Effect of idebenone on cardiomyopathy
in Friedreich’s ataxia: a preliminary study.
Rustin P, von Kleist-Retzow JC,
Chantrel-Groussard K, Sidi D, Munnich A, Rotig A.
Unite de Recherches sur les
Handicaps Genetiques de l’Enfant (INSERM U393), Paris, France.
Lancet 1999 Aug 7;354(9177):477-9
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.