coenzyme-q10 and Muscle-Weakness

Primary coenzyme Q

Topics: Ataxia; Exome; Exome Sequencing; Genome; High-Throughput Nucleotide Sequencing; Humans; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Saccharomyces cerevisiae; Ubiquinone; Whole Genome Sequencing

Coenzyme Q (CoQ) is a key component of the respiratory chain of all eukaryotic cells. Its function is closely related to mitochondrial respiration, where it acts as an electron transporter. However, the cellular functions of coenzyme Q are multiple: it is present in all cell membranes, limiting the toxic effect of free radicals, it is a component of LDL, it is involved in the aging process, and its deficiency is linked to several diseases. Recently, it has been proposed that coenzyme Q contributes to suppressing ferroptosis, a type of iron-dependent programmed cell death characterized by lipid peroxidation. In this review, we report the latest hypotheses and theories analyzing the multiple functions of coenzyme Q. The complete knowledge of the various cellular CoQ functions is essential to provide a rational basis for its possible therapeutic use, not only in diseases characterized by primary CoQ deficiency, but also in large number of diseases in which its secondary deficiency has been found.

Topics: Animals; Ataxia; Cell Membrane; Cell Respiration; Humans; Lipid Peroxidation; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

Coenzyme Q10, or ubiquinone, is a non-prescription nutritional supplement. It is a fat-soluble molecule that acts as an electron carrier in mitochondria, and as a coenzyme for mitochondrial enzymes. Coenzyme Q10 deficiency may be associated with a multitude of diseases, including heart failure. The severity of heart failure correlates with the severity of coenzyme Q10 deficiency. Emerging data suggest that the harmful effects of reactive oxygen species are increased in people with heart failure, and coenzyme Q10 may help to reduce these toxic effects because of its antioxidant activity. Coenzyme Q10 may also have a role in stabilising myocardial calcium-dependent ion channels, and in preventing the consumption of metabolites essential for adenosine-5'-triphosphate (ATP) synthesis. Coenzyme Q10, although not a primary recommended treatment, could be beneficial to people with heart failure. Several randomised controlled trials have compared coenzyme Q10 to other therapeutic modalities, but no systematic review of existing randomised trials was conducted prior to the original version of this Cochrane Review, in 2014.. To review the safety and efficacy of coenzyme Q10 in heart failure.. We searched CENTRAL, MEDLINE, Embase, Web of Science, CINAHL Plus, and AMED on 16 October 2020; ClinicalTrials.gov on 16 July 2020, and the ISRCTN Registry on 11 November 2019. We applied no language restrictions.. We included randomised controlled trials of either parallel or cross-over design that assessed the beneficial and harmful effects of coenzyme Q10 in people with heart failure. When we identified cross-over studies, we considered data only from the first phase.. We used standard Cochrane methods, assessed study risk of bias using the Cochrane 'Risk of bias' tool, and GRADE methods to assess the quality of the evidence. For dichotomous data, we calculated the risk ratio (RR); for continuous data, the mean difference (MD), both with 95% confidence intervals (CI). Where appropriate data were available, we conducted meta-analysis. When meta-analysis was not possible, we wrote a narrative synthesis. We provided a PRISMA flow chart to show the flow of study selection.. We included eleven studies, with 1573 participants, comparing coenzyme Q10 to placebo or conventional therapy (control). In the majority of the studies, sample size was relatively small. There were important differences among studies in daily coenzyme Q10 dose, follow-up period, and the measures of treatment effect. All studies had unclear, or high risk of bias, or both, in one or more bias domains. We were only able to conduct meta-analysis for some of the outcomes. None of the included trials considered quality of life, measured on a validated scale, exercise variables (exercise haemodynamics), or cost-effectiveness. Coenzyme Q10 probably reduces the risk of all-cause mortality more than control (RR 0.58, 95% CI 0.35 to 0.95; 1 study, 420 participants; number needed to treat for an additional beneficial outcome (NNTB) 13.3; moderate-quality evidence). There was low-quality evidence of inconclusive results between the coenzyme Q10 and control groups for the risk of myocardial infarction (RR 1.62, 95% CI 0.27 to 9.59; 1 study, 420 participants), and stroke (RR 0.18, 95% CI 0.02 to 1.48; 1 study, 420 participants). Coenzyme Q10 probably reduces hospitalisation related to heart failure (RR 0.62, 95% CI 0.49 to 0.78; 2 studies, 1061 participants; NNTB 9.7; moderate-quality evidence). Very low-quality evidence suggests that coenzyme Q10 may improve the left ventricular ejection fraction (MD 1.77, 95% CI 0.09 to 3.44; 7 studies, 650 participants), but the results are inconclusive for exercise capacity (MD 48.23, 95% CI -24.75 to 121.20; 3 studies, 91 participants); and the risk of developing adverse events (RR 0.70, 95% CI 0.45 to 1.10; 2 studies, 568 participants). We downgraded the quality of the evidence mainly due to high risk of bias and imprecision.. The included studies provide moderate-quality evidence that coenzyme Q10 probably reduces all-cause mortality and hospitalisation for heart failure. There is low-quality evidence of inconclusive results as to whether coenzyme Q10 has an effect on the risk of myocardial infarction, or stroke. Because of very low-quality evidence, it is very uncertain whether coenzyme Q10 has an effect on either left ventricular ejection fraction or exercise capacity. There is low-quality evidence that coenzyme Q10 may increase the risk of adverse effects, or have little to no difference. There is currently no convincing evidence to support or refute the use of coenzyme Q10 for heart failure. Future trials are needed to confirm our findings.

Topics: Ataxia; Heart Failure; Humans; Mitochondrial Diseases; Muscle Weakness; Myocardial Infarction; Quality of Life; Stroke; Stroke Volume; Ubiquinone; Ventricular Function, Left

Coenzyme Q

Topics: Ataxia; Cardiovascular Diseases; Dietary Supplements; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

Coenzyme Q

Topics: Aging; Alkyl and Aryl Transferases; Animals; Ataxia; Energy Metabolism; Gene Expression Regulation; GTP Phosphohydrolases; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Mutation; Niemann-Pick C1 Protein; Niemann-Pick Disease, Type C; Signal Transduction; Ubiquinone

Coenzyme Q

Topics: Aging; Ataxia; Cardiovascular Diseases; Dietary Supplements; Humans; Mitochondrial Diseases; Muscle Weakness; Neurodegenerative Diseases; Ubiquinone

Coenzyme Q10 (CoQ10) has a number of vital functions in all cells, both mitochondrial and extramitochondrial. In addition to its key role in mitochondrial oxidative phosphorylation, CoQ10 serves as a lipid soluble antioxidant, plays an important role in fatty acid, pyrimidine and lysosomal metabolism, as well as directly mediating the expression of a number of genes, including those involved in inflammation. In view of the central role of CoQ10 in cellular metabolism, it is unsurprising that a CoQ10 deficiency is linked to the pathogenesis of a range of disorders. CoQ10 deficiency is broadly classified into primary or secondary deficiencies. Primary deficiencies result from genetic defects in the multi-step biochemical pathway of CoQ10 synthesis, whereas secondary deficiencies can occur as result of other diseases or certain pharmacotherapies. In this article we have reviewed the clinical consequences of primary and secondary CoQ10 deficiencies, as well as providing some examples of the successful use of CoQ10 supplementation in the treatment of disease.

Topics: Antioxidants; Ataxia; Humans; Inflammation; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

Coenzyme Q10 (CoQ10) is a ubiquitous cofactor in the body, operating in the inner mitochondrial membrane, where it plays a vital role in the generation of adenosine triphosphate (ATP) through the electron transport chain (ETC). In addition to this, CoQ10 serves as an antioxidant, protecting the cell from oxidative stress by reactive oxygen species (ROS) as well as maintaining a proton (H

Topics: Animals; Ataxia; Brain; Humans; Mitochondrial Diseases; Muscle Weakness; Neurodegenerative Diseases; Retina; Ubiquinone

Coenzyme Q (CoQ) is an essential endogenously synthesized molecule that links different metabolic pathways to mitochondrial energy production thanks to its location in the mitochondrial inner membrane and its redox capacity, which also provide it with the capability to work as an antioxidant. Although defects in CoQ biosynthesis in human and mouse models cause CoQ deficiency syndrome, some animals models with particular defects in the CoQ biosynthetic pathway have shown an increase in life span, a fact that has been attributed to the concept of mitohormesis. Paradoxically, CoQ levels decline in some tissues in human and rodents during aging and coenzyme Q

Topics: Adult; Aging; Animals; Antioxidants; Ataxia; Caenorhabditis elegans; Diet; Female; Hormesis; Humans; Male; Mice; Middle Aged; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Rats; Ubiquinone; Young Adult

Coenzyme Q

Topics: Ataxia; Humans; Mitochondrial Diseases; Muscle Weakness; Pathology, Molecular; Ubiquinone

Dysferlin myopathy is an autosomal recessive hereditary muscular dystrophy due to deficiency of dysferlin caused by alteration of the DYSF gene; Limb-girdle muscular dystrophy type 2B (LGMD2B) is the most common in Its clinical phenotypes. However, LGMD2B is rarely seen in clinical cases and may initially present as weakness of proximalpelvis muscles and muscles in the posterior compartments of thighs,which will then cause difficulty in running and limping during walking. Laboratory tests at an early stage of the disease often indicate an increased level of serum creatine kinase (CK). Moreover, polymyositis (PM) is manifested as symmetrical proximal muscle weakness of the four limbs, accompanied by an increased level of serum CK. Thus, both are very difficult to identify in clinical practice.. A 25-year-old woman was admitted to our department as the limb weakness progressively worsened. She began to experience proximal muscle weakness of both lower limbs without obvious inducement, which markedly increased when she climbed the stairs or stood up after squatting. Then her symptoms worsened, with difficulty in proximal and distal lifting of the lower extremities.. Through combined immunohistochemistry and Western-blot analysis, The patient was diagnosed with LGMD2B.. There were symptomatic treatments such as coenzyme Q10.. After symptomatic treatments, the patient's symptoms were obviously relieved, and the CK level decreased.. Through this case, we found that combined application of immunohistochemistry and Western-blot analysis is helpful in early diagnosis of LGMD2B, and a new site of frame-shift mutation in the patient's DYSF gene was found.

Topics: Adult; Blotting, Western; Diagnosis, Differential; Diagnostic Errors; Dysferlin; Electromyography; Female; Humans; Immunohistochemistry; Muscle Weakness; Muscle, Skeletal; Muscular Dystrophies, Limb-Girdle; Mutation; Polymyositis; Ubiquinone

Coenzyme Q (ubiquinone or CoQ) is an essential lipid that plays a role in mitochondrial respiratory electron transport and serves as an important antioxidant. In human and yeast cells, CoQ synthesis derives from aromatic ring precursors and the isoprene biosynthetic pathway.

Topics: Ataxia; Genes, Fungal; Genome, Human; Humans; Mitochondrial Diseases; Mitochondrial Proteins; Models, Biological; Muscle Weakness; Mutation; Parabens; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Ubiquinone

Primary Coenzyme Q deficiencies represent a group of rare conditions caused by mutations in one of the genes required in its biosynthetic pathway at the enzymatic or regulatory level. The associated clinical manifestations are highly heterogeneous and mainly affect central and peripheral nervous system, kidney, skeletal muscle and heart. Genotype-phenotype correlations are difficult to establish, mainly because of the reduced number of patients and the large variety of symptoms. In addition, mutations in the same

Topics: Ataxia; Genotype; Humans; Mitochondrial Diseases; Muscle Weakness; Mutation; Phenotype; Structure-Activity Relationship; Syndrome; Ubiquinone

In recent years, the analytical determination of coenzyme Q10 (CoQ10) has gained importance in clinical diagnosis and in pharmaceutical quality control. CoQ10 is an important cofactor in the mitochondrial respiratory chain and a potent endogenous antioxidant. CoQ10 deficiency is often associated with numerous diseases and patients with these conditions may benefit from administration of supplements of CoQ10. In this regard, it has been observed that the best benefits are obtained when CoQ10 deficiency is diagnosed and treated early. Therefore, it is of great value to develop analytical methods for the detection and quantification of CoQ10 in this type of disease. The methods above mentioned should be simple enough to be used in routine clinical laboratories as well as in quality control of pharmaceutical formulations containing CoQ10. Here, we discuss the advantages and disadvantages of different methods of CoQ10 analysis.

Topics: Ataxia; Chromatography, High Pressure Liquid; Electrophoresis, Capillary; Humans; Mitochondrial Diseases; Muscle Weakness; Pharmaceutical Preparations; Spectrophotometry; Ubiquinone

Coenzyme Q

Topics: Adult; Aged; Ataxia; Calcium-Binding Proteins; Cell Adhesion Molecules, Neuronal; Collectins; Cross-Sectional Studies; Female; Genetic Loci; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Genotype; Humans; Male; Middle Aged; Mitochondrial Diseases; Muscle Weakness; Nerve Degeneration; Nerve Tissue Proteins; Neural Cell Adhesion Molecules; Neurons; Polymorphism, Single Nucleotide; Receptors, Scavenger; Ubiquinone

A short review is given of the potential role of selenium deficiency and selenium intervention trials in atherosclerotic heart disease. Selenium is an essential constituent of several proteins, including the glutathione peroxidases and selenoprotein P. The selenium intake in Europe is generally in the lower margin of recommendations from authorities. Segments of populations in Europe may thus have a deficient intake that may be presented by a deficient anti-oxidative capacity in various illnesses, in particular atherosclerotic disease, and this may influence the prognosis of the disease. Ischemic heart disease and heart failure are two conditions where increased oxidative stress has been convincingly demonstrated. Some of the intervention studies of anti-oxidative substances that have focused on selenium are discussed in this review. The interrelationship between selenium and coenzyme Q10, another anti-oxidant, is presented, pointing to a theoretical advantage in using both substances in an intervention if there are deficiencies within the population. Clinical results from an intervention study using both selenium and coenzyme Q10 in an elderly population are discussed, where reduction in cardiovascular mortality, a better cardiac function according to echocardiography, and finally a lower concentration of the biomarker NT-proBNP as a sign of lower myocardial wall tension could be seen in those on active treatment, compared to placebo.

Topics: Animals; Antioxidants; Ataxia; Cardiovascular Diseases; Coronary Artery Disease; Deficiency Diseases; Diet; Dietary Supplements; Europe; Humans; Mitochondrial Diseases; Muscle Weakness; Nutritional Status; Oxidative Stress; Selenium; Ubiquinone

Coenzyme Q10, or ubiquinone, is a non-prescription nutritional supplement. It is a fat-soluble molecule that acts as an electron carrier in mitochondria and as a coenzyme for mitochondrial enzymes. Coenzyme Q10 deficiency may be associated with a multitude of diseases including heart failure. The severity of heart failure correlates with the severity of coenzyme Q10 deficiency. Emerging data suggest that the harmful effects of reactive oxygen species are increased in patients with heart failure and coenzyme Q10 may help to reduce these toxic effects because of its antioxidant activity. Coenzyme Q10 may also have a role in stabilising myocardial calcium-dependent ion channels and preventing the consumption of metabolites essential for adenosine-5'-triphosphate (ATP) synthesis. Coenzyme Q10, although not a primary recommended treatment, could be beneficial to patients with heart failure. Several randomised controlled trials have compared coenzyme Q10 to other therapeutic modalities, but no systematic review of existing randomised trials has been conducted.. To review the safety and efficacy of coenzyme Q10 in heart failure.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 12); MEDLINE OVID (1950 to January Week 3 2013) and EMBASE OVID (1980 to 2013 Week 03) on 24 January 2013; Web of Science with Conference Proceedings (1970 to January 2013) and CINAHL Plus (1981 to January 2013) on 25 January 2013; and AMED (Allied and Complementary Medicine) (1985 to January 2013) on 28 January 2013. We applied no language restrictions.. We included randomised controlled trials of either parallel or cross-over design that assessed the beneficial and harmful effects of coenzyme Q10 in patients with heart failure. When cross-over studies were identified, we considered data only from the first phase.. Two authors independently extracted data from the included studies onto a pre-designed data extraction form. We then entered the data into Review Manager 5.2 for analysis. We assessed study risk of bias using the Cochrane 'Risk of bias' tool. For dichotomous data, we calculated the risk ratio and for continuous data the mean difference (MD). Where appropriate data were available, we performed meta-analysis. For this review we prioritised data from pooled analyses only. Where meta-analysis was not possible, we wrote a narrative synthesis. We provided a QUOROM flow chart to show the flow of papers.. We included seven studies with 914 participants comparing conenzyme Q10 versus placebo. There were no data on clinical events from published randomised trials. The included studies had small sample sizes. Meta-analysis was only possible for a few physiological measures and there was substantial heterogeneity.Only one study reported on total mortality, major cardiovascular events and hospitalisation. Five trials reported on the New York Heart Association (NYHA) classification of clinical status, but it was impossible to pool data due to heterogeneity. None of the included trials considered quality of life, exercise variables, adverse events or cost-effectiveness as outcome measures. Pooled analysis suggests that the use of coenzyme Q10 has no clear effect on left ventricular ejection fraction (MD -2.26; 95% confidence interval (CI) -15.49 to 10.97, n = 60) or exercise capacity (MD 12.79; 95% CI -140.12 to 165.70, n = 85). Pooled data did indicate that supplementation increased blood levels of coenzyme Q10 (MD 1.46; 95% CI 1.19 to 1.72, n = 112). However, there are only a small number of small studies with a risk of bias, so these results should be interpreted with caution.. No conclusions can be drawn on the benefits or harms of coenzyme Q10 in heart failure at this time as trials published to date lack information on clinically relevant endpoints. Furthermore, the existing data are derived from small, heterogeneous trials that concentrate on physiological measures: their results are inconclusive. Until further evidence emerges to support the use of coenzyme Q10 in heart failure, there might be a need to re-evaluate whether further trials testing coenzyme Q10 in heart failure are desirable.

Topics: Ataxia; Heart Failure; Humans; Mitochondrial Diseases; Muscle Weakness; Randomized Controlled Trials as Topic; Stroke Volume; Ubiquinone; Vitamins

Treatment of mitochondrial respiratory chain (MRC) disorders is extremely difficult, however, coenzyme Q10 (CoQ10) and its synthetic analogues are the only agents which have shown some therapeutic benefit to patients. CoQ10 serves as an electron carrier in the MRC as well as functioning as a potent lipid soluble antioxidant. CoQ10 supplementation is fundamental to the treatment of patients with primary defects in the CoQ10 biosynthetic pathway. The efficacy of CoQ10 and its analogues in the treatment of patients with MRC disorders not associated with a CoQ10 deficiency indicates their ability to restore electron flow in the MRC and/or increase mitochondrial antioxidant capacity may also be important contributory factors to their therapeutic potential.

Topics: Animals; Ataxia; Humans; Mitochondrial Diseases; Molecular Structure; Muscle Weakness; Treatment Outcome; Ubiquinone

Fibromyalgia (FM) is characterized by generalized pain and chronic fatigue of unknown etiology. To evaluate the role of oxidative stress in this disorder, we measured plasma levels of ubiquinone-10, ubiquinol-10, free cholesterol (FC), cholesterol esters (CE), and free fatty acids (FFA) in patients with juvenile FM (n=10) and in healthy control subjects (n=67). Levels of FC and CE were significantly increased in juvenile FM as compared with controls, suggesting the presence of hypercholesterolemia in this disease. However, plasma level of ubiquinol-10 was significantly decreased and the ratio of ubiquinone-10 to total coenzyme Q10 (%CoQ10) was significantly increased in juvenile FM relative to healthy controls, suggesting that FM is associated with coenzyme Q10 deficiency and increased oxidative stress. Moreover, plasma level of FFA was significantly higher and the content of polyunsaturated fatty acids (PUFA) in total FFA was significantly lower in FM than in controls, suggesting increased tissue oxidative damage in juvenile FM. Interestingly, the content of monoenoic acids, such as oleic and palmitoleic acids, was significantly increased in FM relative to controls, probably to compensate for the loss of PUFA. Next, we examined the effect of ubiquinol-10 supplementation (100 mg/day for 12 weeks) in FM patients. This resulted in an increase in coenzyme Q10 levels and a decrease in %CoQ10. No changes were observed in FFA levels or their composition. However, plasma levels of FC and CE significantly decreased and the ratio of FC to CE also significantly decreased, suggesting that ubiquinol-10 supplementation improved cholesterol metabolism. Ubiquinol-10 supplementation also improved chronic fatigue scores as measured by the Chalder Fatigue Scale.

Topics: Adolescent; Antioxidants; Ataxia; Case-Control Studies; Child; Cholesterol; Dietary Supplements; Double-Blind Method; Fatigue; Fatty Acids, Monounsaturated; Fatty Acids, Nonesterified; Female; Fibromyalgia; Humans; Hypercholesterolemia; Male; Mitochondrial Diseases; Muscle Weakness; Oleic Acid; Oxidative Stress; Pain Measurement; Ubiquinone

Statins significantly reduce CV morbidity and mortality. Unfortunately, one of the side effects of statins is myopathy, for which statins cannot be administered in sufficient doses or administered at all. The aim of this study was to demonstrate the effect of coenzyme Q10 in patients with statin myopathy.. Twenty eight patients aged 60.6±10.7 years were monitored (18 women and 10 men) and treated with different types and doses of statin. Muscle weakness and pain was monitored using a scale of one to ten, on which patients expressed the degree of their inconvenience. Examination of muscle problems was performed prior to administration of CQ10 and after 3 and 6 months of dosing. Statistical analysis was performed using Friedman test, Annova and Students t-test.. Pain decreased on average by 53.8% (p<0.0001), muscle weakness by 44.4% (p<0.0001). The CQ10 levels were increased by more than 194% (from 0,903 μg/ml to 2.66 μg/ml; p<0.0001).. After a six-month administration of coenzyme Q10, muscle pain and sensitivity statistically significantly decreased.

Topics: Aged; Cardiovascular Diseases; Drug Therapy, Combination; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Muscle Weakness; Musculoskeletal Pain; Patient Satisfaction; Treatment Outcome; Ubiquinone; Vitamins

Primary Coenzyme Q10 (CoQ

Topics: Ataxia; Dietary Supplements; Humans; Kidney; Mitochondrial Diseases; Muscle Weakness; Mutation; Nephrotic Syndrome; Proteinuria; Steroids; Ubiquinone

Primary coenzyme Q10 (CoQ10) deficiency refers to a group of mitochondrial cytopathies caused by genetic defects in CoQ10 biosynthesis. Primary coenzyme Q10 deficiency-6 (COQ10D6) is an autosomal recessive disorder attributable to biallelic

Topics: Ataxia; Deafness; Hearing Loss, Sensorineural; Humans; Mitochondrial Diseases; Muscle Weakness; Nephrotic Syndrome; Steroids; Ubiquinone

Coenzyme Q

Topics: Alkyl and Aryl Transferases; Ataxia; Cell Line, Tumor; Cholesterol; Energy Metabolism; Glycolysis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Nitrobenzoates; Protein Stability; Ubiquinone

CoenzymeQ10 is one of the main cellular antioxidants and an essential lipid involved in numerous cell reactions, such as energy production and apoptosis modulation. A large number of enzymes are involved in CoQ10 biosynthesis. Mutations in the genes encoding for these enzymes cause a CoQ10 deficiency, characterized by neurological and systemic symptoms. Here we describe two young sisters with sensorineural deafness followed by optic atrophy, due to a novel homozygous pathogenic variant in PDSS1. The visual system seems to be mainly involved when the first steps of CoQ10 synthesis are impaired (PDSS1, PDSS2, and COQ2 deficiency).

Topics: Adolescent; Alkyl and Aryl Transferases; Ataxia; Child; Consanguinity; Female; Hearing Loss, Sensorineural; Humans; Mitochondrial Diseases; Muscle Weakness; Mutation, Missense; Optic Atrophies, Hereditary; Ubiquinone

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.. A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.. The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.

Topics: Adult; Anti-Obesity Agents; Asian People; Carnitine; Female; Humans; Metformin; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Muscle Weakness; Muscular Diseases; Riboflavin; Topiramate; Triiodothyronine; Ubiquinone

Hereditary hemochromatosis (HH) is a group of inherited disorders that causes a slow and progressive iron deposition in diverse organs, particularly in the liver. Iron overload induces oxidative stress and tissue damage. Coenzyme Q10 (CoQ10) is a cofactor in the electron-transport chain of the mitochondria, but it is also a potent endogenous antioxidant. CoQ10 interest has recently grown since various studies show that CoQ10 supplementation may provide protective and safe benefits in mitochondrial diseases and oxidative stress disorders. In the present study we sought to determine CoQ10 plasma level in patients recently diagnosed with HH and to correlate it with biochemical, genetic, and histological features of the disease.. Plasma levels of CoQ10, iron, ferritin, transferrin and vitamins (A, C and E), liver tests (transaminases, alkaline phosphatase and bilirubin), and histology, as well as three HFE gene mutations (H63D, S654C and C282Y), were assessed in thirty-eight patients (32 males, 6 females) newly diagnosed with HH without treatment and in twenty-five age-matched normolipidemic healthy subjects with no HFE gene mutations (22 males, 3 females) and without clinical or biochemical signs of iron overload or liver diseases.. Patients with HH showed a significant decrease in CoQ10 levels respect to control subjects (0.31 ± 0.03 µM vs 0.70 ± 0.06 µM, p < 0.001, respectively) independently of the genetic mutation, cirrhosis, transferrin saturation, ferritin level or markers of hepatic dysfunction. Although a decreasing trend in CoQ10 levels was observed in patients with elevated iron levels, no correlation was found between both parameters in patients with HH. Vitamins C and A levels showed no changes in HH patients. Vitamin E was significantly decreased in HH patients (21.1 ± 1.3 µM vs 29.9 ± 2.5 µM, p < 0.001, respectively), but no correlation was observed with CoQ10 levels.. The decrease in CoQ10 levels found in HH patients suggests that CoQ10 supplementation could be a safe intervention strategy complementary to the traditional therapy to ameliorate oxidative stress and further tissue damage induced by iron overload.

Topics: Ataxia; Case-Control Studies; Female; Hemochromatosis; Humans; Male; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

Topics: Baclofen; Carnitine; Child, Preschool; Diagnosis, Differential; Diet, Ketogenic; Humans; Leigh Disease; Male; Muscle Relaxants, Central; Muscle Weakness; Pyruvate Dehydrogenase Complex Deficiency Disease; Ubiquinone; Vitamins

Intrahepatic cholestasis of pregnancy (ICP) is considered a high-risk condition because it may have serious consequences for the fetus health. ICP is characterized by the accumulation of bile acids in maternal serum which contribute to an imbalance between the production of reactive oxygen species and the antioxidant defenses increasing the oxidative stress experienced by the fetus. Previously, it was reported a significant decrease in plasma coenzyme Q10 (CoQ10) in women with ICP. CoQ10 is a redox substance integrated in the mitochondrial respiratory chain and is recognized as a potent antioxidant playing an intrinsic role against oxidative damage. The objective of the present study was to investigate the levels of CoQ10 in umbilical cord blood during normal pregnancy and in those complicated with ICP, all of them compared to the maternal ones.. CoQ10 levels and bile acid levels in maternal and umbilical cord blood levels during normal pregnancies (n=23) and in those complicated with ICP (n=13), were investigated.. A significant decrease in neonate CoQ10 levels corrected by cholesterol (0.105±0.010 vs. 0.069±0.011, P<0.05, normal pregnancy vs. ICP, respectively), together with an increase of total serum bile acids (2.10±0.02 vs. 7.60±2.30, P<0.05, normal pregnancy vs. ICP, respectively) was observed.. A fetus from an ICP mother is exposed to a greater risk derived from oxidative damage. The recognition of CoQ10 deficiency is important since it could be the starting point for a new and safe intervention strategy which can establish CoQ10 as a promising candidate to prevent the risk of oxidative stress.

Topics: Adult; Ataxia; Bile Acids and Salts; Biomarkers; Birth Weight; Cholestasis, Intrahepatic; Cholesterol; Cholic Acid; Cross-Sectional Studies; Female; Fetal Blood; Fetus; Gestational Age; Humans; Infant, Newborn; Mitochondrial Diseases; Muscle Weakness; Oxidation-Reduction; Oxidative Stress; Pregnancy; Pregnancy Complications; Prospective Studies; Reactive Oxygen Species; Ubiquinone; Young Adult

Coenzyme Q

Topics: Ataxia; Cell Line, Tumor; Chromatography, High Pressure Liquid; Humans; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Neurons; Ubiquinone; Ultraviolet Rays

Primary coenzyme Q10 deficiency refers to a group of diseases characterised by reduced levels of coenzyme Q10 in related tissues or cultured cells associated with the 9 genes involved in the biosynthesis of coenzyme Q10. A biallelic pathogenic variant of COQ8A gene causes the occurrence of the primary coenzyme Q10 deficiency type 4. The objective of this study was to investigate the genetic cause of muscle weakness in a proband who had a negative DMD gene test for Becker muscular dystrophy.. The DNA of the proband was sequenced using whole exome sequencing. With the help of the Human Phenotype Ontology (HPO), the range of related candidate pathogenic genes has been reduced to a certain extent based on "muscle weakness" (HP:0001324). In addition, family linkage analysis, phenotypic-genotype check and protein structure modeling were used to explore the genetic cause of the proband.. The compound heterozygous variant c.836A > C (p.Gln279Pro) and c.1228C > T (p.Arg410Ter) in the COQ8A gene was identified in the proband. According to the 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines for the interpretation of sequence variants, the novel variant c.836A > C could be classified as "likely pathogenic" for the proband.. The p.Gln279Pro was detected in the KxGQ motif and the QKE triplet of the COQ8A protein, whose structures were crucial for the structure and function of the COQ8A protein associated with the biosynthesis of coenzyme Q10 and the proband's clinical symptoms were relatively milder than those previously reported.

Topics: Ataxia; Child; Exome Sequencing; Humans; Male; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Mutation, Missense; Pedigree; Ubiquinone

Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and an important antioxidant present in all cellular membranes. CoQ deficiencies are frequent in aging and in age-related diseases, and current treatments are limited to CoQ supplementation. Strategies that rely on CoQ supplementation suffer from poor uptake and trafficking of this very hydrophobic molecule. In a previous study, the dietary flavonol kaempferol was reported to serve as a CoQ ring precursor and to increase the CoQ content in kidney cells, but neither the part of the molecule entering CoQ biosynthesis nor the mechanism were described. In this study, kaempferol labeled specifically in the B-ring was isolated from

Topics: Animals; Antioxidants; Ataxia; Epithelial Cells; Flavonols; Humans; Kaempferols; Kidney; Mice; Mitochondria; Mitochondrial Diseases; Mitochondrial Membranes; Muscle Weakness; Mutation; Ubiquinone

Glutaric acidemia type 2 (GA2), also called multiple acyl-CoA dehydrogenase deficiency, is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism resulting in excretion of multiple organic acids and glycine conjugates as well as elevation of various plasma acylcarnitine species (C4-C18). It is caused by mutations in the ETFA, ETFB, or ETFDH genes which are involved in the transfer of electrons from 11 flavin-containing dehydrogenases to Coenzyme Q

Topics: Acyl-CoA Dehydrogenase, Long-Chain; Adult; Age of Onset; Ataxia; Child; Electron-Transferring Flavoproteins; Energy Metabolism; Humans; Iron-Sulfur Proteins; Male; Mitochondria; Mitochondrial Diseases; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Muscle Weakness; Oxidoreductases Acting on CH-NH Group Donors; Ubiquinone; Young Adult

Abnormalities of one carbon, glutathione and sulfide metabolisms have recently emerged as novel pathomechanisms in diseases with mitochondrial dysfunction. However, the mechanisms underlying these abnormalities are not clear. Also, we recently showed that sulfide oxidation is impaired in Coenzyme Q10 (CoQ10) deficiency. This finding leads us to hypothesize that the therapeutic effects of CoQ10, frequently administered to patients with primary or secondary mitochondrial dysfunction, might be due to its function as cofactor for sulfide:quinone oxidoreductase (SQOR), the first enzyme in the sulfide oxidation pathway. Here, using biased and unbiased approaches, we show that supraphysiological levels of CoQ10 induces an increase in the expression of SQOR in skin fibroblasts from control subjects and patients with mutations in Complex I subunits genes or CoQ biosynthetic genes. This increase of SQOR induces the downregulation of the cystathionine β-synthase and cystathionine γ-lyase, two enzymes of the transsulfuration pathway, the subsequent downregulation of serine biosynthesis and the adaptation of other sulfide linked pathways, such as folate cycle, nucleotides metabolism and glutathione system. These metabolic changes are independent of the presence of sulfur aminoacids, are confirmed in mouse models, and are recapitulated by overexpression of SQOR, further proving that the metabolic effects of CoQ10 supplementation are mediated by the overexpression of SQOR. Our results contribute to a better understanding of how sulfide metabolism is integrated in one carbon metabolism and may explain some of the benefits of CoQ10 supplementation observed in mitochondrial diseases.

Topics: Animals; Ataxia; Carbon; Electron Transport; Electron Transport Complex I; Fibroblasts; Glutathione; Humans; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Oxidoreductases Acting on Sulfur Group Donors; Skin; Sulfides; Transcriptome; Ubiquinone; Vitamins

Topics: Ataxia; Fibroblasts; Humans; Infant; Male; Mitochondrial Diseases; Muscle Weakness; Muscle, Skeletal; Ubiquinone

Primary coenzyme Q10 deficiency-6 (COQ10D6) is a rare autosomal recessive disorder caused by COQ6 mutations. The main clinical manifestations are infantile progressive nephrotic syndrome (NS) leading to end-stage renal disease and sensorineural deafness. A 7-year-old girl was diagnosed with steroid-resistant NS (SRNS) and an audiological work-up revealed bilateral sensorineural deafness. A renal biopsy demonstrated focal segmental glomerulosclerosis. Despite immunosuppressive therapy, her serum levels of creatinine increased and haemodialysis was indicated within 1 year after the diagnosis. Living-donor kidney transplantation was performed in the eighth month of haemodialysis. A diagnostic custom-designed panel-gene test including 30 genes for NS revealed homozygous c.1058C > A [rs397514479] in exon nine of COQ6. Her older brother, who had sensorineural hearing loss with no renal or neurological involvement, had the same mutation in homozygous form. COQ6 mutations should be considered not only in patients with SRNS with sensorineural hearing loss but also in patients with isolated sensorineural hearing loss with a family history of NS. The reported p.His174 variant of COQ8B was suggested to be a risk factor for secondary CoQ deficiency, while p.Arg174 appeared to improve the condition in a yeast model. Family segregation and the co-occurrence of biallelic p.Arg174 of COQ8B in a brother with hearing loss implied that the interaction of the altered COQ8B with the mutant COQ6 alleviated the symptoms in this family. CoQ10 replacement therapy should be initiated for these patients, as primary CoQ10 deficiency is considered the only known treatable mitochondrial disease.

Topics: Ataxia; Child; Female; Homozygote; Humans; Kidney; Kidney Failure, Chronic; Male; Mitochondrial Diseases; Muscle Weakness; Mutation; Nephrotic Syndrome; Phenotype; Siblings; Ubiquinone

Mitochondrial acyl-CoA dehydrogenase 9 (ACAD9) deficiency is one of the common causes of respiratory chain complex I deficiency, which is characterized by cardiomyopathy, lactic acidemia, and muscle weakness. Infantile cardiomyopathy is the most common phenotype and is usually lethal by the age of 5 years. Riboflavin treatment is known to be effective in ~65% of the patients; however, the remaining are unresponsive to riboflavin and are in need of additional treatment measures. In this report, we describe a patient with ACAD9 deficiency who developed progressive cardiomyopathy at 8 months of age. As the patient's left ventricular ejection fraction (LVEF) kept decreasing to 45.4% at 1 year 8 months, sodium pyruvate treatment was introduced together with a beta-blocker and coenzyme Q10. This resulted in a steady improvement, with full and sustained normalization of cardiac function without riboflavin. The therapy, therefore, might be a useful addition for the treatment of ACAD9 deficiency.

Topics: Acidosis; Acyl-CoA Dehydrogenase; Acyl-CoA Dehydrogenases; Adrenergic beta-Antagonists; Amino Acid Metabolism, Inborn Errors; Cardiomyopathies; Cardiomyopathy, Hypertrophic; Carvedilol; Drug Therapy, Combination; Female; Humans; Infant, Newborn; Mitochondrial Diseases; Muscle Weakness; Prognosis; Pyruvates; Ubiquinone; Vitamins

Primary deficiency of coenzyme Q10 (CoQ10 ubiquinone), is classified as a mitochondrial respiratory chain disorder with phenotypic variability. The clinical manifestation may involve one or multiple tissue with variable severity and presentation may range from infancy to late onset. ADCK3 gene mutations are responsible for the most frequent form of hereditary CoQ10 deficiency (Q10 deficiency-4 OMIM #612016) which is mainly associated with autosomal recessive spinocerebellar ataxia (ARCA2, SCAR9). Here we provide the clinical, biochemical and genetic investigation for unrelated three nuclear families presenting an autosomal form of Spino-Cerebellar Ataxia due to novel mutations in the ADCK3 gene. Using next generation sequence technology we identified a homozygous Gln343Ter mutation in one family with severe, early onset of the disease and compound heterozygous mutations of Gln343Ter and Ser608Phe in two other families with variable manifestations. Biochemical investigation in fibroblasts showed decreased activity of the CoQ dependent mitochondrial respiratory chain enzyme succinate cytochrome c reductase (complex II + III). Exogenous CoQ slightly improved enzymatic activity, ATP production and decreased oxygen free radicals in some of the patient's cells. Our results are presented in comparison to previously reported mutations and expanding the clinical, molecular and biochemical spectrum of ADCK3 related CoQ10 deficiencies.

Topics: Ataxia; Cerebellar Ataxia; Child, Preschool; Female; Fibroblasts; Humans; Infant; Male; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Mutation; Ubiquinone

Coenzyme Q

Topics: Animals; Ataxia; Drosophila melanogaster; Electron Transport; HeLa Cells; Humans; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Mutation; Ubiquinone; Vitamin K 2

Coenzyme Q (CoQ or ubiquinone) serves as an essential redox-active lipid in respiratory electron and proton transport during cellular energy metabolism. CoQ also functions as a membrane-localized antioxidant protecting cells against lipid peroxidation. CoQ deficiency is associated with multiple human diseases; CoQ

Topics: Antioxidants; Ataxia; Humans; Lipid Peroxidation; Mass Spectrometry; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Oxidative Stress; Phosphoproteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Ubiquinone

A 7-month-old male infant was admitted because he was suffering from nephrotic syndrome, along with encephalomyopathy, hypertrophic cardiomyopathy, clinically suspected deafness and retinitis pigmentosa, and an elevated serum lactate level.. Coenzyme Q. The results of genetic tests, available postmortem, explored two hitherto undescribed mutations in the PDSS2 gene. Both were located within the polyprenyl synthetase domain. Clinical exome sequencing revealed a heterozygous missense mutation in exon 3, and our in-house joint-analysis algorithm detected a heterozygous large 2923-bp deletion that affected the 5 prime end of exon 8. Other causative defects in the CoQ. Until now, the clinical features and the mutational status of 6 patients with a PDSS2 gene defect have been reported in the English literature. Here, we describe for the first time detailed kidney morphology features in a patient with nephrotic syndrome carrying mutations in the PDSS2 gene.

Topics: Alkyl and Aryl Transferases; Ataxia; Autopsy; Fatal Outcome; Genetic Testing; Humans; Infant; Kidney; Male; Mitochondrial Diseases; Muscle Weakness; Mutation; Nephrotic Syndrome; Sclerosis; Ubiquinone

Primary disorders of the human coenzyme Q

Topics: Animals; Apoptosis; Ataxia; Biosynthetic Pathways; Cytochrome P-450 Enzyme System; Disease Models, Animal; Humans; Hydroxybenzoates; Mice; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Pyrimidines; Solubility; Treatment Outcome; Ubiquinone; Vitamins

Coenzyme Q. Muscle samples were homogenized whereby 600 ×g supernatants were used to analyze RC enzyme activities, followed by quantification of CoQ. Central 95% reference intervals (RI) were established for CoQ. In this retrospective study, we report a central 95% reference interval for 600 ×g muscle supernatants prepared from frozen samples. The study reiterates the importance of including CoQ

Topics: Adult; Ataxia; Cells, Cultured; Electron Transport; Energy Metabolism; Female; Gene Expression Regulation; Humans; Male; Middle Aged; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Muscle, Skeletal; Retrospective Studies; Ubiquinone

Nephrotic syndrome can be caused by a subgroup of mitochondrial diseases classified as primary coenzyme Q. We report three pediatric patients with COQ2 variants presenting with nephrotic syndrome. Two of these patients had normal leukocyte CoQ. COQ2 nephropathy should be suspected in patients presenting with nephrotic syndrome, although less common than disease due to mutations in NPHS1, NPHS2, and WT1. The index of suspicion should remain high, and we suggest that providers consider genetic evaluation even in patients with normal leukocyte CoQ

Topics: Alkyl and Aryl Transferases; Ataxia; Biopsy; Child; Child, Preschool; Genetic Testing; Humans; Kidney; Kidney Transplantation; Male; Mitochondrial Diseases; Muscle Weakness; Nephrotic Syndrome; Treatment Outcome; Ubiquinone

Nephrotic syndrome (NS), a frequent chronic kidney disease in children and young adults, is the most common phenotype associated with primary coenzyme Q

Topics: Alkyl and Aryl Transferases; Animals; Antioxidants; Ataxia; Disease Models, Animal; HeLa Cells; Humans; Hydrogen Sulfide; Kidney; Metabolic Networks and Pathways; Mice; Mice, Transgenic; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Nephrotic Syndrome; Oxidation-Reduction; Oxidative Stress; Oxidoreductases Acting on Sulfur Group Donors; Reactive Oxygen Species; Ubiquinone

COQ2 mutations cause a rare infantile multisystemic disease with heterogeneous clinical features. Promising results have been reported in response to Coenzyme Q10 treatment, especially for kidney involvement, but little is known about the long-term outcomes.. We report four new patients from two families with the c.437G→A (p.Ser146Asn) mutation in COQ2 and the outcomes of two patients after long-term coenzyme Q10 treatment.. Index cases from two families presented with vomiting, nephrotic range proteinuria, and diabetes in early infancy. These patients were diagnosed with coenzyme Q10 deficiency and died shortly after diagnosis. Siblings of the index cases later presented with neonatal diabetes and proteinuria and were diagnosed at the first day of life. Coenzyme Q10 treatment was started immediately. The siblings responded dramatically to coenzyme Q10 treatment with normalized glucose and proteinuria levels, but they developed refractory focal clonic seizures beginning at three months of life that progressed to encephalopathy.. In our cohort with CoQ10 deficiency, neurological involvement did not improve with oral coenzyme Q10 treatment despite the initial recovery from the diabetes and nephrotic syndrome.

Topics: Adaptor Proteins, Vesicular Transport; Ataxia; Cohort Studies; Diabetes Mellitus; Family Health; Female; Humans; Infant; Kidney; Magnetic Resonance Imaging; Male; Mitochondrial Diseases; Muscle Weakness; Mutation; Proteinuria; Ubiquinone

Topics: Ataxia; Computer Simulation; DNA Mutational Analysis; Female; Humans; Male; Mitochondrial Diseases; Muscle Weakness; Mutation; Nephrotic Syndrome; Pedigree; Ubiquinone

Coenzyme Q10 (CoQ10 or ubiquinone) deficiency can be due either to mutations in genes involved in CoQ10 biosynthesis pathway, or to mutations in genes unrelated to CoQ10 biosynthesis. CoQ10 defect is the only oxidative phosphorylation disorder that can be clinically improved after oral CoQ10 supplementation. Thus, early diagnosis, first evoked by mitochondrial respiratory chain (MRC) spectrophotometric analysis, then confirmed by direct measurement of CoQ10 levels, is of critical importance to prevent irreversible damage in organs such as the kidney and the central nervous system. It is widely reported that CoQ10 deficient patients present decreased quinone-dependent activities (segments I + III or G3P + III and II + III) while MRC activities of complexes I, II, III, IV and V are normal. We previously suggested that CoQ10 defect may be associated with a deficiency of CoQ10-independent MRC complexes. The aim of this study was to verify this hypothesis in order to improve the diagnosis of this disease.. To determine whether CoQ10 defect could be associated with MRC deficiency, we quantified CoQ10 by LC-MSMS in a cohort of 18 patients presenting CoQ10-dependent deficiency associated with MRC defect. We found decreased levels of CoQ10 in eight patients out of 18 (45 %), thus confirming CoQ10 disease.. Our study shows that CoQ10 defect can be associated with MRC deficiency. This could be of major importance in clinical practice for the diagnosis of a disease that can be improved by CoQ10 supplementation.

Topics: Adolescent; Adult; Aged; Ataxia; Biopsy; Cells, Cultured; Child; Child, Preschool; Chromatography, Liquid; Electron Transport; Female; Fibroblasts; Humans; Infant; Male; Middle Aged; Mitochondrial Diseases; Muscle Weakness; Muscles; Mutation; Spectrophotometry; Tandem Mass Spectrometry; Ubiquinone; Young Adult

Inherited ataxias are a group of heterogeneous disorders in children or adults but their genetic definition remains still undetermined in almost half of the patients. However, CoQ10 deficiency is a rare cause of cerebellar ataxia and ADCK3 is the most frequent gene associated with this defect. We herein report a 48 year old man, who presented with dysarthria and walking difficulties. Brain magnetic resonance imaging showed a marked cerebellar atrophy. Serum lactate was elevated. Tissues obtained by muscle and skin biopsies were studied for biochemical and genetic characterization. Skeletal muscle biochemistry revealed decreased activities of complexes I+III and II+III and a severe reduction of CoQ10 , while skin fibroblasts showed normal CoQ10 levels. A mild loss of maximal respiration capacity was also found by high-resolution respirometry. Molecular studies identified a novel homozygous deletion (c.504del_CT) in ADCK3, causing a premature stop codon. Western blot analysis revealed marked reduction of ADCK3 protein levels. Treatment with CoQ10 was started and, after 1 year follow-up, patient neurological condition slightly improved. This report suggests the importance of investigating mitochondrial function and, in particular, muscle CoQ10 levels, in patients with adult-onset cerebellar ataxia. Moreover, clinical stabilization by CoQ10 supplementation emphasizes the importance of an early diagnosis.

Topics: Ataxia; Cerebellar Ataxia; Codon, Nonsense; Delayed Diagnosis; Electron Transport Chain Complex Proteins; Fibroblasts; Gene Expression; Homozygote; Humans; Lactic Acid; Magnetic Resonance Imaging; Male; Middle Aged; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Muscle, Skeletal; Skin; Ubiquinone

The Coq protein complex assembled from several Coq proteins is critical for coenzyme Q6 (CoQ6) biosynthesis in yeast. Secondary CoQ10 deficiency is associated with mitochondrial DNA (mtDNA) mutations in patients. We previously demonstrated that carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) suppressed CoQ10 levels and COQ5 protein maturation in human 143B cells.. This study explored the putative COQ protein complex in human cells through two-dimensional blue native-polyacrylamide gel electrophoresis and Western blotting to investigate its status in 143B cells after FCCP treatment and in cybrids harboring the mtDNA mutation that caused myoclonic epilepsy with ragged-red fibers (MERRF) syndrome. Ubiquinol-10 and ubiquinone-10 levels were detected by high-performance liquid chromatography. Mitochondrial energy status, mRNA levels of various PDSS and COQ genes, and protein levels of COQ5 and COQ9 in cybrids were examined.. A high-molecular-weight protein complex containing COQ5, but not COQ9, in the mitochondria was identified and its level was suppressed by FCCP and in cybrids with MERRF mutation. That was associated with decreased mitochondrial membrane potential and mitochondrial ATP production. Total CoQ10 levels were decreased under both conditions, but the ubiquinol-10:ubiquinone-10 ratio was increased in mutant cybrids. The expression of COQ5 was increased but COQ5 protein maturation was suppressed in the mutant cybrids.. A novel COQ5-containing protein complex was discovered in human cells. Its destabilization was associated with reduced CoQ10 levels and mitochondrial energy deficiency in human cells treated with FCCP or exhibiting MERRF mutation.. The findings elucidate a possible mechanism for mitochondrial dysfunction-induced CoQ10 deficiency in human cells.

Topics: Ataxia; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Cell Line; DNA, Mitochondrial; Humans; Membrane Potential, Mitochondrial; MERRF Syndrome; Methyltransferases; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Mutation; RNA, Messenger; Ubiquinone

In familial and sporadic multiple system atrophy (MSA) patients, deficiency of coenzyme Q10 (CoQ10) has been associated with mutations in COQ2, which encodes the second enzyme in the CoQ10 biosynthetic pathway. Cerebellar ataxia is the most common presentation of CoQ10 deficiency, suggesting that the cerebellum might be selectively vulnerable to low levels of CoQ10 To investigate whether CoQ10 deficiency represents a common feature in the brains of MSA patients independent of the presence of COQ2 mutations, we studied CoQ10 levels in postmortem brains of 12 MSA, 9 Parkinson disease (PD), 9 essential tremor (ET) patients, and 12 controls. We also assessed mitochondrial respiratory chain enzyme activities, oxidative stress, mitochondrial mass, and levels of enzymes involved in CoQ biosynthesis. Our studies revealed CoQ10 deficiency in MSA cerebellum, which was associated with impaired CoQ biosynthesis and increased oxidative stress in the absence of COQ2 mutations. The levels of CoQ10 in the cerebella of ET and PD patients were comparable or higher than in controls. These findings suggest that CoQ10 deficiency may contribute to the pathogenesis of MSA. Because no disease modifying therapies are currently available, increasing CoQ10 levels by supplementation or upregulation of its biosynthesis may represent a novel treatment strategy for MSA patients.

Topics: Aged; Aged, 80 and over; Ataxia; Case-Control Studies; Cerebellum; Female; Humans; Male; Middle Aged; Mitochondrial Diseases; Multiple System Atrophy; Muscle Weakness; Oxidative Stress; Ubiquinone

Statin-induced myopathy (SIM) has been partially attributed to deficiency of dolichol and coenzyme Q10 (CoQ10). We aimed to test the safety and efficacy of plant polyprenols in combination with CoQ10 for alleviation of SIM.. In an open-label, one-center prospective pilot study patients with SIM received conifer-tree needle polyprenols (4mg/day) and CoQ10 (100mg/day) for 8 weeks. Symptoms and safety were evaluated according to symptom severity score (0-10), creatine kinase (CK) levels, exercise test, dynamometry, complete blood count, clinical biochemistry and electrocardiography.. Of the 14 patients, 11 completed the study per protocol. Two patients withdrew consent due to travels abroad, and it was discontinued for one patient with stage 3 chronic kidney disease due to asymptomatic elevations of liver enzymes at week 4. No safety parameters changed significantly in per protocol group. Non-significant increase of CK levels was observed (P=0.231). Muscle pain (n=10) and weakness (n=7) scores improved significantly (P<0.001 and P=0.018, respectively). Muscle pain completely disappeared in 2 patients, weakness resolved in 3 patients and cramps disappeared in two patients. Four patients assessed improvement strong enough to consider increase of statin dose. No changes were observed in exercise test or dynamometry.. Conifer-tree polyprenols in combination with CoQ10 may be generally safe in patients with SIM, but caution should be exercised in patients with glomerular filtration rate <60mL/min and routine monitoring of the liver enzymes and CK is advocated in all patients. The observed efficacy provides the rationale for a larger, double-blind controlled study with polyprenols.

Topics: Aged; Aged, 80 and over; Biomarkers; Double-Blind Method; Drug Therapy, Combination; Electrocardiography; Exercise Test; Female; Glomerular Filtration Rate; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Muscle Weakness; Myalgia; Pain Measurement; Pilot Projects; Prospective Studies; Terpenes; Tracheophyta; Treatment Outcome; Ubiquinone

Multiple acyl-CoA dehydrogenase deficiency- (MADD-), also called glutaric aciduria type 2, associated leukodystrophy may be severe and progressive despite conventional treatment with protein- and fat-restricted diet, carnitine, riboflavin, and coenzyme Q10. Administration of ketone bodies was described as a promising adjunct, but has only been documented once.. We describe a Portuguese boy of consanguineous parents who developed progressive muscle weakness at 2.5 y of age, followed by severe metabolic decompensation with hypoglycaemia and coma triggered by a viral infection. Magnetic resonance (MR) imaging showed diffuse leukodystrophy. MADD was diagnosed by biochemical and molecular analyses. Clinical deterioration continued despite conventional treatment. Enteral sodium D,L-3-hydroxybutyrate (NaHB) was progressively introduced and maintained at 600 mg/kg BW/d (≈ 3% caloric need). Follow up was 3 y and included regular clinical examinations, biochemical studies, and imaging.. During follow up, the initial GMFC-MLD (motor function classification system, 0 = normal, 6 = maximum impairment) level of 5-6 gradually improved to 1 after 5 mo. Social functioning and quality of life recovered remarkably. We found considerable improvement of MR imaging and spectroscopy during follow up, with a certain lag behind clinical recovery. There was some persistent residual developmental delay.. NaHB is a highly effective and safe treatment that needs further controlled studies.

Topics: Brain; Carnitine; Child, Preschool; Coma; Consanguinity; Dietary Fats; Hereditary Central Nervous System Demyelinating Diseases; Humans; Hypoglycemia; Ketones; Magnetic Resonance Imaging; Male; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Muscle Weakness; Riboflavin; Treatment Outcome; Ubiquinone

Coenzyme Q10 deficiency is a clinically and genetically heterogeneous disorder, with manifestations that may range from fatal neonatal multisystem failure, to adult-onset encephalopathy. We report a patient who presented at birth with severe lactic acidosis, proteinuria, dicarboxylic aciduria, and hepatic insufficiency. She also had dilation of left ventricle on echocardiography. Her neurological condition rapidly worsened and despite aggressive care she died at 23 h of life. Muscle histology displayed lipid accumulation. Electron microscopy showed markedly swollen mitochondria with fragmented cristae. Respiratory-chain enzymatic assays showed a reduction of combined activities of complex I+III and II+III with normal activities of isolated complexes. The defect was confirmed in fibroblasts, where it could be rescued by supplementing the culture medium with 10 μM coenzyme Q10. Coenzyme Q10 levels were reduced (28% of controls) in these cells. We performed exome sequencing and focused the analysis on genes involved in coenzyme Q10 biosynthesis. The patient harbored a homozygous c.545T>G, p.(Met182Arg) alteration in COQ2, which was validated by functional complementation in yeast. In this case the biochemical and morphological features were essential to direct the genetic diagnosis. The parents had another pregnancy after the biochemical diagnosis was established, but before the identification of the genetic defect. Because of the potentially high recurrence risk, and given the importance of early CoQ10 supplementation, we decided to treat with CoQ10 the newborn child pending the results of the biochemical assays. Clinicians should consider a similar management in siblings of patients with CoQ10 deficiency without a genetic diagnosis.

Topics: Acidosis, Lactic; Alkyl and Aryl Transferases; Ataxia; Consanguinity; Fatal Outcome; Female; Gene Expression; Hepatic Insufficiency; Humans; Infant, Newborn; Intellectual Disability; Mitochondria, Muscle; Mitochondrial Diseases; Muscle Weakness; Muscle, Skeletal; Point Mutation; Proteinuria; Renal Aminoacidurias; Sequence Analysis, DNA; Ubiquinone

Coenzyme Q10 (CoQ10) is an important cofactor in the mitochondrial respiratory chain and a potent endogenous antioxidant. CoQ10 deficiency is often associated with numerous diseases, and patients can benefit from CoQ10 supplementation, being more effective when diagnosed and treated early. Due to the increased interest in CoQ10 deficiency, several methods for CoQ10 analysis from plasmatic, muscular, fibroblast, and platelet matrices have been developed. These sampling techniques are not only highly invasive but also too traumatic for periodic clinical monitoring. In the present work, we describe the development and validation of a novel non-invasive sampling method for quantification of CoQ10 in buccal mucosa cells (BMCs) by microHPLC. This method is suitable for using in a routine laboratory and useful for sampling patients in pediatry. CoQ10 correlation was demonstrated between BMCs and plasma levels (Spearman r, 0.4540; p < 0.001). The proposed method is amenable to be applied in the post treatment monitoring, especially in pediatric patients as a non-invasive sample collection. More studies are needed to assess whether this determination could be used for diagnosis and if this matrix could replace the traditional ones.

Topics: Adult; Ataxia; Child; Chromatography, High Pressure Liquid; Humans; Limit of Detection; Mitochondrial Diseases; Mouth Mucosa; Muscle Weakness; Ubiquinone

S-adenosylmethionine (SAM) is the predominant methyl group donor and has a large spectrum of target substrates. As such, it is essential for nearly all biological methylation reactions. SAM is synthesized by methionine adenosyltransferase from methionine and ATP in the cytoplasm and subsequently distributed throughout the different cellular compartments, including mitochondria, where methylation is mostly required for nucleic-acid modifications and respiratory-chain function. We report a syndrome in three families affected by reduced intra-mitochondrial methylation caused by recessive mutations in the gene encoding the only known mitochondrial SAM transporter, SLC25A26. Clinical findings ranged from neonatal mortality resulting from respiratory insufficiency and hydrops to childhood acute episodes of cardiopulmonary failure and slowly progressive muscle weakness. We show that SLC25A26 mutations cause various mitochondrial defects, including those affecting RNA stability, protein modification, mitochondrial translation, and the biosynthesis of CoQ10 and lipoic acid.

Topics: Amino Acid Sequence; Amino Acid Transport Systems; Calcium-Binding Proteins; Child, Preschool; DNA Methylation; Female; Humans; Male; Mitochondrial Diseases; Molecular Sequence Data; Muscle Weakness; Mutation; Pedigree; Prognosis; RNA Stability; S-Adenosylmethionine; Sequence Homology, Amino Acid; Thioctic Acid; Ubiquinone

Primary coenzyme Q₁₀ (CoQ₁₀) deficiencies are associated with mutations in genes encoding enzymes important for its biosynthesis and patients are responsive to CoQ₁₀ supplementation. Early treatment allows better prognosis of the disease and therefore, early diagnosis is desirable. The complex phenotype and genotype and the frequent secondary CoQ₁₀ deficiencies make it difficult to achieve a definitive diagnosis by direct quantification of CoQ₁₀. We developed a non-radioactive methodology for the quantification of CoQ₁₀ biosynthesis in fibroblasts that allows the identification of primary deficiencies. Fibroblasts were incubated 72 h with 28 μmol/L (2)H₃-mevalonate or 1.65 mmol/L (13)C₆-p-hydroxybenzoate. The newly synthesized (2)H₃- and (13)C₆- labelled CoQ₁₀ were analysed by high performance liquid chromatography-tandem mass spectrometry. The mean and the reference range for (13)C₆-CoQ₁₀ and (2)H₃-CoQ₁₀ biosynthesis were 0.97 (0.83-1.1) and 0.13 (0.09-0.17) nmol/Unit of citrate synthase, respectively. We validated the methodology through the study of one patient with COQ2 mutations and six patients with CoQ₁₀ deficiency secondary to other inborn errors of metabolism. Afterwards we investigated 16 patients' fibroblasts and nine showed decreased CoQ₁₀ biosynthesis. Therefore, the next step is to study the COQ genes in order to reach a definitive diagnosis in these nine patients. In the patients with normal rates the deficiency is probably secondary. In conclusion, we have developed a non-invasive non-radioactive method suitable for the detection of defects in CoQ₁₀ biosynthesis, which offers a good tool for the stratification of patients with these treatable mitochondrial diseases.

Topics: Ataxia; Cell Line; Chromatography, High Pressure Liquid; Citrate (si)-Synthase; Fibroblasts; Genotype; Humans; Mitochondrial Diseases; Molecular Diagnostic Techniques; Muscle Weakness; Mutation; Phenotype; Reference Values; Reproducibility of Results; Skin; Tandem Mass Spectrometry; Time Factors; Ubiquinone

Human COQ6 encodes a monooxygenase which is responsible for the C5-hydroxylation of the quinone ring of coenzyme Q (CoQ). Mutations in COQ6 cause primary CoQ deficiency, a condition responsive to oral CoQ10 supplementation. Treatment is however still problematic given the poor bioavailability of CoQ10. We employed S. cerevisiae lacking the orthologous gene to characterize the two different human COQ6 isoforms and the mutations found in patients. COQ6 isoform a can partially complement the defective yeast, while isoform b, which lacks part of the FAD-binding domain, is inactive but partially stable, and could have a regulatory/inhibitory function in CoQ10 biosynthesis. Most mutations identified in patients, including the frameshift Q461fs478X mutation, retain residual enzymatic activity, and all patients carry at least one hypomorphic allele, confirming that the complete block of CoQ biosynthesis is lethal. These mutants are also partially stable and allow the assembly of the CoQ biosynthetic complex. In fact treatment with two hydroxylated analogues of 4-hydroxybenzoic acid, namely, vanillic acid or 3-4-hydroxybenzoic acid, restored the respiratory growth of yeast Δcoq6 cells expressing the mutant huCOQ6-isoa proteins. These compounds, and particularly vanillic acid, could therefore represent an interesting therapeutic option for COQ6 patients.

Topics: Amino Acid Sequence; Aminobenzoates; Ataxia; Gene Expression; Humans; Hydroxybenzoates; Mitochondria; Mitochondrial Diseases; Models, Molecular; Molecular Sequence Data; Muscle Weakness; Mutation; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Sequence Alignment; Sequence Homology, Amino Acid; Ubiquinone; Vanillic Acid

Nitrogen-bisphosphonates (N-BPs) are the most widely used drugs for bone fragility disorders. Long-term or high-dose N-BP use is associated with unusual serious side effects such as osteonecrosis of the jaw, musculoskeletal pain, and atypical fractures of long bones. It has escaped notice that the pathway N-BPs block is central for the endogenous synthesis of coenzyme Q10, an integral enzyme of the mitochondrial respiratory chain and an important lipid-soluble antioxidant. Our objective was to assess the coenzyme Q10 and antioxidant status in relation to N-BP exposure in women with postmenopausal osteoporosis.. Seventy-one postmenopausal women (age, 73.5 ± 5.5 y) with osteoporosis and no other malignancy were included in this cross-sectional study. Seventeen were treatment naive, 27 were on oral N-BP, and 27 were on i.v. N-BP.. Vitamin E γ-tocopherol levels (μmol/mL) were significantly reduced in N-BP users [oral, H(2) = 18.5, P = .02; i.v., H(2) = 25.2, P < .001; mean rank comparisons after Kruskal-Wallis test). Length of time (days) of N-BP exposure, but not age, was inversely associated with the coenzyme Q10/cholesterol ratio (μmol/mol) (β = -0.27; P = .025), which was particularly low for those on i.v. N-BP (mean difference = -35.0 ± 16.9; 95% confidence interval, -65.2 to -4.9; P = .02).. The degree of N-BP exposure appears related to compromised coenzyme Q10 status and vitamin E γ-tocopherol levels in postmenopausal women with osteoporosis. This phenomenon may link to certain adverse N-BP-associated effects. Confirmation of this would suggest that therapeutic supplementation could prevent or reverse certain complications of long-term N-BP therapy for at-risk individuals.

Topics: Aged; Ataxia; Cross-Sectional Studies; Diphosphonates; Estrogen Replacement Therapy; Female; Humans; Mitochondrial Diseases; Muscle Weakness; Nitrogen; Osteoporosis, Postmenopausal; Postmenopause; Prognosis; Ubiquinone; Vitamin E; Vitamin E Deficiency

Coenzyme Q10 (CoQ10) deficiency can manifest diversely, from isolated myopathy to multisystem involvement. Immune dysregulation has not been reported as a feature of the disease. We report a four-year old girl with failure to thrive, recurrent infections, developmental delay with hypotonia, and CoQ10 deficiency with impaired immune function, which improved after CoQ10 and immunoglobulin replacement therapy. Immune dysfunction in CoQ10 deficiency should be considered and treated appropriately.

Topics: Ataxia; Child, Preschool; Enzyme Replacement Therapy; Female; Humans; Immunity; Immunoglobulin G; Lymphocyte Subsets; Mitochondrial Diseases; Muscle Weakness; Treatment Outcome; Ubiquinone

It has been demonstrated that glucose transporter (GLUT1) deficiency in a mouse model causes a diminished cerebral lipid synthesis. This deficient lipid biosynthesis could contribute to secondary CoQ deficiency. We report here, for the first time an association between GLUT1 and coenzyme Q10 deficiency in a pediatric patient.. We report a 15 year-old girl with truncal ataxia, nystagmus, dysarthria and myoclonic epilepsy as the main clinical features. Blood lactate and alanine values were increased, and coenzyme Q10 was deficient both in muscle and fibroblasts. Coenzyme Q10 supplementation was initiated, improving ataxia and nystagmus. Since dysarthria and myoclonic epilepsy persisted, a lumbar puncture was performed at 12 years of age disclosing diminished cerebrospinal glucose concentrations. Diagnosis of GLUT1 deficiency was confirmed by the presence of a de novo heterozygous variant (c.18+2T>G) in the SLC2A1 gene. No mutations were found in coenzyme Q10 biosynthesis related genes. A ketogenic diet was initiated with an excellent clinical outcome. Functional studies in fibroblasts supported the potential pathogenicity of coenzyme Q10 deficiency in GLUT1 mutant cells when compared with controls.. Our results suggest that coenzyme Q10 deficiency might be a new factor in the pathogenesis of G1D, although this deficiency needs to be confirmed in a larger group of G1D patients as well as in animal models. Although ketogenic diet seems to correct the clinical consequences of CoQ deficiency, adjuvant treatment with CoQ could be trialled in this condition if our findings are confirmed in further G1D patients.

Topics: Adolescent; Ataxia; Cation Transport Proteins; Diet, Ketogenic; Dietary Supplements; Female; Glucose Transporter Type 1; Humans; Mitochondrial Diseases; Muscle Weakness; Mutation; Sodium-Hydrogen Exchanger 1; Sodium-Hydrogen Exchangers; Ubiquinone; Vitamins

Neurological disorders with low tissue coenzyme Q10 (CoQ10) levels are important to identify, as they may be treatable.. We evaluated retrospectively clinical, laboratory, and muscle histochemistry and oxidative enzyme characteristics in 49 children with suspected mitochondrial disorders. We compared 18 with CoQ10 deficiency in muscle to 31 with normal CoQ10 values.. Muscle from CoQ10-deficient patients averaged 5.5-fold more frequent type 2C muscle fibers than controls (P < 0.0001). A type 2C fiber frequency of ≥ 5% had 89% sensitivity and 84% specificity for CoQ10 deficiency in this cohort. No biopsy showed active myopathy. There were no differences between groups in frequencies of mitochondrial myopathologic, clinical, or laboratory features. Multiple abnormalities in muscle oxidative enzyme activities were more frequent in CoQ10-deficient patients than in controls.. When a childhood mitochondrial disorder is suspected, an increased frequency of type 2C fibers in morphologically normal muscle suggests CoQ10 deficiency.

Topics: Abnormalities, Multiple; Ataxia; Child; Child, Preschool; Female; Humans; Incidence; Infant; Male; Mitochondrial Diseases; Muscle Fibers, Fast-Twitch; Muscle Weakness; Quadriceps Muscle; Retrospective Studies; Sensitivity and Specificity; Ubiquinone

We evaluated coenzyme Q₁₀ (CoQ) levels in patients studied under suspicion of mitochondrial DNA depletion syndromes (MDS) (n=39). CoQ levels were quantified by HPLC, and the percentage of mtDNA depletion by quantitative real-time PCR. A high percentage of MDS patients presented with CoQ deficiency as compared to other mitochondrial patients (Mann-Whitney-U test: p=0.001). Our findings suggest that MDS are frequently associated with CoQ deficiency, as a possible secondary consequence of disease pathophysiology. Assessment of muscle CoQ status seems advisable in MDS patients since the possibility of CoQ supplementation may then be considered as a candidate therapy.

Topics: Adolescent; Ataxia; Child; Child, Preschool; Chromatography, High Pressure Liquid; DNA, Mitochondrial; Female; Humans; Infant; Infant, Newborn; Male; Metabolism, Inborn Errors; Mitochondrial Diseases; Mitochondrial Myopathies; Muscle Weakness; Muscular Diseases; Real-Time Polymerase Chain Reaction; Ubiquinone; Young Adult

Coenzyme Q10 (CoQ10) is essential for the energy production of the cells and as an electron transporter in the mitochondrial respiratory chain. CoQ10 links the mitochondrial fatty acid β-oxidation to the respiratory chain by accepting electrons from electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO). Recently, it was shown that a group of patients with the riboflavin responsive form of multiple acyl-CoA dehydrogenation deficiency (RR-MADD) carrying inherited amino acid variations in ETF-QO also had secondary CoQ10 deficiency with beneficial effects of CoQ10 treatment, thus adding RR-MADD to an increasing number of diseases involving secondary CoQ10 deficiency. In this study, we show that moderately decreased CoQ10 levels in fibroblasts from six unrelated RR-MADD patients were associated with increased levels of mitochondrial reactive oxygen species (ROS). Treatment with CoQ10, but not with riboflavin, could normalize the CoQ10 level and decrease the level of ROS in the patient cells. Additionally, riboflavin-depleted control fibroblasts showed moderate CoQ10 deficiency, but not increased mitochondrial ROS, indicating that variant ETF-QO proteins and not CoQ10 deficiency are the causes of mitochondrial ROS production in the patient cells. Accordingly, the corresponding variant Rhodobacter sphaeroides ETF-QO proteins, when overexpressed in vitro, bind a CoQ10 pseudosubstrate, Q10Br, less tightly than the wild-type ETF-QO protein, suggesting that molecular oxygen can get access to the electrons in the misfolded ETF-QO protein, thereby generating superoxide and oxidative stress, which can be reversed by CoQ10 treatment.

Topics: Acyl Coenzyme A; Ataxia; Bacterial Proteins; Cells, Cultured; Electron-Transferring Flavoproteins; Fibroblasts; Genetic Variation; Humans; Iron-Sulfur Proteins; Mitochondria; Mitochondrial Diseases; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Muscle Weakness; Oxidation-Reduction; Oxidative Stress; Oxidoreductases Acting on CH-NH Group Donors; Reactive Oxygen Species; Rhodobacter sphaeroides; Riboflavin; Ubiquinone

Disorders of coenzyme Q(10) (CoQ(10)) biosynthesis represent the most treatable subgroup of mitochondrial diseases. Neurological involvement is frequently observed in CoQ(10) deficiency, typically presenting as cerebellar ataxia and/or seizures. The aetiology of the neurological presentation of CoQ(10) deficiency has yet to be fully elucidated and therefore in order to investigate these phenomena we have established a neuronal cell model of CoQ(10) deficiency by treatment of neuronal SH-SY5Y cell line with para-aminobenzoic acid (PABA). PABA is a competitive inhibitor of the CoQ(10) biosynthetic pathway enzyme, COQ2. PABA treatment (1 mM) resulted in a 54 % decrease (46 % residual CoQ(10)) decrease in neuronal CoQ(10) status (p < 0.01). Reduction of neuronal CoQ(10) status was accompanied by a progressive decrease in mitochondrial respiratory chain enzyme activities, with a 67.5 % decrease in cellular ATP production at 46 % residual CoQ(10). Mitochondrial oxidative stress increased four-fold at 77 % and 46 % residual CoQ(10). A 40 % increase in mitochondrial membrane potential was detected at 46 % residual CoQ(10) with depolarisation following oligomycin treatment suggesting a reversal of complex V activity. This neuronal cell model provides insights into the effects of CoQ(10) deficiency on neuronal mitochondrial function and oxidative stress, and will be an important tool to evaluate candidate therapies for neurological conditions associated with CoQ(10) deficiency.

Topics: 4-Aminobenzoic Acid; Adenosine Triphosphate; Ataxia; Cell Line, Tumor; Cerebellar Ataxia; DNA, Mitochondrial; Electron Transport; Energy Metabolism; Humans; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Diseases; Mitochondrial Membranes; Mitochondrial Proton-Translocating ATPases; Muscle Weakness; Oxidative Stress; Ubiquinone

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a metabolic disorder due to dysfunction of electron transfer flavoprotein (ETF) or ETF-ubiquinone oxidoreductase (ETF-QO). Mutations in ETFDH, encoding ETF-QO have been associated with both riboflavin-responsive and non-responsive MADD as well as a myopathic form of CoQ(10) deficiency, although pathomechanisms responsible for these different phenotypes are not well-defined. We performed mutation analysis in four Taiwanese MADD patients. Three novel ETFDH mutations were identified in four patients and all harbored the p.A84T mutation. Muscle CoQ(10) levels and respiratory chain activities measured in two patients were normal. Three patients improved on riboflavin together with carnitine. Our results show that not all MADD patients have CoQ(10) deficiency. Based upon our data, riboflavin and carnitine may be the first-line treatment for MADD.

Topics: Adult; Age of Onset; Asian People; Carnitine; Child; DNA Mutational Analysis; Electron Transport; Electron-Transferring Flavoproteins; Energy Metabolism; Female; Genetic Predisposition to Disease; Humans; Iron-Sulfur Proteins; Male; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Muscle Weakness; Muscle, Skeletal; Mutation; Oxidoreductases Acting on CH-NH Group Donors; Riboflavin; Taiwan; Ubiquinone; Young Adult

Three unrelated, sporadic patients with muscle coenzyme Q10 (CoQ10) deficiency presented at 32, 29, and 6 years of age with proximal muscle weakness and elevated serum creatine kinase (CK) and lactate levels, but without myoglobinuria, ataxia, or seizures. Muscle biopsy showed lipid storage myopathy, combined deficiency of respiratory chain complexes I and III, and CoQ10 levels below 50% of normal. Oral high-dose CoQ10 supplementation improved muscle strength dramatically and normalized serum CK.

Topics: Adult; Coenzymes; Creatine Kinase; Delivery, Obstetric; Disease Progression; Electron Transport Complex I; Electron Transport Complex III; Female; Humans; Lactic Acid; Lipid Metabolism; Male; Metabolism, Inborn Errors; Muscle Weakness; Muscle, Skeletal; Muscular Diseases; Pregnancy; Pregnancy Complications; Ubiquinone

Topics: Aged; Ascomycota; Atorvastatin; Biological Products; Coenzymes; Creatine Kinase; Dietary Supplements; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Muscle Weakness; Muscle, Skeletal; Pyrroles; Ubiquinone

Primary coenzyme Q(10) (CoQ(10)) deficiency is rare. The encephalomyopathic form, described in few families, is characterized by exercise intolerance, recurrent myoglobinuria, developmental delay, ataxia, and seizures.. To report a rare manifestation of CoQ(10) deficiency with isolated mitochondrial myopathy without central nervous system involvement.. The patient was evaluated for progressive muscle weakness. Comprehensive clinical evaluation and muscle biopsy were performed for histopathologic analysis and mitochondrial DNA and respiratory chain enzyme studies. The patient began taking 150 mg/d of a CoQ(10) supplement.. The elevated creatine kinase and lactate levels with abnormal urine organic acid and acylcarnitine profiles in this patient suggested a mitochondrial disorder. Skeletal muscle histochemical evaluation revealed ragged red fibers, and respiratory chain enzyme analyses showed partial reductions in complex I, I + III, and II + III activities with greater than 200% of normal citrate synthase activity. The CoQ(10) concentration in skeletal muscle was 46% of the normal reference mean. The in vitro addition of 50 micromol/L of coenzyme Q(1) to the succinate cytochrome-c reductase assay of the patient's skeletal muscle whole homogenate increased the succinate cytochrome-c reductase activity 8-fold compared with 2.8-fold in the normal control homogenates. Follow-up of the patient in 6 months demonstrated significant clinical improvement with normalization of creatine kinase and lactate levels.. The absence of central nervous system involvement and recurrent myoglobinuria expands the clinical phenotype of this treatable mitochondrial disorder. The complete recovery of myopathy with exogenous CoQ(10) supplementation observed in this patient highlights the importance of early identification and treatment of this genetic disorder.

Topics: Biopsy; Child; Coenzymes; Creatine Kinase; DNA, Mitochondrial; Electron Transport; Humans; Lactic Acid; Male; Microscopy, Electron, Transmission; Mitochondria, Muscle; Mitochondrial Myopathies; Muscle Weakness; Muscle, Skeletal; Staining and Labeling; Ubiquinone