Effect of idebenone on cardiomyopathy in Friedreich's ataxia
a preliminary study


Pierre Rustin, Jürgen-Christoph von Kleist-Retzow, Karine Chantrel-Groussard, Daniel Sidi, Arnold Munnich, Agnès Rötig

Unité de Recherches sur les Handicaps Génétiques de I'Enfant (INSERM U393) (P Rustin PhD, J-C von Kleist-Retzow MD, K Chantrel-Groussard PhD, Prof A Munnich MD, A Rötig PhD); and Service de Cardiologie Pédiatrique, Hôpital des Enfants-Malades (Prof D Sidi MD), Paris, France

Correspondence to: Dr Arnold Munnich, INSERM U393, Tour Lavoisier, Hôpital des Enfants-Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France (e-mail:munnich@necker.fr)

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).

 Findings 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).

 Interpretation 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.


Lancet 1999; 354: 477-79
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