Early ReportQuinone-responsive multiple respiratory-chain dysfunction due to widespread coenzyme Q10 deficiency
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.
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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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