidi
authors.forename: A
authors.initials: A
authors.lastname: Munnich
authors.forename: A
authors.initials: A
authors.lastname: Rötig
mesh_terms: D000328:Adult; D000975:Antioxidants / Q000009:adverse effects / Q000627:therapeutic use*; D016227:Benzoquinones / Q000009:adverse effects / Q000627:therapeutic use*; D002306:Cardiac Volume / Q000187:drug effects; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000473:pathology; D002648:Child; D042963:Electron Transport Complex II; D005260:Female; D005621:Friedreich Ataxia / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007502:Iron Chelating Agents / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D010088:Oxidoreductases / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives
chemical_list: D000975:Antioxidants; D016227:Benzoquinones; D007502:Iron Chelating Agents; D009097:Multienzyme Complexes; D014451:Ubiquinone; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; C036619:idebenone