ubiquinone and Ataxia

Coenzyme Q (CoQ) is a remarkably hydrophobic, redox-active lipid that empowers diverse cellular processes. Although most known for shuttling electrons between mitochondrial electron transport chain (ETC) complexes, the roles for CoQ are far more wide-reaching and ever-expanding. CoQ serves as a conduit for electrons from myriad pathways to enter the ETC, acts as a cofactor for biosynthetic and catabolic reactions, detoxifies damaging lipid species, and engages in cellular signaling and oxygen sensing. Many open questions remain regarding the biosynthesis, transport, and metabolism of CoQ, which hinders our ability to treat human CoQ deficiency. Here, we recount progress in filling these knowledge gaps, highlight unanswered questions, and underscore the need for novel tools to enable discoveries and improve the treatment of CoQ-related diseases.

Topics: Ataxia; Humans; Lipids; Mitochondrial Diseases; Oxidation-Reduction; Ubiquinone

Coenzyme Q10 (CoQ10) is one of the essential substances for mitochondrial energy synthesis and extra-mitochondrial vital function. Primary CoQ10 deficiency is a rare disease resulting from interruption of CoQ10 biosynthetic pathway and biallelic COQ4 variants are one of the genetic etiologies recognized in this hereditary disorder. The clinical heterogenicity is broad with wide onset age from prenatal period to adulthood. The typical manifestations include early pharmacoresistant seizure, severe cognition and/or developmental delay, dystonia, ataxia, and spasticity. Patients may also have multisystemic involvements such as cardiomyopathy, lactic acidosis or gastro-esophageal regurgitation disease. Oral CoQ10 supplement is the major therapeutic medication currently. Among those patients, c.370G > A variant is the most common pathogenic variant detected, especially in Asian population. This phenomenon also suggests that this specific allele may be the founder variants in Asia. In this article, we report two siblings with infantile onset seizures, developmental delay, cardiomyopathy, and diffuse brain atrophy. Genetic analysis of both two cases revealed homozygous COQ4 c.370G > A (p.Gly124Ser) variants. We also review the clinical manifestations of primary CoQ10 deficiency patients and possible treatment categories, which are still under survey. As oral CoQ10 supplement may improve or stabilize disease severity, early precise diagnosis of primary CoQ10 deficiency and early treatment are the most important issues. This review article helps to further understand clinical spectrum and treatment categories of primary CoQ10 deficiency with COQ4 variant.

Topics: Ataxia; Cardiomyopathies; Epilepsy; Female; Humans; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Mutation; Pregnancy; Ubiquinone

Primary Coenzyme Q10 deficiency is a rare mitochondriopathy with a wide spectrum of organ involvement, including steroid-resistant nephrotic syndrome mainly associated with disease-causing variants in the genes COQ2, COQ6 or COQ8B. We performed a systematic literature review, PodoNet, mitoNET, and CCGKDD registries queries and an online survey, collecting comprehensive clinical and genetic data of 251 patients spanning 173 published (47 updated) and 78 new cases. Kidney disease was first diagnosed at median age 1.0, 1.2 and 9.8 years in individuals with disease-causing variants in COQ2, COQ6 and COQ8B, respectively. Isolated kidney involvement at diagnosis occurred in 34% of COQ2, 10.8% of COQ6 and 70.7% of COQ8B variant individuals. Classic infantile multiorgan involvement comprised 22% of the COQ2 variant cohort while 47% of them developed neurological symptoms at median age 2.7 years. The association of steroid-resistant nephrotic syndrome and sensorineural hearing loss was confirmed as the distinctive phenotype of COQ6 variants, with hearing impairment manifesting at average age three years. None of the patients with COQ8B variants, but 50% of patients with COQ2 and COQ6 variants progressed to kidney failure by age five. At adult age, kidney survival was equally poor (20-25%) across all disorders. A number of sequence variants, including putative local founder mutations, had divergent clinical presentations, in terms of onset age, kidney and non-kidney manifestations and kidney survival. Milder kidney phenotype was present in those with biallelic truncating variants within the COQ8B variant cohort. Thus, significant intra- and inter-familial phenotype variability was observed, suggesting both genetic and non-genetic modifiers of disease severity.

Topics: Ataxia; Genetic Association Studies; Humans; Mitochondrial Diseases; Muscle Weakness; Mutation; Nephrotic Syndrome; Steroids; Ubiquinone

Coenzyme Q

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

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 (CoQ) is a redox active lipid that plays a central role in cellular homeostasis. It was discovered more than 60 years ago because of its role as electron transporter in the mitochondrial respiratory chain. Since then it has become evident that CoQ has many other functions, not directly related to bioenergetics. It is a cofactor of several mitochondrial dehydrogenases involved in the metabolism of lipids, amino acids, and nucleotides, and in sulfide detoxification. It is a powerful antioxidant and it is involved in the control of programmed cell death by modulating both apoptosis and ferroptosis. CoQ deficiency is a clinically and genetically heterogeneous group of disorders characterized by the impairment of CoQ biosynthesis. CoQ deficient patients display defects in cellular bioenergetics, but also in the other pathways in which CoQ is involved. In this review we will focus on the functions of CoQ not directly related to the respiratory chain, and on how their impairment is relevant for the pathophysiology of CoQ deficiency. A better understanding of the complex set of events triggered by CoQ deficiency will allow to design novel approaches for the treatment of this condition.

Topics: Ataxia; Homeostasis; Humans; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

Primary Coenzyme Q (CoQ) deficiencies are clinically heterogeneous conditions and lack clear genotype-phenotype correlations, complicating diagnosis and prognostic assessment. Here we present a compilation of all the symptoms and patients with primary CoQ deficiency described in the literature so far and analyse the most common clinical manifestations associated with pathogenic variants identified in the different COQ genes. In addition, we identified new associations between the age of onset of symptoms and different pathogenic variants, which could help to a better diagnosis and guided treatment. To make these results useable for clinicians, we created an online platform (https://coenzymeQbiology.github.io/clinic-CoQ-deficiency) about clinical manifestations of primary CoQ deficiency that will be periodically updated to incorporate new information published in the literature. Since CoQ primary deficiency is a rare disease, the available data are still limited, but as new patients are added over time, this tool could become a key resource for a more efficient diagnosis of this pathology.

Topics: Ataxia; Genetic Association Studies; Humans; 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

Cerebellar ataxia is a hallmark of coenzyme Q

Topics: Adult; Ataxia; Child; Disease Progression; Dystonic Disorders; Female; Handwriting; Heterozygote; Humans; Male; Middle Aged; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Ubiquinone; Young Adult

Coenzyme Q

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

Coenzyme Q (CoQ, or ubiquinone) is a remarkable lipid that plays an essential role in mitochondria as an electron shuttle between complexes I and II of the respiratory chain, and complex III. It is also a cofactor of other dehydrogenases, a modulator of the permeability transition pore and an essential antioxidant. CoQ is synthesized in mitochondria by a set of at least 12 proteins that form a multiprotein complex. The exact composition of this complex is still unclear. Most of the genes involved in CoQ biosynthesis (COQ genes) have been studied in yeast and have mammalian orthologues. Some of them encode enzymes involved in the modification of the quinone ring of CoQ, but for others the precise function is unknown. Two genes appear to have a regulatory role: COQ8 (and its human counterparts ADCK3 and ADCK4) encodes a putative kinase, while PTC7 encodes a phosphatase required for the activation of Coq7. Mutations in human COQ genes cause primary CoQ(10) deficiency, a clinically heterogeneous mitochondrial disorder with onset from birth to the seventh decade, and with clinical manifestation ranging from fatal multisystem disorders, to isolated encephalopathy or nephropathy. The pathogenesis of CoQ(10) deficiency involves deficient ATP production and excessive ROS formation, but possibly other aspects of CoQ(10) function are implicated. CoQ(10) deficiency is unique among mitochondrial disorders since an effective treatment is available. Many patients respond to oral CoQ(10) supplementation. Nevertheless, treatment is still problematic because of the low bioavailability of the compound, and novel pharmacological approaches are currently being investigated. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.

Topics: Adenosine Triphosphate; Animals; Ataxia; Electron Transport; Electron Transport Chain Complex Proteins; Humans; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Mutation; Protein Multimerization; Reactive Oxygen Species; Saccharomyces cerevisiae; 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

Coenzyme Q(10) is a remarkable lipid involved in many cellular processes such as energy production through the mitochondrial respiratory chain (RC), beta-oxidation of fatty acids, and pyrimidine biosynthesis, but it is also one of the main cellular antioxidants. Its biosynthesis is still incompletely characterized and requires at least 15 genes. Mutations in eight of them (PDSS1, PDSS2, COQ2, COQ4, COQ6, ADCK3, ADCK4, and COQ9) cause primary CoQ(10) deficiency, a heterogeneous group of disorders with variable age of onset (from birth to the seventh decade) and associated clinical phenotypes, ranging from a fatal multisystem disease to isolated steroid resistant nephrotic syndrome (SRNS) or isolated central nervous system disease. The pathogenesis is complex and related to the different functions of CoQ(10). It involves defective ATP production and oxidative stress, but also an impairment of pyrimidine biosynthesis and increased apoptosis. CoQ(10) deficiency can also be observed in patients with defects unrelated to CoQ(10) biosynthesis, such as RC defects, multiple acyl-CoA dehydrogenase deficiency, and ataxia and oculomotor apraxia.Patients with both primary and secondary deficiencies benefit from high-dose oral supplementation with CoQ(10). In primary forms treatment can stop the progression of both SRNS and encephalopathy, hence the critical importance of a prompt diagnosis. Treatment may be beneficial also for secondary forms, although with less striking results.In this review we will focus on CoQ(10) biosynthesis in humans, on the genetic defects and the specific clinical phenotypes associated with CoQ(10) deficiency, and on the diagnostic strategies for these conditions.

Topics: Adenosine Triphosphate; Animals; Ataxia; Central Nervous System Diseases; Disease Models, Animal; Electron Transport; Humans; Mice; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Nephrotic Syndrome; Oxidative Stress; Phenotype; 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 (CoQ) deficiency syndromes comprise a growing number of neurological and extraneurological disorders. Primary-genetic but also secondary CoQ deficiencies have been reported. The biochemical determination of CoQ is a good tool for the rapid identification of CoQ deficiencies but does not allow the selection of candidate genes for molecular diagnosis. Moreover, the metabolic pathway for CoQ synthesis is an intricate and not well-understood process, where a large number of genes are implicated. Thus, only next-generation sequencing techniques (either genetic panels of whole-exome and -genome sequencing) are at present appropriate for a rapid and realistic molecular diagnosis of these syndromes. The potential treatability of CoQ deficiency strongly supports the necessity of a rapid molecular characterization of patients, since primary CoQ deficiencies may respond well to CoQ treatment.

Topics: Ataxia; Humans; Mitochondrial Diseases; Molecular Diagnostic Techniques; Muscle Weakness; Ubiquinone; Yeasts

Oxidative phosphorylation (OXPHOS) is a metabolic pathway that uses energy released by the oxidation of nutrients to generate adenosine triphosphate (ATP). Coenzyme Q10 (CoQ10), also known as ubiquinone, plays an essential role in the human body not only by generating ATP in the mitochondrial respiratory chain but also by providing protection from reactive oxygen species (ROS) and functioning in the activation of many mitochondrial dehydrogenases and enzymes required in pyrimidine nucleoside biosynthesis. The presentations of primary CoQ10 deficiencies caused by genetic mutations are very heterogeneous. The phenotypes related to energy depletion or ROS production may depend on the content of CoQ10 in the cell, which is determined by the severity of the mutation. Primary CoQ10 deficiency is unique among mitochondrial disorders because early supplementation with CoQ10 can prevent the onset of neurological and renal manifestations. In this review I summarize primary CoQ10 deficiencies caused by various genetic abnormalities, emphasizing its nephropathic form.

Topics: Ataxia; Humans; Kidney Diseases; 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 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

Coenzyme Q, or ubiquinone, is an endogenously synthesized lipid-soluble antioxidant that plays a major role in the mitochondrial respiratory chain. Although extensively studied for decades, recent data on coenzyme Q have painted an exciting albeit incomplete picture of the multiple facets of this molecule's function. In humans, mutations in the genes involved in the biosynthesis of coenzyme Q lead to a heterogeneous group of rare disorders, with most often severe and debilitating symptoms. In this review, we describe the current understanding of coenzyme Q biosynthesis, provide a detailed overview of human coenzyme Q deficiencies and discuss the existing mouse models for coenzyme Q deficiency. Furthermore, we briefly examine the current state of affairs in non-mitochondrial coenzyme Q functions and the latter's link to statin.

Topics: Animals; Ataxia; Disease Models, Animal; Gene Expression Regulation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mevalonic Acid; Mice; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Mutation; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Ubiquinone

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

Mitochondrial respiratory chain defects (RCD) often exhibit multiorgan involvement, affecting mainly tissues with high-energy requirements such as the brain. Epilepsy is frequent during the evolution of mitochondrial disorders (30%) with different presentation in childhood and adulthood in term of type of epilepsy, of efficacy of treatment and also in term of prognosis.. Mitochondrial disorders can begin at any age but the diseases with early onset during childhood have generally severe or fatal outcome in few years. Four age-related epileptic phenotypes could be identified in infancy: infantile spasms, refractory or recurrent status epilepticus, epilepsia partialis continua and myoclonic epilepsy. Except for infantile spasms, epilepsy is difficult to control in most cases (95%). In pediatric patients, mitochondrial epilepsy is more frequent due to mutations in nDNA-located than mtDNA-located genes and vice versa in adults. Ketogenic diet could be an interesting alternative treatment in case of recurrent status epilepticus or pharmacoresistant epilepsy.. Epileptic seizures increase the energy requirements of the metabolically already compromised neurons establishing a vicious cycle resulting in worsening energy failure and neuronal death.

Topics: Adult; Ataxia; Child; Diffuse Cerebral Sclerosis of Schilder; DNA Polymerase gamma; DNA-Directed DNA Polymerase; Epilepsy; Humans; Mitochondrial Diseases; Muscle Weakness; Mutation; Phenotype; Ubiquinone

Chronic ataxias are an heterogeneous group of disorders that affect the child at different ages. Thus, the congenital forms, generally non progressive are observed from first months of life and are expressed by hypotonia and motor delay long before the ataxia became evident. The cerebral magnetic resonance images (MRI) may be diagnostic in some pictures like Joubert syndrome. The group of progressive hereditary ataxias, usually begin after the infant period. The clinical signs are gait instability and ocular apraxia that can be associated with oculocutaneous telangiectasias (ataxia-telangiesctasia) or with sensory neuropathy (Friedreich ataxia). In this review are briefly described congenital ataxias and in more detailed form the progressive hereditary ataxias autosomal recessive, autosomal dominants and mitochondrials. The importance of genetic study is emphasized, because it is the key to obtain the diagnosis in the majority of these diseases. Although now there are no treatments for the majority of progressive hereditary ataxias, some they have like Refsum disease, vitamine E deficiency, Coenzyme Q10 deficiency and others, thus the diagnosis in these cases is even more important. At present the diagnosis of childhood hereditary ataxia not yet treatable is fundamental to obtain suitable handling, determine a precise outcome and to give to the family an opportune genetic counseling.

Topics: Ataxia; Cerebellar Ataxia; Child; Chronic Disease; Female; Humans; Male; Mitochondrial Diseases; Muscle Weakness; Spinocerebellar Degenerations; Ubiquinone

Autosomal recessive cerebellar ataxias belong to a broader group of disorders known as inherited ataxias. In most cases onset occurs before the age of 20. These neurological disorders are characterized by degeneration or abnormal development of the cerebellum and spinal cord. Currently, specific treatment is only available for some of the chronic ataxias, more specifically those related to a known metabolic defect, such as abetalipoproteinemia, ataxia with vitamin E deficiency, and cerebrotendinous xanthomatosis. Treatment based on a diet with reduced intake of fat, supplementation of oral vitamins E and A, and the administration of chenodeoxycholic acid could modify the course of the disease. Although for most of autosomal recessive ataxias there is no definitive treatment, iron chelators and antioxidants have been proposed to reduce the mitochondrial iron overload in Friederich's ataxia patients. Corticosteroids have been used to reduce ataxia symptoms in ataxia telangiectasia. Coenzyme Q10 deficiency associated with ataxia may be responsive to Co Q10 or ubidecarenone supplementations. Early treatment of these disorders may be associated with a better drug response.

Topics: Adrenal Cortex Hormones; Ataxia; Cerebellar Ataxia; Chronic Disease; Frataxin; Friedreich Ataxia; Humans; Iron-Binding Proteins; Mitochondrial Diseases; Muscle Weakness; Ubiquinone; Vitamin E; Vitamin E Deficiency

This article provides an overview of recent advances in the field of inherited ataxias. In the past few years, new causative mutations that broaden the diagnostic spectrum of ataxias have been described. In addition, important advances have unveiled the molecular pathology of these disorders, resulting in a classification based on the pathogenetic pathways rather than clinical or genetic features. As concepts of treatment principles emerge, debate continues as to whether such concepts might be applicable to more than one genetically defined disorder or whether each ataxia disorder requires its own unique therapeutic approach. New clinical assessment instruments have been developed that will facilitate future interventional trials. A recent phase 2 clinical trial suggested a positive effect of high-dose idebenone in Friedreich's ataxia, raising hopes that a treatment option will soon be available for this disorder.

Topics: Antioxidants; Ataxia; Humans; Ubiquinone

Since the identification of the genetic mutation causing Friedreich's ataxia (FRDA) our understanding of the mechanisms underlying disease pathogenesis have improved markedly. The genetic abnormality results in the deficiency of frataxin, a protein targeted to the mitochondrion. There is extensive evidence that mitochondrial respiratory chain dysfunction, oxidative damage and iron accumulation play significant roles in the disease mechanism. There remains considerable debate as to the normal function of frataxin, but it is likely to be involved in mitochondrial iron handling, antioxidant regulation, and/or iron sulphur centre regulation. Therapeutic avenues for patients with FRDA are beginning to be explored in particular targeting antioxidant protection, enhancement of mitochondrial oxidative phosphorylation, iron chelation and more recently increasing FRDA transcription. The use of quinone therapy has been the most extensively studied to date with clear benefits demonstrated using evaluations of both disease biomarkers and clinical symptoms, and this is the topic that will be covered in this review.

Topics: Animals; Ataxia; Benzoquinones; Coenzymes; Disease Models, Animal; Friedreich Ataxia; Humans; Iron; Mutation; Neurodegenerative Diseases; Oxidative Stress; Oxygen; Quinones; Time Factors; Ubiquinone; Vitamin E

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

We assessed the clinical outcome after coenzyme Q(10) (CoQ(10)) therapy in 14 patients presenting ataxia classified into two groups according to CoQ(10) values in muscle (deficient or not). We performed an open-label prospective study: patients were evaluated clinically (international cooperative ataxia rating scale [ICARS] scale, MRI, and videotape registration) at baseline and every 6 months during a period of 2 years after CoQ(10) treatment (30 mg/kg/day). Patients with CoQ(10) deficiency showed a statistically significant reduction of ICARS scores (Wilcoxon test: P = 0.018) after 2 years of CoQ(10) treatment when compared with baseline conditions. In patients without CoQ(10) deficiency, no statistically significant differences were observed in total ICARS scores after therapy, although 1 patient from this group showed a remarkable clinical amelioration. Biochemical diagnosis of CoQ(10) deficiency was a useful tool for the selection of patients who are good candidates for treatment as all of them responded to therapy. However, the remarkable clinical response in 1 case without CoQ(10) deficiency highlights the importance of treatment trials for identification of patients with CoQ(10)-responsive ataxia.

Topics: Adolescent; Adult; Ataxia; Child; Child, Preschool; Female; Humans; Longitudinal Studies; Male; Neurologic Examination; Statistics, Nonparametric; Time Factors; Treatment Outcome; Ubiquinone; Vitamins; Young Adult

Distal hereditary motor neuropathy represents a group of motor inherited neuropathies leading to distal weakness. We report a family of two brothers and a sister affected by distal hereditary motor neuropathy in whom a homozygous variant c.3G>T (p.1Met?) was identified in the COQ7 gene. This gene encodes a protein required for coenzyme Q10 biosynthesis, a component of the respiratory chain in mitochondria. Mutations of COQ7 were previously associated with severe multi-organ disorders characterized by early childhood onset and developmental delay. Using patient blood samples and fibroblasts derived from a skin biopsy, we investigated the pathogenicity of the variant of unknown significance c.3G>T (p.1Met?) in the COQ7 gene and the effect of coenzyme Q10 supplementation in vitro. We showed that this variation leads to a severe decrease in COQ7 protein levels in the patient's fibroblasts, resulting in a decrease in coenzyme Q10 production and in the accumulation of 6-demethoxycoenzyme Q10, the COQ7 substrate. Interestingly, such accumulation was also found in the patient's plasma. Normal coenzyme Q10 and 6-demethoxycoenzyme Q10 levels were restored in vitro by using the coenzyme Q10 precursor 2,4-dihydroxybenzoic acid, thus bypassing the COQ7 requirement. Coenzyme Q10 biosynthesis deficiency is known to impair the mitochondrial respiratory chain. Seahorse experiments showed that the patient's cells mainly rely on glycolysis to maintain sufficient ATP production. Consistently, the replacement of glucose by galactose in the culture medium of these cells reduced their proliferation rate. Interestingly, normal proliferation was restored by coenzyme Q10 supplementation of the culture medium, suggesting a therapeutic avenue for these patients. Altogether, we have identified the first example of recessive distal hereditary motor neuropathy caused by a homozygous variation in the COQ7 gene, which should thus be included in the gene panels used to diagnose peripheral inherited neuropathies. Furthermore, 6-demethoxycoenzyme Q10 accumulation in the blood can be used to confirm the pathogenic nature of the mutation. Finally, supplementation with coenzyme Q10 or derivatives should be considered to prevent the progression of COQ7-related peripheral inherited neuropathy in diagnosed patients.

Topics: Ataxia; Child, Preschool; Humans; Male; Mitochondrial Diseases; Mutation; Ubiquinone

Coenzyme Q (CoQ, ubiquinone) is an essential cellular cofactor composed of a redox-active quinone head group and a long hydrophobic polyisoprene tail. How mitochondria access cytosolic isoprenoids for CoQ biosynthesis is a longstanding mystery. Here, via a combination of genetic screening, metabolic tracing and targeted uptake assays, we reveal that Hem25p-a mitochondrial glycine transporter required for haem biosynthesis-doubles as an isopentenyl pyrophosphate (IPP) transporter in Saccharomyces cerevisiae. Mitochondria lacking Hem25p failed to efficiently incorporate IPP into early CoQ precursors, leading to loss of CoQ and turnover of CoQ biosynthetic proteins. Expression of Hem25p in Escherichia coli enabled robust IPP uptake and incorporation into the CoQ biosynthetic pathway. HEM25 orthologues from diverse fungi, but not from metazoans, were able to rescue hem25∆ CoQ deficiency. Collectively, our work reveals that Hem25p drives the bulk of mitochondrial isoprenoid transport for CoQ biosynthesis in fungi.

Topics: Ataxia; Humans; Mitochondria; Mitochondrial Diseases; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Ubiquinone

Coenzyme Q10 deficiency can be due to mutations in Coenzyme Q10-biosynthesis genes (primary) or genes unrelated to biosynthesis (secondary). Primary Coenzyme Q10 deficiency-4 (COQ10D4), also known as autosomal recessive spinocerebellar ataxia-9 (SCAR9), is an autosomal recessive disorder caused by mutations in the ADCK3 gene. This disorder is characterized by several clinical manifestations such as severe infantile multisystemic illness, encephalomyopathy, isolated myopathy, cerebellar ataxia, or nephrotic syndrome.. In this study, whole-exome sequencing was performed in order to identify disease-causing variants in an affected girl with developmental regression and Epilepsia Partialis Continua (EPC). Next, Sanger sequencing method was used to confirm the identified variant in the patient and segregation analysis in her parents.. The proband is an affected 11-year-old girl with persistent seizures, EPC, and developmental regression including motor, cognition, and speech. Seizures were not controlled with various anticonvulsant drugs despite adequate dosing. Progressive cerebellar atrophy, stroke-like cortical involvement, multifocal hyperintense bright objects, and restriction in diffusion-weighted imaging (DWI) were seen in the brain magnetic resonance imaging (MRI).. A novel homozygous missense variant [NM_020247.5: c.814G>T; (p.Gly272Cys)] was identified within the ADCK3 gene, which is the first mutation in this gene in the Iranian population. Bioinformatics analysis showed this variant is damaging. Based on our patient, clinicians should consider genetic testing earlier to instant diagnosis and satisfactory treatment based on exact etiology to prevent further neurologic sequelae.

Topics: Ataxia; Child; Epilepsia Partialis Continua; Female; Humans; Iran; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

Brown adipose tissue (BAT) mitochondria generate heat via uncoupled respiration due to excessive proton leak through uncoupling proteins (UCPs). We previously found hyperthermia in a newborn mouse model of fragile X syndrome and excessive leak in Fmr1 KO forebrain mitochondria caused by CoQ deficiency. The inefficient thermogenic nature of Fmr1 mutant forebrain mitochondria was reminiscent of BAT metabolic features. Thus, we aimed to characterize BAT mitochondrial function in these hyperthermic mice using a top-down approach. Although there was no change in steady-state levels of UCP1 expression between strains, BAT weighed significantly less in Fmr1 mutants compared with controls. Fmr1 KO BAT mitochondria demonstrated impaired substrate oxidation, lower mitochondrial membrane potentials and rates of respiration, and CoQ deficiency. The CoQ analog decylubiquinone normalized CoQ-dependent electron flux and unmasked excessive proton leak. Unlike mutant forebrain, where such deficiency resulted in pathological proton leak, CoQ deficiency within BAT mitochondria resulted largely in abnormal substrate oxidation. This suggests that CoQ is important in BAT for uncoupled respiration to produce heat during development. Although our data provide further evidence of a link between fragile X mental retardation protein (FMRP) and CoQ biosynthesis, the results highlight the importance of CoQ in developing tissues and suggest tissue-specific differences from CoQ deficiency. Because BAT mitochondria are primarily responsible for regulating core body temperature, the defects we describe in Fmr1 KOs could manifest as an adaptive downregulated response to hyperthermia or could result from FMRP deficiency directly.

Topics: Adipose Tissue, Brown; Animals; Ataxia; Fragile X Mental Retardation Protein; Fragile X Syndrome; Mice; Mice, Knockout; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Protons; Ubiquinone

Primary coenzyme Q10 (CoQ10) deficiency, a recessive disorder associated with various defects of CoQ10 biosynthesis and widely varying clinical presentation, is customarily managed by oral Q10 supplementation but the benefit is debated.. To address this question, we mapped individual responses in two patients with COQ8A-related ataxia following coenzyme Q10 supplementation using noninvasive imaging. Metabolic. Post-treatment change in energy metabolite levels differed in the two patients, with higher energy levels and improved dysarthria and leg coordination in one, and decreased energy levels without clinical benefit in the other.. Our results suggest that the cerebellar bioenergetic state may predict treatment response in COQ8A-related ataxia and highlight the potential of pathophysiology-orientated neuroimaging evidence to inform treatment decisions.

Topics: Ataxia; Cerebellar Ataxia; Energy Metabolism; Humans; Mitochondrial Diseases; Muscle Weakness; Ubiquinone

Primary Coenzyme Q10 (CoQ

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

We report a 19-month-old patient with cardiomyopathy as the first presenting feature of primary COQ10 deficiency-6. This case expands the phenotypic spectrum of this disorder. Furthermore, it shows that genetic testing for primary COQ10 deficiency should be considered in patients with pediatric-onset cardiomyopathy as it can guide treatment options.

Topics: Ataxia; Cardiomyopathies; Humans; Infant; Mitochondrial Diseases; Muscle Weakness; Mutation; Ubiquinone

COQ4 codes for a mitochondrial protein required for coenzyme Q. In-house exome and genome datasets (n = 14,303) were screened for patients with bi-allelic variants in COQ4. Work-up included clinical characterization and functional studies in patient-derived cell lines.. Six different COQ4 variants, three of them novel, were identified in six adult patients from four different families. Three patients had a phenotype of hereditary spastic paraparesis, two sisters showed a predominant cerebellar ataxia, and one patient had mild signs of both. Studies in patient-derived fibroblast lines revealed significantly reduced amounts of COQ4 protein, decreased CoQ. We report bi-allelic variants in COQ4 causing an adult-onset ataxia-spasticity spectrum phenotype and a disease course much milder than previously reported. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Topics: Ataxia; Cerebellar Ataxia; Humans; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Spasticity; Muscle Weakness; Mutation; 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

Overexposure to manganese disrupts cellular energy metabolism across species, but the molecular mechanism underlying manganese toxicity remains enigmatic. Here, we report that excess cellular manganese selectively disrupts coenzyme Q (CoQ) biosynthesis, resulting in failure of mitochondrial bioenergetics. While respiratory chain complexes remain intact, the lack of CoQ as lipophilic electron carrier precludes oxidative phosphorylation and leads to premature cell and organismal death. At a molecular level, manganese overload causes mismetallation and proteolytic degradation of Coq7, a diiron hydroxylase that catalyzes the penultimate step in CoQ biosynthesis. Coq7 overexpression or supplementation with a CoQ headgroup analog that bypasses Coq7 function fully corrects electron transport, thus restoring respiration and viability. We uncover a unique sensitivity of a diiron enzyme to mismetallation and define the molecular mechanism for manganese-induced bioenergetic failure that is conserved across species.

Topics: Ataxia; Humans; Manganese; Mitochondrial Diseases; Mixed Function Oxygenases; Muscle Weakness; Ubiquinone

The spectrum of coenzyme Q

Topics: Adult; Ataxia; Cerebellar Ataxia; Dystonic Disorders; Female; Homozygote; Humans; Mitochondrial Proteins; Mutation; 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

Topics: Ataxia; Humans; Mitochondrial Diseases; Muscle Weakness; 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

Mutations affecting mitochondrial coenzyme Q (CoQ) biosynthesis lead to kidney failure due to selective loss of podocytes, essential cells of the kidney filter. Curiously, neighboring tubular epithelial cells are spared early in disease despite higher mitochondrial content. We sought to illuminate noncanonical, cell-specific roles for CoQ, independently of the electron transport chain (ETC). Here, we demonstrate that CoQ depletion caused by Pdss2 enzyme deficiency in podocytes results in perturbations in polyunsaturated fatty acid (PUFA) metabolism and the Braf/Mapk pathway rather than ETC dysfunction. Single-nucleus RNA-Seq from kidneys of Pdss2kd/kd mice with nephrotic syndrome and global CoQ deficiency identified a podocyte-specific perturbation of the Braf/Mapk pathway. Treatment with GDC-0879, a Braf/Mapk-targeting compound, ameliorated kidney disease in Pdss2kd/kd mice. Mechanistic studies in Pdss2-depleted podocytes revealed a previously unknown perturbation in PUFA metabolism that was confirmed in vivo. Gpx4, an enzyme that protects against PUFA-mediated lipid peroxidation, was elevated in disease and restored after GDC-0879 treatment. We demonstrate broader human disease relevance by uncovering patterns of GPX4 and Braf/Mapk pathway gene expression in tissue from patients with kidney diseases. Our studies reveal ETC-independent roles for CoQ in podocytes and point to Braf/Mapk as a candidate pathway for the treatment of kidney diseases.

Topics: Alkyl and Aryl Transferases; Animals; Ataxia; Drug Delivery Systems; HEK293 Cells; Humans; Indenes; Kidney Diseases; Lipid Peroxidation; MAP Kinase Signaling System; Mice; Mitochondrial Diseases; Muscle Weakness; Podocytes; Proto-Oncogene Proteins B-raf; Pyrazoles; RNA-Seq; Ubiquinone

Coenzyme Q (CoQ) is a ubiquitous lipid serving essential cellular functions. It is the only component of the mitochondrial respiratory chain that can be exogenously absorbed. Here, we provide an overview of current knowledge, controversies, and open questions about CoQ intracellular and tissue distribution, in particular in brain and skeletal muscle. We discuss human neurological diseases and mouse models associated with secondary CoQ deficiency in these tissues and highlight pharmacokinetic and anatomical challenges in exogenous CoQ biodistribution, recent improvements in CoQ formulations and imaging, as well as alternative therapeutical strategies to CoQ supplementation. The last section proposes possible mechanisms underlying secondary CoQ deficiency in human diseases with emphasis on neurological and neuromuscular disorders.

Topics: Ataxia; Humans; Mitochondrial Diseases; Muscle Weakness; Tissue Distribution; 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: Animals; Ataxia; Fibroblasts; Humans; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Muscles; Neurodevelopmental Disorders; Ubiquinone; Zebrafish

Depletion of coenzyme Q (CoQ) is associated with disease, ranging from myopathy to heart failure. To induce a CoQ deficit, C2C12 myotubes were incubated with high dose simvastatin. This resulted in a concentration-dependent inhibition of cell viability. Simvastatin-induced effects were prevented by co-incubation with mevalonic acid. When myotubes were incubated with 60 μM simvastatin, mitochondrial CoQ content decreased while co-incubation with CoQ nanodisks (ND) increased mitochondrial CoQ levels and improved cell viability. Incubation of myotubes with simvastatin also led to a reduction in oxygen consumption rate (OCR). When myotubes were co-incubated with simvastatin and CoQ ND, the decline in OCR was ameliorated. The data indicate that CoQ ND represent a water soluble vehicle capable of delivering CoQ to cultured myotubes. Thus, these biocompatible nanoparticles have the potential to bypass poor CoQ oral bioavailability as a treatment option for individuals with severe CoQ deficiency syndromes and/or aging-related CoQ depletion.

Topics: Animals; Ataxia; Cell Line; Cell Survival; Heart Failure; Humans; Mice; Mitochondria; Mitochondrial Diseases; Muscle Fibers, Skeletal; Muscle Weakness; Muscular Diseases; Nanocomposites; Oxygen Consumption; Simvastatin; Ubiquinone

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; Biological Products; High-Throughput Screening Assays; Humans; Mitochondria; Mitochondrial Diseases; Models, Genetic; Muscle Weakness; Mutation; Saccharomyces cerevisiae; Ubiquinone

Background Coenzyme Q10 (CoQ10) serves as a shuttle for electrons from complexes I and II to complex III in the respiratory chain, and has important functions within the mitochondria. Primary CoQ10 deficiency is a mitochondrial disorder which has devastating effects, and which may be partially treated with exogenous CoQ10 supplementation. Case presentation A 9-month-old girl patient was referred to our clinic due to growth retardation, microcephaly and seizures. She was the third child of consanguineous parents (first-degree cousins) of Pakistani origin, born at 38 weeks gestation, weighing 2000 g after an uncomplicated pregnancy, and was hospitalized for 3 days due to respiratory distress. She had sustained clonic seizures when she was 4 months old. Physical examination showed microcephaly, truncal hypotonia and dysmorphic features. Metabolic tests were inconclusive. Abdominal ultrasonography revealed cystic appearance of the kidneys. Non-compaction of the left ventricle was detected in echocardiography. Cranial magnetic resonance imaging (MRI) showed hypoplasia of the cerebellar vermis and brain stem, corpus callosum agenesis, and cortical atrophy. A panel testing of 450 genes involved in inborn errors of metabolism (IEM) was performed that showed a novel frameshift c.384delG (Gly129Valfs*17) homozygous mutation in COQ9. A treatment of 5 mg/kg/day exogenous CoQ10 was started when she was 10 months old, and the dosage was increased to 50 mg/kg/day after the exact diagnosis. No objective neurological improvement could be observed after the adjustment of the drug dosage. Conclusions We report a case of CoQ10 deficiency due to a novel COQ9 gene mutation that adds clinical data from a newly diagnosed patient. Our case also outlines the importance of genetic panels used for specific diseases including IEM.

Topics: Ataxia; Female; Humans; Infant; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Mutation; Prognosis; Rare Diseases; Ubiquinone

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 is a rare disease that results in diverse and variable clinical manifestations. Nephropathy, myopathy and neurologic involvement are commonly associated, however retinopathy has also been observed with certain pathogenic variants of genes in the coenzyme Q biosynthesis pathway. In this report, we describe a novel presentation of the disease that includes nephropathy and retinopathy without neurological involvement, and which is the result of a compound heterozygous state arising from the inheritance of two recessive potentially pathogenic variants, previously not described.. Retrospective report, with complete ophthalmic examination, multimodal imaging, electroretinography, and whole exome sequencing performed on a family with three affected siblings.. We show that affected individuals in the described family inherited two heterozygous variants of the COQ2 gene, resulting in a frameshift variant in one allele, and a predicted deleterious missense variant in the second allele (c.288dupC,p.(Ala97Argfs*56) and c.376C > G,p.(Arg126Gly) respectively). Electroretinography results were consistent with rod-cone dystrophy in the affected individuals. All affected individuals in the family exhibited the characteristic retinopathy as well as end-stage nephropathy, without evidence of any neurological involvement.. We identified two novel compound heterozygous variants of the COQ2 gene that result in primary coenzyme Q deficiency. Targeted sequencing of coenzyme Q biosynthetic pathway genes may be useful in diagnosing oculorenal clinical presentations syndromes not explained by more well known syndromes (e.g., Senior-Loken and Bardet-Biedl syndromes).

Topics: Ataxia; Humans; Mitochondrial Diseases; Muscle Weakness; Mutation; Pedigree; Retrospective Studies; 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

COQ4 mutations have recently been shown to cause a broad spectrum of mitochondrial disorders in association with CoQ10 deficiency. Herein, we report the clinical phenotype, in silico and biochemical analyses, and intervention for a novel c.370 G > A (p.G124S) COQ4 mutation in a Chinese family. This mutation is exclusively present in the East Asian population (allele frequency of ~0.001). The homozygous mutation caused CoQ10 deficiency-associated Leigh syndrome with an onset at 1-2 months of age, presenting as respiratory distress, lactic acidosis, dystonia, seizures, failure to thrive, and detectable lesions in the midbrain and basal ganglia. No renal impairment was involved. The levels of CoQ10 and mitochondrial respiratory chain complex (C) II + III activity were clearly lower in cultured fibroblasts derived from the patient than in those from unaffected carriers; the decreased CII + III activity could be increased by CoQ10 treatment. Follow-up studies suggested that our patient benefitted from the oral supplementation of CoQ10, which allowed her to maintain a relatively stable health status. Based on the genetic testing, preimplantation and prenatal diagnoses were performed, confirming that the next offspring of this family was unaffected. Our cases expand the phenotypic spectrum of COQ4 mutations and the genotypic spectrum of Leigh syndrome.

Topics: Asian People; Ataxia; Child, Preschool; Computer Simulation; Female; Fibroblasts; Genetic Testing; Heterozygote; Homozygote; Humans; Infant; Leigh Disease; Male; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Mutation; Phenotype; Ubiquinone

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

Primary CoQ deficiency occurs because of the defective biosynthesis of coenzyme Q, one of the key components of the mitochondrial electron transport chain. Patients with this disease present with a myriad of non-specific symptoms and signs, posing a diagnostic challenge. Whole-exome sequencing is vital in the diagnosis of these cases.. Three unrelated cases presenting as either encephalopathy or cardiomyopathy have been diagnosed to harbor a common pathogenic variant c.370G > A in COQ4. COQ4 encodes a key structural component for stabilizing the multienzymatic CoQ biosynthesis complex. This variant is detected only among East and South Asian populations.. Based on the population data and our case series, COQ4-related mitochondriopathy is likely an underrecognized condition. We recommend including the COQ4 c.370G > A variant as a part of the screening process for mitochondriopathy in Chinese populations.

Topics: Ataxia; Exome Sequencing; Female; Genetic Variation; Humans; Infant; Infant, Newborn; Male; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Mutation; 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

Insulin resistance in muscle, adipocytes and liver is a gateway to a number of metabolic diseases. Here, we show a selective deficiency in mitochondrial coenzyme Q (CoQ) in insulin-resistant adipose and muscle tissue. This defect was observed in a range of in vitro insulin resistance models and adipose tissue from insulin-resistant humans and was concomitant with lower expression of mevalonate/CoQ biosynthesis pathway proteins in most models. Pharmacologic or genetic manipulations that decreased mitochondrial CoQ triggered mitochondrial oxidants and insulin resistance while CoQ supplementation in either insulin-resistant cell models or mice restored normal insulin sensitivity. Specifically, lowering of mitochondrial CoQ caused insulin resistance in adipocytes as a result of increased superoxide/hydrogen peroxide production via complex II. These data suggest that mitochondrial CoQ is a proximal driver of mitochondrial oxidants and insulin resistance, and that mechanisms that restore mitochondrial CoQ may be effective therapeutic targets for treating insulin resistance.

Topics: Adipocytes; Adipose Tissue; Animals; Ataxia; Humans; Insulin Resistance; Mice; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Muscles; Oxidants; Sensitivity and Specificity; Ubiquinone

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

Primary CoQ

Topics: Acidosis, Lactic; Ataxia; Autopsy; Exome Sequencing; Female; Humans; Infant, Newborn; Leigh Disease; Male; Mitochondrial Diseases; Muscle Weakness; Mutation; Pregnancy; Siblings; 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

Idebenone is a hydrophilic short-chain coenzyme (Co) Q analogue, which has been used as a potential bypass of defective complex I in both Leber Hereditary Optic Neuropathy and OPA1-dependent Dominant Optic Atrophy. Based on its potential antioxidant effects, it has also been tested in degenerative disorders such as Friedreich's ataxia, Huntington's and Alzheimer's diseases. Idebenone is rapidly modified but the biological effects of its metabolites have been characterized only partially. Here we have studied the effects of quinones generated during in vivo metabolism of idebenone with specific emphasis on 6-(9-carboxynonyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (QS10). QS10 partially restored respiration in cells deficient of complex I or of CoQ without inducing the mitochondrial permeability transition, a detrimental effect of idebenone that may offset its potential benefits [Giorgio et al. (2012) Biochim. Biophys. Acta 1817: 363-369]. Remarkably, respiration was largely rotenone-insensitive in complex I deficient cells and rotenone-sensitive in CoQ deficient cells. These findings indicate that, like idebenone, QS10 can provide a bypass to defective complex I; and that, unlike idebenone, QS10 can partially replace endogenous CoQ. In zebrafish (Danio rerio) treated with rotenone, QS10 was more effective than idebenone in allowing partial recovery of respiration (to 40% and 20% of the basal respiration of untreated embryos, respectively) and allowing zebrafish survival (80% surviving embryos at 60 h post-fertilization, a time point at which all rotenone-treated embryos otherwise died). We conclude that QS10 is potentially more active than idebenone in the treatment of diseases caused by complex I defects, and that it could also be used in CoQ deficiencies of genetic and acquired origin.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Ataxia; Cell Respiration; Cells, Cultured; Electron Transport; Electron Transport Complex I; Embryo, Nonmammalian; Mice; Mitochondria, Liver; Mitochondrial Diseases; Muscle Weakness; Ubiquinone; Zebrafish

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

Familial Hypercholesterolemia (FH) is an autosomal co-dominant genetic disorder characterized by elevated low-density lipoprotein (LDL) cholesterol levels and increased risk for premature cardiovascular disease. Here, we examined FH pathophysiology in skin fibroblasts derived from FH patients harboring heterozygous mutations in the LDL-receptor. Fibroblasts from FH patients showed a reduced LDL-uptake associated with increased intracellular cholesterol levels and coenzyme Q

Topics: Ataxia; Cells, Cultured; Cholesterol; Fibroblasts; Humans; Hyperlipoproteinemia Type II; Lipoproteins, LDL; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Diseases; Mitophagy; Muscle Weakness; Reactive Oxygen Species; Receptors, LDL; 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

Dysfunction of the oxidative phosphorylation (OXPHOS) system is a major cause of human disease and the cellular consequences are highly complex. Here, we present comparative analyses of mitochondrial proteomes, cellular transcriptomes and targeted metabolomics of five knockout mouse strains deficient in essential factors required for mitochondrial DNA gene expression, leading to OXPHOS dysfunction. Moreover, we describe sequential protein changes during post-natal development and progressive OXPHOS dysfunction in time course analyses in control mice and a middle lifespan knockout, respectively. Very unexpectedly, we identify a new response pathway to OXPHOS dysfunction in which the intra-mitochondrial synthesis of coenzyme Q (ubiquinone, Q) and Q levels are profoundly decreased, pointing towards novel possibilities for therapy. Our extensive omics analyses provide a high-quality resource of altered gene expression patterns under severe OXPHOS deficiency comparing several mouse models, that will deepen our understanding, open avenues for research and provide an important reference for diagnosis and treatment.

Topics: Animals; Ataxia; Gene Expression Profiling; Metabolome; Mice, Knockout; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Proteome; Ubiquinone

Primary ubiquinone (UQ) deficiency is an important subset of mitochondrial disease that is caused by mutations in UQ biosynthesis genes. To guide therapeutic efforts we sought to estimate the number of individuals who are born with pathogenic variants likely to cause this disorder. We used the NCBI ClinVar database and literature reviews to identify pathogenic genetic variants that have been shown to cause primary UQ deficiency, and used the gnomAD database of full genome or exome sequences to estimate the frequency of both homozygous and compound heterozygotes within seven genetically-defined populations. We used known population sizes to estimate the number of afflicted individuals in these populations and in the mixed population of the USA. We then performed the same analysis on predicted pathogenic loss-of-function and missense variants that we identified in gnomAD. When including only known pathogenic variants, our analysis predicts 1,665 affected individuals worldwide and 192 in the USA. Adding predicted pathogenic variants, our estimate grows to 123,789 worldwide and 1,462 in the USA. This analysis predicts that there are many undiagnosed cases of primary UQ deficiency, and that a large proportion of these will be in developing regions of the world.

Topics: Ataxia; Databases, Nucleic Acid; Exome; Exome Sequencing; Gene Frequency; High-Throughput Nucleotide Sequencing; Humans; Mitochondrial Diseases; Muscle Weakness; Mutation; Phenotype; Ubiquinone

SUCLA2 defects have been associated with mitochondrial DNA (mtDNA) depletion and the triad of hypotonia, dystonia/Leigh-like syndrome, and deafness. A 9-year-old Brazilian boy of consanguineous parents presented with psychomotor delay, deafness, myopathy, ataxia, and chorea. Despite the prominent movement disorder, brain magnetic resonance imaging (MRI) was normal while

Topics: Ataxia; Brain; Child; Diagnosis, Differential; Homozygote; Humans; Male; Mitochondrial Diseases; Movement Disorders; Muscle Weakness; Muscle, Skeletal; Mutation; Succinate-CoA Ligases; Ubiquinone

Coenzyme Q (CoQ) is an electron acceptor for sulfide-quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway. Here, we show that lack of CoQ in human skin fibroblasts causes impairment of hydrogen sulfide oxidation, proportional to the residual levels of CoQ. Biochemical and molecular abnormalities are rescued by CoQ supplementation in vitro and recapitulated by pharmacological inhibition of CoQ biosynthesis in skin fibroblasts and ADCK3 depletion in HeLa cells. Kidneys of Pdss2

Topics: Alkyl and Aryl Transferases; Animals; Ataxia; Cells, Cultured; Fibroblasts; Humans; Mice; Mice, Knockout; Mitochondrial Diseases; Muscle Weakness; Oxidation-Reduction; Quinone Reductases; Sulfides; Ubiquinone

Coenzyme Q (CoQ) is a key component of the mitochondrial respiratory chain, but it also has several other functions in the cellular metabolism. One of them is to function as an electron carrier in the reaction catalyzed by sulfide:quinone oxidoreductase (SQR), which catalyzes the first reaction in the hydrogen sulfide oxidation pathway. Therefore, SQR may be affected by CoQ deficiency. Using human skin fibroblasts and two mouse models with primary CoQ deficiency, we demonstrate that severe CoQ deficiency causes a reduction in SQR levels and activity, which leads to an alteration of mitochondrial sulfide metabolism. In cerebrum of Coq9

Topics: Animals; Ataxia; Blood Pressure; Cells, Cultured; Cerebrum; Disease Models, Animal; Fibroblasts; Humans; Mice; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Oxidation-Reduction; Quinone Reductases; Sulfides; Ubiquinone

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

Topics: Ataxia; Humans; Mitochondrial Diseases; Muscle Weakness; Nephrotic Syndrome; 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

Defects of coenzyme Q10 (CoQ10) metabolism cause a variety of disorders ranging from isolated myopathy to multisystem involvement. ADCK3 is one of several genes associated with CoQ10 deficiency that presents with progressive cerebellar ataxia, epilepsy, migraine and psychiatric disorders. Diagnosis is challenging due to the wide clinical spectrum and overlap with other mitochondrial disorders.. A detailed description of three new patients and one previously reported patient from three Norwegian families with novel and known ADCK3 mutations is provided focusing on the epileptic semiology and response to treatment. Mutations were identified by whole exome sequencing and in two measurement of skeletal muscle CoQ10 was performed.. All four patients presented with childhood-onset epilepsy and progressive cerebellar ataxia. Three patients had epilepsia partialis continua and stroke-like episodes affecting the posterior brain. Electroencephalography showed focal epileptic activity in the occipital and temporal lobes. Genetic investigation revealed ADCK3 mutations in all patients including a novel change in exon 15: c.T1732G, p.F578V. There was no apparent genotype-phenotype correlation.. ADCK3 mutations can cause a combination of progressive ataxia and acute epileptic encephalopathy with stroke-like episodes. The clinical, radiological and electrophysiological features of this disorder mimic the phenotype of polymerase gamma (POLG) related encephalopathy and it is therefore suggested that ADCK3 mutations be considered in the differential diagnosis of mitochondrial encephalopathy with POLG-like features.

Topics: Adult; Ataxia; Cerebellar Ataxia; Diagnosis, Differential; Epilepsy; Female; Humans; Male; Mitochondrial Diseases; Mitochondrial Encephalomyopathies; Mitochondrial Proteins; Muscle Weakness; Mutation; Phenotype; Ubiquinone; Young Adult

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

Topics: Ataxia; Humans; Mitochondrial Diseases; Muscle Weakness; 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

COQ2 (p-hydroxybenzoate polyprenyl transferase) encodes the enzyme required for the second step of the final reaction sequence of Coenzyme Q

Topics: Alkyl and Aryl Transferases; Ataxia; Gene Expression Regulation; Genotype; Humans; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Mutant Proteins; Mutation; Saccharomyces cerevisiae; Severity of Illness Index; Ubiquinone

Two independent investigations based on the power of yeast genetics, but using radically different discovery-driven approaches, have solved a long-pursued goal: the understanding of the early steps in CoQ biosynthesis, which may help diagnose CoQ deficiencies of unknown origin (Payet et al., 2016; Stefely et al., 2016).

Topics: Ataxia; Mitochondrial Diseases; Muscle Weakness; 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

Brown adipose tissue (BAT) possesses the inherent ability to dissipate metabolic energy as heat through uncoupled mitochondrial respiration. An essential component of the mitochondrial electron transport chain is coenzyme Q (CoQ). While cells synthesize CoQ mostly endogenously, exogenous supplementation with CoQ has been successful as a therapy for patients with CoQ deficiency. However, which tissues depend on exogenous CoQ uptake as well as the mechanism by which CoQ is taken up by cells and the role of this process in BAT function are not well understood. Here, we report that the scavenger receptor CD36 drives the uptake of CoQ by BAT and is required for normal BAT function. BAT from mice lacking CD36 displays CoQ deficiency, impaired CoQ uptake, hypertrophy, altered lipid metabolism, mitochondrial dysfunction, and defective nonshivering thermogenesis. Together, these data reveal an important new role for the systemic transport of CoQ to BAT and its function in thermogenesis.

Topics: Adipose Tissue, Brown; Animals; Ataxia; CD36 Antigens; Chromatography, High Pressure Liquid; Male; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Oxidation-Reduction; Palmitic Acid; Thermogenesis; Ubiquinone

Primary coenzyme Q10 (CoQ10) deficiencies are rare, clinically heterogeneous disorders caused by mutations in several genes encoding proteins involved in CoQ10 biosynthesis. CoQ10 is an essential component of the electron transport chain (ETC), where it shuttles electrons from complex I or II to complex III. By whole-exome sequencing, we identified five individuals carrying biallelic mutations in COQ4. The precise function of human COQ4 is not known, but it seems to play a structural role in stabilizing a multiheteromeric complex that contains most of the CoQ10 biosynthetic enzymes. The clinical phenotypes of the five subjects varied widely, but four had a prenatal or perinatal onset with early fatal outcome. Two unrelated individuals presented with severe hypotonia, bradycardia, respiratory insufficiency, and heart failure; two sisters showed antenatal cerebellar hypoplasia, neonatal respiratory-distress syndrome, and epileptic encephalopathy. The fifth subject had an early-onset but slowly progressive clinical course dominated by neurological deterioration with hardly any involvement of other organs. All available specimens from affected subjects showed reduced amounts of CoQ10 and often displayed a decrease in CoQ10-dependent ETC complex activities. The pathogenic role of all identified mutations was experimentally validated in a recombinant yeast model; oxidative growth, strongly impaired in strains lacking COQ4, was corrected by expression of human wild-type COQ4 cDNA but failed to be corrected by expression of COQ4 cDNAs with any of the mutations identified in affected subjects. COQ4 mutations are responsible for early-onset mitochondrial diseases with heterogeneous clinical presentations and associated with CoQ10 deficiency.

Topics: Amino Acid Sequence; Ataxia; Base Sequence; Exome; Fatal Outcome; Female; Gene Components; Humans; Male; Mitochondrial Diseases; Mitochondrial Proteins; Molecular Sequence Data; Muscle Weakness; Mutation; Pedigree; Phenotype; Saccharomyces cerevisiae; Sequence Analysis, DNA; Ubiquinone

Primary coenzyme Q10 (CoQ10) deficiency is due to mutations in genes involved in CoQ biosynthesis. The disease has been associated with five major phenotypes, but a genotype-phenotype correlation is unclear. Here, we compare two mouse models with a genetic modification in Coq9 gene (Coq9(Q95X) and Coq9(R239X)), and their responses to 2,4-dihydroxybenzoic acid (2,4-diHB). Coq9(R239X) mice manifest severe widespread CoQ deficiency associated with fatal encephalomyopathy and respond to 2,4-diHB increasing CoQ levels. In contrast, Coq9(Q95X) mice exhibit mild CoQ deficiency manifesting with reduction in CI+III activity and mitochondrial respiration in skeletal muscle, and late-onset mild mitochondrial myopathy, which does not respond to 2,4-diHB. We show that these differences are due to the levels of COQ biosynthetic proteins, suggesting that the presence of a truncated version of COQ9 protein in Coq9(R239X) mice destabilizes the CoQ multiprotein complex. Our study points out the importance of the multiprotein complex for CoQ biosynthesis in mammals, which may provide new insights to understand the genotype-phenotype heterogeneity associated with human CoQ deficiency and may have a potential impact on the treatment of this mitochondrial disorder.

Topics: Animals; Ataxia; Disease Models, Animal; Genetic Variation; Genotype; Hydroxybenzoates; Mammals; Mice; Mice, Transgenic; Mitochondrial Diseases; Muscle Weakness; Mutation, Missense; 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

Coenzyme Q is an essential mitochondrial electron carrier, redox cofactor and a potent antioxidant in the majority of cellular membranes. Coenzyme Q deficiency has been associated with a range of metabolic diseases, as well as with some drug treatments and ageing.. We used whole exome sequencing (WES) to investigate patients with inherited metabolic diseases and applied a novel ultra-pressure liquid chromatography-mass spectrometry approach to measure coenzyme Q in patient samples.. We identified a homozygous missense mutation in the COQ7 gene in a patient with complex mitochondrial deficiency, resulting in severely reduced coenzyme Q levels We demonstrate that the coenzyme Q analogue 2,4-dihydroxybensoic acid (2,4DHB) was able to specifically bypass the COQ7 deficiency, increase cellular coenzyme Q levels and rescue the biochemical defect in patient fibroblasts.. We report the first patient with primary coenzyme Q deficiency due to a homozygous COQ7 mutation and a potentially beneficial treatment using 2,4DHB.

Topics: Amino Acid Sequence; Ataxia; Child; Child, Preschool; Chromatography, Liquid; DNA Mutational Analysis; Exome; Homozygote; Humans; Hydroxybenzoates; Infant, Newborn; Male; Mitochondria; Mitochondrial Diseases; Molecular Sequence Data; Muscle Weakness; Mutation, Missense; Sequence Alignment; Tandem Mass Spectrometry; Ubiquinone

Topics: Adult; Ataxia; Electron-Transferring Flavoproteins; Humans; Iron-Sulfur Proteins; Male; Mitochondrial Diseases; Muscle Weakness; Mutation; Oxidoreductases Acting on CH-NH Group Donors; Ubiquinone; Young Adult

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

Primary Coenzyme Q10 (CoQ10) deficiency is an autosomal recessive disorder with a heterogeneous clinical presentation. Common presenting features include both muscle and neurological dysfunction. Muscle abnormalities can improve, both clinically and biochemically following CoQ10 supplementation, however neurological symptoms are only partially ameliorated. At present, the reasons for the refractory nature of the neurological dysfunction remain unknown. In order to investigate this at the biochemical level we evaluated the effect of CoQ10 treatment upon a previously established neuronal cell model of CoQ10 deficiency. This model was established by treatment of human SH-SY5Y neuronal cells with 1 mM para-aminobenzoic acid (PABA) which induced a 54% decrease in cellular CoQ10 status. CoQ10 treatment (2.5 μM) for 5 days significantly (p<0.0005) decreased the level of mitochondrial superoxide in the CoQ10 deficient neurons. In addition, CoQ10 treatment (5 μM) restored mitochondrial membrane potential to 90% of the control level. However, CoQ10 treatment (10 μM) was only partially effective at restoring mitochondrial electron transport chain (ETC) enzyme activities. ETC complexes II/III activity was significantly (p<0.05) increased to 82.5% of control levels. ETC complexes I and IV activities were restored to 71.1% and 77.7%, respectively of control levels. In conclusion, the results of this study have indicated that although mitochondrial oxidative stress can be attenuated in CoQ10 deficient neurons following CoQ10 supplementation, ETC enzyme activities appear partially refractory to treatment. Accordingly, treatment with >10 μM CoQ10 may be required to restore ETC enzyme activities to control level. Accordingly, these results have important implication for the treatment of the neurological presentations of CoQ10 deficiency and indicate that high doses of CoQ10 may be required to elicit therapeutic efficacy.

Topics: Ataxia; Cell Line, Tumor; Dietary Supplements; DNA, Mitochondrial; Electron Transport; Energy Metabolism; Humans; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Neuroblastoma; Neurons; Oxidative Stress; Reactive Oxygen Species; Ubiquinone

Coenzyme Q10 (CoQ10) deficiency (MIM 607426) causes a mitochondrial syndrome with variability in the clinical presentations. Patients with CoQ10 deficiency show inconsistent responses to oral ubiquinone-10 supplementation, with the highest percentage of unsuccessful results in patients with neurological symptoms (encephalopathy, cerebellar ataxia or multisystemic disease). Failure in the ubiquinone-10 treatment may be the result of its poor absorption and bioavailability, which may be improved by using different pharmacological formulations. In a mouse model (Coq9(X/X)) of mitochondrial encephalopathy due to CoQ deficiency, we have evaluated oral supplementation with water-soluble formulations of reduced (ubiquinol-10) and oxidized (ubiquinone-10) forms of CoQ10. Our results show that CoQ10 was increased in all tissues after supplementation with ubiquinone-10 or ubiquinol-10, with the tissue levels of CoQ10 with ubiquinol-10 being higher than with ubiquinone-10. Moreover, only ubiquinol-10 was able to increase the levels of CoQ10 in mitochondria from cerebrum of Coq9(X/X) mice. Consequently, ubiquinol-10 was more efficient than ubiquinone-10 in increasing the animal body weight and CoQ-dependent respiratory chain complex activities, and reducing the vacuolization, astrogliosis and oxidative damage in diencephalon, septum-striatum and, to a lesser extent, in brainstem. These results suggest that water-soluble formulations of ubiquinol-10 may improve the efficacy of CoQ10 therapy in primary and secondary CoQ10 deficiencies, other mitochondrial diseases and neurodegenerative diseases.

Topics: Animals; Ataxia; Brain Diseases; Brain Stem; Corpus Striatum; Electron Transport; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Diseases; Mitochondrial Encephalomyopathies; Muscle Weakness; Oxidative Stress; Ubiquinone

Large-scale phenotyping projects such as the Sanger Mouse Genetics project are ongoing efforts to help identify the influences of genes and their modification on phenotypes. Gene-phenotype relations are crucial to the improvement of our understanding of human heritable diseases as well as the development of drugs. However, given that there are ∼: 20 000 genes in higher vertebrate genomes and the experimental verification of gene-phenotype relations requires a lot of resources, methods are needed that determine good candidates for testing.. In this study, we applied an association rule mining approach to the identification of promising secondary phenotype candidates. The predictions rely on a large gene-phenotype annotation set that is used to find occurrence patterns of phenotypes. Applying an association rule mining approach, we could identify 1967 secondary phenotype hypotheses that cover 244 genes and 136 phenotypes. Using two automated and one manual evaluation strategies, we demonstrate that the secondary phenotype candidates possess biological relevance to the genes they are predicted for. From the results we conclude that the predicted secondary phenotypes constitute good candidates to be experimentally tested and confirmed.. The secondary phenotype candidates can be browsed through at http://www.sanger.ac.uk/resources/databases/phenodigm/gene/secondaryphenotype/list.. ao5@sanger.ac.uk or ds5@sanger.ac.uk. Supplementary data are available at Bioinformatics online.

Topics: Animals; Ataxia; Data Mining; Disease; Genes; Humans; Mice; Mitochondrial Diseases; Muscle Weakness; Phenotype; Ubiquinone

Inherited ataxias are heterogeneous disorders affecting both children and adults, with over 40 different causative genes, making molecular genetic diagnosis challenging. Although recent advances in next-generation sequencing have significantly improved mutation detection, few treatments exist for patients with inherited ataxia. In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10, which encodes anoctamin 10, a member of a family of putative calcium-activated chloride channels, and the causative gene for autosomal recessive spinocerebellar ataxia-10 (SCAR10). Both patients presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade. Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other. The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation.

Topics: Adolescent; Adult; Anoctamins; Ataxia; Child; Female; Humans; Membrane Proteins; Middle Aged; Mitochondrial Diseases; Muscle Weakness; Mutation; Ubiquinone; Young Adult

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

Mitochondrial diseases are notoriously difficult to diagnose due to extreme locus and allelic heterogeneity, with both nuclear and mitochondrial genomes potentially liable. Using exome sequencing we demonstrate the ability to rapidly and cost effectively evaluate both the nuclear and mitochondrial genomes to obtain a molecular diagnosis for four patients with three distinct mitochondrial disorders. One patient was found to have Leigh syndrome due to a mutation in MT-ATP6, two affected siblings were discovered to be compound heterozygous for mutations in the NDUFV1 gene, which causes mitochondrial complex I deficiency, and one patient was found to have coenzyme Q10 deficiency due to compound heterozygous mutations in COQ2. In all cases conventional diagnostic testing failed to identify a molecular diagnosis. We suggest that additional studies should be conducted to evaluate exome sequencing as a primary diagnostic test for mitochondrial diseases, including those due to mtDNA mutations.

Topics: Ataxia; Child, Preschool; Electron Transport Complex I; Exome; Female; Genetic Variation; Genome, Mitochondrial; Heterozygote; High-Throughput Nucleotide Sequencing; Humans; Infant; Infant, Newborn; Leigh Disease; Mitochondria; Mitochondrial Diseases; Molecular Diagnostic Techniques; Muscle Weakness; Pedigree; Sequence Analysis, DNA; Sequence Analysis, RNA; Ubiquinone

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

Primary coenzyme Q10 (CoQ10) deficiencies are heterogeneous autosomal recessive disorders. CoQ2 mutations have been identified only rarely in patients. All affected individuals presented with nephrotic syndrome in the first year of life.. An infant is studied with myoclonic seizures and hypertrophic cardiomyopathy in the first months of life and developed a nephrotic syndrome in a later stage.. At three weeks of age, the index patient developed myoclonic seizures. In addition, he had hypertrophic cardiomyopathy and increased CSF lactate. A skeletal muscle biopsy performed at two months of age disclosed normal activities of the oxidative phosphorylation complexes. The child was supplemented with CoQ10 (5 mg/kg/day). At the age of four months, brain MR images showed bilateral increased signal intensities in putamen and cerebral cortex. After that age, he developed massive proteinuria. The daily dose of CoQ10 was increased to 30 mg/kg. Renal biopsy showed focal segmental glomerulosclerosis. Biochemical analyses of a kidney biopsy sample revealed a severely decreased activity of succinate cytochrome c reductase [complex II + III] suggesting ubiquinone depletion. Incorporation of labelled precursors necessary for CoQ10 synthesis was significantly decreased in cultured skin fibroblasts. His condition deteriorated and he died at the age of five months. A novel homozygous mutation c.326G > A (p.Ser109Asn) was found in COQ2.. In contrast to previously reported patients with CoQ2 the proband presented with early myoclonic epilepsy, hypertrophic cardiomyopathy and only in a later stage developed a nephrotic syndrome. The phenotype of this patient enlarges the phenotypical spectrum of the multisystem infantile variant.

Topics: Alkyl and Aryl Transferases; Ataxia; Cardiomyopathy, Hypertrophic; Diffusion Magnetic Resonance Imaging; Electroencephalography; Epilepsies, Myoclonic; Genetic Testing; Humans; Infant; Kidney; Magnetic Resonance Spectroscopy; Male; Microscopy, Electron, Transmission; Mitochondrial Diseases; Muscle Weakness; Muscle, Skeletal; Mutation; Nephrotic Syndrome; Ubiquinone

Ubiquinone (UQ), a.k.a. coenzyme Q, is a redox-active lipid that participates in several cellular processes, in particular mitochondrial electron transport. Primary UQ deficiency is a rare but severely debilitating condition. Mclk1 (a.k.a. Coq7) encodes a conserved mitochondrial enzyme that is necessary for UQ biosynthesis. We engineered conditional Mclk1 knockout models to study pathogenic effects of UQ deficiency and to assess potential therapeutic agents for the treatment of UQ deficiencies. We found that Mclk1 knockout cells are viable in the total absence of UQ. The UQ biosynthetic precursor DMQ9 accumulates in these cells and can sustain mitochondrial respiration, albeit inefficiently. We demonstrated that efficient rescue of the respiratory deficiency in UQ-deficient cells by UQ analogues is side chain length dependent, and that classical UQ analogues with alkyl side chains such as idebenone and decylUQ are inefficient in comparison with analogues with isoprenoid side chains. Furthermore, Vitamin K2, which has an isoprenoid side chain, and has been proposed to be a mitochondrial electron carrier, had no efficacy on UQ-deficient mouse cells. In our model with liver-specific loss of Mclk1, a large depletion of UQ in hepatocytes caused only a mild impairment of respiratory chain function and no gross abnormalities. In conjunction with previous findings, this surprisingly small effect of UQ depletion indicates a nonlinear dependence of mitochondrial respiratory capacity on UQ content. With this model, we also showed that diet-derived UQ10 is able to functionally rescue the electron transport deficit due to severe endogenous UQ deficiency in the liver, an organ capable of absorbing exogenous UQ.

Topics: Alleles; Animals; Ataxia; Cell Respiration; Cell Survival; Disease Models, Animal; Electron Transport; Liver; Membrane Proteins; Mice; Mice, Knockout; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Mixed Function Oxygenases; Muscle Weakness; Oxygen Consumption; Ubiquinone; Vitamin K 2

A 22-year-old man without pre-existing medical conditions presented to our hospital with a progressive reduction of his physical overall performance, muscle weakness of the extremities, and diarrhea for the last 2 months concomitant with elevated liver enzymes and creatine kinase activity. After ruling out infectious diseases, neoplasia, and autoimmune disorders as a cause of these symptoms, the histology of liver and muscle samples led us to suspect a diagnosis of a rare lipid metabolism disorder. Molecular biologic testing provided the diagnosis of multiple acyl-coA dehydrogenase deficiency with ubiquinone deficiency and late onset. The course of disease was complicated by liver failure and severe pneumonia requiring ventilatory assistance. With the substitution of riboflavin and ubiquinone, the patient showed a gradual recovery of his clinical presentation and an improvement of his laboratory tests. A congenital lipid metabolic disorder might be a rare cause of severe myopathy and hepatopathy in a young adult.

Topics: Adult; Ataxia; Diagnosis, Differential; Humans; Liver Failure; Male; Mitochondrial Diseases; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Muscle Weakness; Riboflavin; Treatment Outcome; 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

Ataxia with oculomotor apraxia type1 (AOA1, MIM 208920) is a rare autosomal recessive disease caused by mutations in the APTX gene. We screened a cohort of 204 patients with cerebellar ataxia and 52 patients with early-onset isolated chorea. APTX gene mutations were found in 13 ataxic patients (6%). Eleven patients were homozygous for the known p.W279X, p.W279R, and p.P206L mutations. Three novel APTX mutations were identified: c.477delC (p.I159fsX171), c.C541T (p.Q181X), and c.C916T (p.R306X). Expression of mutated proteins in lymphocytes from these patients was greatly decreased. No mutations were identified in subjects with isolated chorea. Two heterozygous APTX sequence variants (p.L248M and p.D185E) were found in six families with ataxic phenotype. Analyses of coenzyme Q10 in muscle, fibroblasts, and plasma demonstrated normal levels of coenzyme in five of six mutated subjects. The clinical phenotype was homogeneous, irrespectively of the type and location of the APTX mutation, and it was mainly characterized by early-onset cerebellar signs, sensory neuropathy, cognitive decline, and oculomotor deficits. Three cases had slightly raised alpha-fetoprotein. Our survey describes one of the largest series of AOA1 patients and contributes in defining clinical, molecular, and biochemical characteristics of this rare hereditary neurological condition.

Topics: Abnormalities, Multiple; Adolescent; Adult; Apraxias; Ataxia; Child; Cohort Studies; DNA Mutational Analysis; DNA-Binding Proteins; Female; Gene Frequency; Genetic Association Studies; Humans; Italy; Male; Middle Aged; Mutation; Nuclear Proteins; Oculomotor Nerve; Oculomotor Nerve Diseases; Ubiquinone; Young Adult

The lipophilic antioxidant coenzyme Q10 is an effective inhibitor of oxidative damage. Furthermore coenzyme Q10 is involved in electron transport related to the mitochondrial respiratorial chain. Because of this double function coenzyme Q10 has become a special role in the group of antioxidants. Little is known about coenzyme Q10 in healthy and sick children. The aim of the study was to determine the role of coenzyme Q10 in the pathophysiological concept of pediatric diseases. At first a HPLC-method for the detection of coenzyme Q10 in plasma, erythrocytes and platelets was developed and age-related reference values for children were established. Based on these reference values the CoQ10 status was measured in different pediatric diseases. By this way various conditions for low coenzyme Q10 plasma values in children could be defined. Furthermore there were different in vivo models developed to define pharmacokinetic and pharmacodynamic characteristics of coenzyme Q10. The established methods and measured data might be a helpful contribution for estimating coenzyme Q10 deficiency and for planning therapeutical studies with coenzyme Q10 in childhood.

Topics: Antioxidants; Ataxia; Child; Hepatitis; Humans; Migraine Disorders; Mitochondria, Muscle; Mitochondrial Diseases; Oxidative Stress; Severity of Illness Index; Ubiquinone

APTX gene mutations responsible for ataxia-oculomotor apraxia 1 (AOA1) were identified in a family previously reported with ataxia and coenzyme Q10 (CoQ10) deficiency. We measured muscle CoQ10 levels in six patients with AOA1 and found decreased levels in five. Patients homozygous for the W279X mutation had lower values (p = 0.003). A therapeutic trial of CoQ10 may be warranted in patients with AOA1.

Topics: Adult; Apraxias; Ataxia; Coenzymes; DNA-Binding Proteins; Humans; Male; Middle Aged; Mutation; Nuclear Proteins; Oculomotor Nerve Diseases; Ubiquinone

Topics: Ataxia; Child; Female; Humans; Ubiquinone