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Redefining infantile-onset multisystem phenotypes of coenzyme Q10-deficiency in the next-generation sequencing era

ABSTRACT: Primary coenzyme Q10 (CoQ10) deficiency encompasses a subset of mitochondrial diseases caused by mutations affecting proteins involved in the CoQ10 biosynthetic pathway. One of the most frequent clinical syndromes associated with primary CoQ10 deficiency is the severe infantile multisystemic form, which, until recently, was underdiagnosed. In the last few years, the availability of genetic screening through whole exome sequencing and whole genome sequencing has enabled molecular diagnosis in a growing number of patients with this syndrome and has revealed new disease phenotypes and molecular defects in CoQ10 biosynthetic pathway genes. Early genetic screening can rapidly and non-invasively diagnose primary CoQ10 deficiencies. Early diagnosis is particularly important in cases of CoQ10 deficient steroid-resistant nephrotic syndrome, which frequently improves with treatment. In contrast, the infantile multisystemic forms of CoQ10 deficiency, particularly when manifesting with encephalopathy, present therapeutic challenges, due to poor responses to CoQ10 supplementation. Administration of CoQ10 biosynthetic intermediate compounds is a promising alternative to CoQ10; however, further pre-clinical studies are needed to establish their safety and efficacy, as well as to elucidate the mechanism of actions of the intermediates. Here, we review the molecular defects causes of the multisystemic infantile phenotype of primary CoQ10 deficiency, genotype-phenotype correlations, and recent therapeutic advances.

SUBMITTER: Berardo A

PROVIDER: S-EPMC7791541 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:BackgroundFarnesol is an acyclic sesquiterpene alcohol present in the essential oils of various plants in nature. It has been reported to be valuable in medical applications, such as alleviation of allergic asthma, gliosis, and edema as well as anti-cancerous and anti-inflammatory effects. Coenzyme Q10 (CoQ10), an essential cofactor in the aerobic respiratory electron transport chain, has attracted growing interest owing to its clinical benefits and important applications in the pharmaceutical, food, and health industries. In this work, co-production of (E,E)-farnesol (FOH) and CoQ10 was achieved by combining 3 different exogenous terpenes or sesquiterpene synthase with the RNA interference of psy (responsible for phytoene synthesis in Rhodobacter sphaeroides GY-2).ResultsFOH production was significantly increased by overexpressing exogenous terpene synthase (TPS), phosphatidylglycerophosphatase B (PgpB), and sesquiterpene synthase (ATPS), as well as RNAi-mediated silencing of psy coding phytoene synthase (PSY) in R. sphaeroides strains. Rs-TPS, Rs-ATPS, and Rs-PgpB respectively produced 68.2%, 43.4%, and 21.9% higher FOH titers than that of the control strain. Interestingly, the CoQ10 production of these 3 recombinant R. sphaeroides strains was exactly opposite to that of FOH. However, CoQ10 production was almost unaffected in R. sphaeroides strains modified by psy RNA interference. The highest FOH production of 40.45 mg/L, which was twice as high as that of the control, was obtained from the TPS-PSYi strain, where the exogenous TPS was combined with the weakening of the phytoene synthesis pathway via psy RNA interference. CoQ10 production in TPS-PSYi, ATPS-PSYi, and PgpB-PSYi was decreased and lower than that of the control strain.ConclusionsThe original flux that contributed to phytoene synthesis was effectively redirected to provide precursors toward FOH or CoQ10 synthesis via psy RNA interference, which led to weakened carotenoid synthesis. The improved flux that was originally involved in CoQ10 production and phytoene synthesis was redirected toward FOH synthesis via metabolic modification. This is the first reported instance of FOH and CoQ10 co-production in R. sphaeroides using a metabolic engineering strategy.

Project description:BackgroundOxidative stress is highly prevalent in patients with end-stage renal disease and is linked to excess cardiovascular risk. Identifying therapies that reduce oxidative stress has the potential to improve cardiovascular outcomes in patients undergoing maintenance dialysis.Study designPlacebo-controlled, 3-arm, double-blind, randomized, clinical trial.Setting & participants65 patients undergoing thrice-weekly maintenance hemodialysis.InterventionPatients were randomly assigned in a 1:1:1 ratio to receive once-daily coenzyme Q10 (CoQ10; 600 or 1,200mg) or matching placebo for 4 months.OutcomesThe primary outcome was plasma oxidative stress, defined as plasma concentration of F2-isoprotanes. Secondary outcomes included levels of plasma isofurans, levels of cardiac biomarkers, predialysis blood pressure, and safety/tolerability.MeasurementsF2-isoprostanes and isofurans were measured as plasma markers of oxidative stress, and N-terminal pro-brain natriuretic peptide and troponin T were measured as cardiac biomarkers at baseline and 1, 2, and 4 months.ResultsOf 80 randomly assigned patients, 15 were excluded due to not completing at least 1 postbaseline study visit and 65 were included in the primary intention-to-treat analysis. No treatment-related major adverse events occurred. Daily treatment with 1,200mg, but not 600mg, of CoQ10 significantly reduced plasma F2-isoprostanes concentrations at 4 months compared to placebo (adjusted mean changes of -10.7 [95% CI, -7.1 to -14.3] pg/mL [P<0.001] and -8.3 [95% CI, -5.5 to -11.0] pg/mL [P=0.1], respectively). There were no significant effects of CoQ10 treatment on levels of plasma isofurans, cardiac biomarkers, or predialysis blood pressures.LimitationsStudy not powered to detect small treatment effects; difference in baseline characteristics among randomized groups.ConclusionsIn patients undergoing maintenance hemodialysis, daily supplementation with 1,200mg of CoQ10 is safe and results in a reduction in plasma concentrations of F2-isoprostanes, a marker of oxidative stress. Future studies are needed to determine whether CoQ10 supplementation improves clinical outcomes for patients undergoing maintenance hemodialysis.

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Redefining infantile-onset multisystem phenotypes of coenzyme Q10-deficiency in the next-generation sequencing era

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