Infantile and pediatric quinone deficiency diseases
Introduction
Coenzyme Q (CoQ, ubiquinone) is a lipophilic component located in the inner mitochondrial membrane that has a pivotal role in oxidative phosphorylation (OXPHOS). Indeed, CoQ shuttles electrons from complex I and complex II to complex III. Being in large excess compared to any other component of the respiratory chain (RC), it forms a kinetically compartmentalized pool, the redox status of which tightly regulates the activity of the dehydrogenases. CoQ also plays a critical function in antioxidant defenses. Ubiquinone is composed by a redox active benzoquinone ring connected to a long isoprenoid side chain. Ubiquinone is present in prokaryotes and eukaryotes but the length of its isoprenoid chain varies among species. Humans and rodents produce mainly CoQ10 and CoQ9, respectively, whereas Saccharomyces cerevisiae synthesizes CoQ6 and Escherichia coli CoQ8. In human, CoQ10 is present in all tissues and cells but in variable amount. It ranges between 114 μg/g in heart to 8 μg/g in lung (Turunen et al., 2004). However, a small amount of CoQ9 (2–7%) is also synthesized in human tissues. Moreover, it has been shown in bovine brain that the concentration of ubiquinone varies among cells and regions of a specific organ.
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Clinical presentation
Primary coenzyme Q10 deficiency is a rare, clinically heterogeneous disorder of the respiratory chain. The first patient was described 17 years ago and less than 40 patients have been further reported. CoQ10 deficiency is presumably inherited as an autosomal recessive trait as all enzymes involved in ubiquinone biosynthesis pathway are nuclearly encoded.
Four major phenotypes have been described (i) a encephalomyopathic form characterized by exercise intolerance, mitochondrial myopathy,
Diagnosis of ubiquinone deficiency
Most of the patients (except those with the ataxic form) presented clinical symptoms and metabolic anomalies suggestive of a mitochondrial respiratory chain deficiency. Therefore, the diagnosis of CoQ10 deficiency is usually done by polarographic and/or spectrophotometric analysis of the respiratory chain. In these patients, the various respiratory chain enzymes are normal but the quinone-dependent activities (CI+III, CII+III) are deficient. The hypothesis of ubiquinone deficiency can be
Replacement therapy of CoQ10 depletion
CoQ10 has been given for long to a large number of individuals with or without ubiquinone deficiency and was found to be safe. This could be related to the fact that CoQ10 is not taken up by the cells with normal ubiquinone content as there is no possibility to place more lipids into the limited space in the mitochondrial membrane. However, when the lipid is missing, as it is the case in ubiquinone synthesis defects, the inner mitochondrial membrane has the capacity to accept exogenous CoQ10
Genetic bases of ubiquinone deficiency
Little is known regarding CoQ10 biosynthesis in human but the biosynthesis pathway has been extensively studied in bacteria and in the yeast S. cerevisiae (Turunen et al., 2004). Briefly, the polyprenyl pyrophosphate chain deriving from mevalonate is condensed to the ring structure, 4-hydroxybenzoate. Based on protein homology, several genes have been identified in the human genome. All S. cerevisiae genes encoding proteins involved in ubiquinone synthesis and assembly (COQ1-COQ10) present
Conclusion
Since the first report of ubiquinone deficiency in 1989, a large spectrum of phenotypes has been reported in this specific mitochondrial disorder. The clinical heterogeneity of ubiquinone deficiency is suggestive of a genetic heterogeneity that should be related to the large number of enzymes, and corresponding genes, involved in ubiquinone biosynthesis. Identification of disease-causing genes in patients will help elucidating the clinical variability of these rare conditions. Finally, whatever
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