Elsevier

The Lancet

Volume 354, Issue 9177, 7 August 1999, Pages 477-479
The Lancet

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

https://doi.org/10.1016/S0140-6736(99)01341-0Get rights and content

Summary

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 Krebscycle enzyme, aconitase, and three mitochondrial respiratorychain 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 ironinduced 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.

Introduction

Friedreich's ataxia is a degenerative disease with autosomal recessive inheritance characterised by progressive limb and gait ataxia, areflexia and pyramidal signs in the legs, and hypertrophic cardiomyopathy;1, 2 the incidence is 1 per 30 000 livebirths. The disease gene encodes a ubiquitous mitochondrial protein called frataxin.3, 4, 5, 6, 7, 8, 9 Friedreich's ataxia is primarily caused by a GAA repeat expansion in the first intron of the frataxin gene.4

We have previously reported a combined deficiency of a Krebs-cycle enzyme, aconitase, and three mitochondrial respiratory-chain complexes (complexes I to III), in endomyocardial biopsy samples from patients with Friedreich's ataxia.10 All four enzymes share iron-sulphur cluster-containing proteins (ISP), which are extremely sensitive to injury by oxygen free radicals.11 Both heart tissue from patients with Friedreich's ataxia and yeast strains encoding a deleted frataxin-gene counterpart, accumulate intracellular iron;7, 8, 12 we therefore postulated that alteration of ISP might result from iron overload through generation of oxygen free radicals in Friedreich's ataxia.10

Idebenone, a short-chain quinone analogue acts as a potent free-radical scavenger. We investigated whether this drug can protect mitochondrial enzymes from ironinduced injury in vitro. Since the drug has no known side-effects,13, 14 we then investigated its effects in three patients with Friedreich's ataxia.

Section snippets

Patients and methods

The patients treated were an 11-year-old girl, and two young adults (aged 19 and 21 years). Informed consent was given. The diagnosis of Friedreich's ataxia was confirmed by detection of a trinucleotide-repeat expansion in the first intron of the frataxin gene (patient 1, expansion of 2·6 kb and 5·0 kb; patient 2 2·8 kb and 3·5 kb; patient 3 3·1 kb and 4·6 kb; controls below 75 bp). For molecular analyses, the total DNA extracted from leucocytes was amplified by PCR with previously designed

Results

There was a rapid loss of complex II activity (more than 75%) in the presence of reduced iron (5 nmol/L/Fe2+; figure 1) but no loss of activity was observed when oxidised iron (Fe3+) was substituted for Fe2+ (not shown). Idebenone efficiently protected complex II activity against iron-induced injury when reduced in the respiratory chain by succinate (figure 1). In the absence of succinate, idebenone remained oxidised and was ineffective as was succinate alone. Reduced iron also triggered a

Disussion

Friedreich's ataxia has been linked to a deficiency of frataxin, a protein that probably acts as a regulator of iron transport into the mitochondria.5, 6, 7, 8, 9 We have previously hypothesised10 that the disease stems from a mitochondrial iron overload, which triggers the generation of oxygen free radicals. These radicals are toxic for the ISP of the mitochondrial respiratory chain and the Krebs cycle (figure 3).

We have developed an experimental system that mimics the iron-induced damage

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