Elsevier

The Lancet

Volume 356, Issue 9227, 29 July 2000, Pages 391-395
The Lancet

Early Report
Quinone-responsive multiple respiratory-chain dysfunction due to widespread coenzyme Q10 deficiency

https://doi.org/10.1016/S0140-6736(00)02531-9Get rights and content

Summary

Background

The respiratory-chain deficiencies are a broad group of largely untreatable diseases. Among them, coenzyme Q10 (ubiquinone) deficiency constitutes a subclass that deserves early and accurate diagnosis.

Methods

We assessed respiratory-chain function in two siblings with severe encephalomyopathy and renal failure. We used high-performance liquid chromatography analyses, combined with radiolabelling experiments, to quantify cellular coenzyme Q10 content. Clinical follow-up and detailed biochemical investigations of respiratory chain activity were carried out over the 3 years of oral quinone administration.

Findings

Deficiency of coenzyme Q10-dependent respiratory-chain activities was identified in muscle biopsy, circulating lymphocytes, and cultured skin fibroblasts. Undetectable coenzyme Q10 and results of radiolabelling experiments in cultured fibroblasts supported the diagnosis of widespread coenzyme Q10 deficiency. Stimulation of respiration and fibroblast enzyme activities by exogenous quinones in vitro prompted us to treat the patients with oral ubidecarenone (5 mg/kg daily), which resulted in a substantial improvement of their condition over 3 years of therapy.

Interpretation

Particular attention should be paid to multiple quinone-responsive respiratory-chain enzyme deficiency because this rare disorder can be successfully treated by oral ubidecarenone.

Introduction

Mitochondrial encephalomyopathies represent a heterogeneous group of genetic disorders caused by various types of respiratory-chain dysfunction. The respiratory chain consists in five major complexes (complexes I-V) and catalyses the transduction of energy from respiratory substrates into a proton-motive force that is used to synthesise ATP. Coenzyme Q10 (ubiquinone) transfers reducing equivalents from various dehydrogenases to complex III (ubiquinone cytochrome c reductase) and acts as a transmembrane hydrogen carrier.1, 2 No cure for mitochondrial encephalomyopathy is currently available and most therapeutic trials have failed to provide biochemical evidence of improved respiratory-chain function.

We report quinone-responsive mitochondrial encephalomyopathy in two siblings with multiple respiratory enzyme deficiency ascribed to a deficiency of coenzyme Q10 biosynthesis in various tissues, and assessed the efficacy of oral ubidecarenone therapy in these patients.

Section snippets

Patients

Patient 1 was a boy who was born after a term pregnancy and normal delivery (birthweight 3600 g, length 54 cm, head circumference 35·5 cm) to healthy parents from western France. His older brother (by 5 years) was healthy, but his two older sisters (patients 2 and 3) were also affected. He did well during the first weeks of life, but nystagmus was noted early, and he gradually developed severe myopia and bilateral visual loss. At 10 years, he was diagnosed with retinitis pigmentosa with optic

Results

Respiratory enzyme activity in circulating lymphocytes (table 1) and skeletal muscle mitochondria from patients 1 and 3, and cultured skin fibroblasts from patient 1 (not shown), was within the normal range. However, quinone-dependent activities in lymphocytes (complex I and III, complex II and III, glycerol-3-phosphate and complex III) were in the lowest absolute control values, and activity ratios, which are used to detect unbalanced respiratory chain enzyme functions,12, 13 differed

Discussion

Unlike previous cases, in whom quinone deficiency was confined to neuromuscular tissues,14, 16 our patients had widespread multitissue quinone depletion. This finding provided the unique opportunity to investigate the mechanism of coenzyme Q10 depletion in what we believe to be a novel but treatable inborn error of metabolism.

The incorporation of 3H-mevalonate into cholesterol and dolichol but not into coenzyme Q10 suggests that a specific step of endogenous coenzyme Q10 synthesis is impaired.

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