Unite de Recherches sur les Handicaps Genetiques de l'Enfant (INSERM U393),
Paris, France.
Lancet 1999 Aug 7;354(9177):477-9
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).
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.
