ubiquinone and Metabolism--Inborn-Errors

Seizures may be the first and the major presenting feature of an inborn error of metabolism (IEM), for example in a neonate with pyridoxine-dependent epilepsy. In other IEMs, seizures may be preceded by other major symptoms: by a reduced level of consciousness in a child with an organic acidaemia or urea cycle defect; or by loss of skills, progressive weakness, ataxia, and upper motor signs in a child with a lysosomal storage disorder or peroxisomal leukodystrophy. This review concentrates on those IEMs for which specific treatment is available. The common metabolic causes of seizures vary according to the age at presentation. Features from the history, examination, imaging, and first line biochemical investigations can all provide clues to an inborn error. This review attempts to delineate these and to provide a guide to the specific tests that can be used to make the diagnosis of disorders with specific treatment.

Topics: Age Factors; Epilepsy; Humans; Infant; Metabolism, Inborn Errors; Pyridoxine; Ubiquinone

The inherited disorders of muscle metabolism affect both substrate utilization and the final intramitochondrial oxidation through the Krebs cycle and the respiratory chain. Almost every step of these complex biochemical pathways can be affected by inborn errors, whose expression depends on peculiar tissue-specific or systemic gene expression. This review updates current knowledge in this broad field.. New inherited defects are still being discovered, such as the beta-enolase deficiency in glycogenosis type XIII and mutations in the gene encoding an esterase/lipase/thioesterase protein in Chanarin-Dorfman syndrome, a multisystem triglyceride storage disease.. Therapeutic approaches to the metabolic myopathies are still lagging behind, although remarkable observations have been made on the rare coenzyme Q10 deficiency syndrome. However, transgenic animal models may offer the opportunity both to investigate muscle pathogenesis and explore therapeutic targets. Finally, human myotoxicity may provide novel paradigms for naturally occurring muscle disorders.

Topics: Animals; Animals, Genetically Modified; Antioxidants; Coenzymes; Glycogen Storage Disease; Humans; Hypolipidemic Agents; Lipid Metabolism; Metabolism, Inborn Errors; Mitochondria, Muscle; Mitochondrial Diseases; Muscular Diseases; Mutation; Phosphopyruvate Hydratase; Ubiquinone

The syndrome of exercise intolerance, cramps, and myoglobinuria is a common presentation of metabolic myopathies and has been associated with several specific inborn errors of glycogen or lipid metabolism. As disorders in fuel utilization presumably impair muscle energy production, it was more than a little surprising that exercise intolerance and myoglobinuria had not been associated with defects in the mitochondrial respiratory chain, the terminal energy-yielding pathway. Recently, however, specific defects in complex I, complex III, and complex IV have been identified in patients with severe exercise intolerance with or without myoglobinuria. All patients were sporadic cases and all harbored mutations in protein-coding genes of muscle mtDNA, suggesting that these were somatic mutations not affecting the germ-line. Another respiratory chain defect, primary coenzyme Q10 (CoQ10) deficiency, also causes exercise intolerance and recurrent myoglobinuria, usually in conjunction with brain symptoms, such as seizures or cerebellar ataxia. Primary CoQ10 deficiency is probably due to mutations in nuclear gene(s) encoding enzymes involved in CoQ10 biosynthesis.

Topics: Adolescent; Adult; Coenzymes; Electron Transport; Electron Transport Complex I; Electron Transport Complex III; Energy Metabolism; Exercise; Exercise Tolerance; Fatty Acids; Female; Glycogen; Humans; Intracellular Membranes; Male; Metabolism, Inborn Errors; Middle Aged; Mitochondria, Muscle; Mitochondrial Myopathies; Muscle Cramp; Muscles; Myoglobinuria; NADH, NADPH Oxidoreductases; Ubiquinone

Topics: Amino Acids; Animals; Avitaminosis; Chemical Phenomena; Chemistry; Dietetics; Haplorhini; Humans; Lipid Metabolism; Metabolism, Inborn Errors; Rabbits; Rats; Tyrosine; Ubiquinone

Topics: Animals; Avitaminosis; Benzoates; Binding Sites; Electron Transport; Folic Acid; Haplorhini; Humans; Lipid Metabolism; Metabolism, Inborn Errors; Mevalonic Acid; Mice; Muscular Dystrophies; Oxidoreductases; Peroxides; Rabbits; Rats; Saccharomyces; Semantics; Succinate Dehydrogenase; Ubiquinone; Vitamin E Deficiency; Vitamins

Identifying diseases displaying chronic low plasma Coenzyme Q

Topics: Adolescent; Adult; Case-Control Studies; Child; Child, Preschool; Chromatography, High Pressure Liquid; Female; Humans; Infant; Infant, Newborn; Male; Metabolism, Inborn Errors; Mucopolysaccharidoses; Mutation; Nervous System Diseases; Phenylketonurias; Retrospective Studies; Sequence Analysis, DNA; Ubiquinone; Young Adult

Ndufc2, a subunit of the NADH: ubiquinone oxidoreductase, plays a key role in the assembly and activity of complex I within the mitochondrial OXPHOS chain. Its deficiency has been shown to be involved in diabetes, cancer and stroke. To improve our knowledge on the mechanisms underlying the increased disease risk due to Ndufc2 reduction, we performed the present in vitro study aimed at the fine characterization of the derangements in mitochondrial structure and function consequent to Ndufc2 deficiency. We found that both fibroblasts obtained from skin of heterozygous Ndufc2 knock-out rat model showed marked mitochondrial dysfunction and PBMC obtained from subjects homozygous for the TT genotype of the rs11237379/NDUFC2 variant, previously shown to associate with reduced gene expression, demonstrated increased generation of reactive oxygen species and mitochondrial damage. The latter was associated with increased oxidative stress and significant ultrastructural impairment of mitochondrial morphology with a loss of internal cristae. In both models the exposure to stress stimuli, such as high-NaCl concentration or LPS, exacerbated the mitochondrial damage and dysfunction. Resveratrol significantly counteracted the ROS generation. These findings provide additional insights on the role of an altered pattern of mitochondrial structure-function as a cause of human diseases. In particular, they contribute to underscore a potential genetic risk factor for cardiovascular diseases, including stroke.

Topics: Animals; Electron Transport Complex I; Fibroblasts; Humans; Leukocytes, Mononuclear; Metabolism, Inborn Errors; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Protein Subunits; Rats; Rats, Inbred SHR; Reactive Oxygen Species; Stroke; 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

The content of coenzyme Q(10) (CoQ(10)) was examined in skin fibroblasts of 10 patients with mevalonic aciduria (MVA) and of 22 patients with methylmalonic aciduria (MMA). Patients with these inborn errors of metabolism are thought to be at risk for CoQ(10) depletion either by direct inhibition of the proximal pathway of CoQ(10) synthesis (MVA) or indirectly by inhibition of mitochondrial energy metabolism (MMA). We demonstrated that CoQ(10) concentrations were not significantly different from controls in MVA patients, suggesting that there may be upregulatory effects. On the other hand the CoQ(10) content in fibroblasts of patients with MMA was significantly reduced.

Topics: Case-Control Studies; Cells, Cultured; Down-Regulation; Female; Fibroblasts; Humans; Metabolism, Inborn Errors; Methylmalonic Acid; Mevalonate Kinase Deficiency; Muscles; Ubiquinone

Topics: Bone Marrow Transplantation; Cholesterol; Fever; Humans; Inflammation; Metabolism, Inborn Errors; Mevalonic Acid; Phosphotransferases (Alcohol Group Acceptor); Protein Prenylation; Transplantation, Homologous; Ubiquinone

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

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

Predominant cerebellar involvement has not been previously reported as a common neuroradiologic feature in pediatric mitochondrial cytopathies. Here we report the neuroradiologic findings of predominant cerebellar volume loss in children with various mitochondrial disorders.. A retrospective analysis of the medical records of 400 consecutive patients referred for evaluation of mitochondrial encephalomyopathies was performed. In 113 cases, definite diagnosis of mitochondrial disease was based on the modified adult criteria that include clinical, histologic, biochemical, functional, molecular, and metabolic parameters.. Predominant cerebellar volume loss with progressive cerebellar atrophy and, less often, cerebellar hypoplasia were found in a heterogeneous group of patients with mitochondrial disease that consisted of four patients with complex I deficiency; four patients with multiple respiratory chain deficiencies; two patients with combined complex I + III and II + III deficiencies, including one patient with partial coenzyme Q10 deficiency; three patients with complex II deficiency; two patients with complex IV deficiency; one patient with mitochondrial neurogastrointestinal encephalomyopathy; and two patients with mitochondrial encephalomyopathy, lactic acidosis, and strokes.. Our retrospective study shows that isolated or predominant cerebellar involvement can be found in various respiratory chain defects or mitochondrial disorders expanding the classical neuroradiologic findings observed in mitochondrial encephalomyopathies. The diagnostic workup in patients with neuromuscular features whose brain MR imaging exhibits cerebellar volume loss should include the evaluation for mitochondrial encephalomyopathies.

Topics: Acidosis, Lactic; Adolescent; Adult; Cerebellum; Child; Child, Preschool; Female; Humans; Infant; Leigh Disease; Magnetic Resonance Imaging; Male; Metabolism, Inborn Errors; Mitochondrial Encephalomyopathies; Multienzyme Complexes; Retrospective Studies; Stroke; Ubiquinone

Isolated complex I deficiency is the most common oxidative phosphorylation defect and is associated with substantial morbidity and mortality. The diagnosis is made by enzymatic analysis and for most patients the molecular pathology remains undefined. Various cofactors and vitamins are frequently administered, but their efficacy have been difficult to assess. We employed determination of ATP production in fibroblast cell lines from patients with complex I deficiency to evaluate the usefulness of therapeutic agents. The effect of each additive varied among the different patients with certain agents favorably affecting ATP production rate in some of the patients and adversely affecting it in others. The reduced nicotinamide adenine dinucleotide (NADH)-ferricyanide reductase assay in muscle mitochondria correlated better than the NADH-coenzyme Q and NADH-cytochrome c assays with ATP production rate in fibroblasts. Our results underscore the necessity of evaluation of different agents for each patient separately. The NADH-ferricyanide reductase assay play a helpful role in directing mutation analysis and identifying patients which are more likely to have their cells amenable for ATP production assessment.

Topics: Adenosine Triphosphate; Cytochromes c; Electron Transport; Electron Transport Complex I; Fibroblasts; Humans; Infant; Infant, Newborn; Metabolism, Inborn Errors; Mitochondria, Muscle; Mutation; NAD; NADH, NADPH Oxidoreductases; Oxidation-Reduction; Ubiquinone

CoQ transfers electrons from complexes I and II of the mitochondrial respiratory chain to complex III. There are very few reports on human CoQ deficiency. The clinical presentation is usually characterized by: epilepsy, muscle weakness, ataxia, cerebellar atrophy, migraine, myogloblinuria and developmental delay. We describe a patient who presented with neonatal liver and pancreatic insufficiency, tyrosinemia and hyperammonemia and later developed sensorineural hearing loss and Leigh syndrome. Liver biopsy revealed markedly reduced complex I+III and II+III. Addition of CoQ to the liver homogenate restored the activities, suggesting CoQ depletion. Histological staining showed prominent bridging; septal fibrosis and widening of portal spaces with prominent mixed inflammatory infiltrate, associated with interface hepatitis, bile duct proliferation with numerous bile plugs. Electron microscopy revealed a large number of mitochondria, which were altered in shape and size, widened and disordered intercristal spaces. This may be the first case of Leigh syndrome with liver and pancreas insufficiency, possibly caused by CoQ responsive oxphos deficiency.

Topics: Biopsy; Electron Transport Complex I; Electron Transport Complex II; Electron Transport Complex III; Hearing Loss, Sensorineural; Humans; Hyperammonemia; Infant; Leigh Disease; Liver; Liver Failure, Acute; Male; Metabolism, Inborn Errors; Mitochondria, Liver; Mitochondrial Diseases; Oxidative Phosphorylation; Pancreas; Ubiquinone

Near-infrared spectrometry (NIRS) is a well-known method used to measure in vivo tissue oxygenation and hemodynamics. This method is used to derive relative measures of hemoglobin (Hb) + myoglobin (Mb) oxygenation and total Hb (tHb) accumulation from measurements of optical attenuation at discrete wavelengths. We present the design and validation of a new NIRS oxygenation analyzer for the measurement of muscle oxygenation kinetics. This design optimizes optical sensitivity and detector wavelength flexibility while minimizing component and construction costs. Using in vitro validations, we demonstrate 1) general optical linearity, 2) system stability, and 3) measurement accuracy for isolated Hb. Using in vivo validations, we demonstrate 1) expected oxygenation changes during ischemia and reactive hyperemia, 2) expected oxygenation changes during muscle exercise, 3) a close correlation between changes in oxyhemoglobin and oxymyoglobin and changes in deoxyhemoglobin and deoxymyoglobin and limb volume by venous occlusion plethysmography, and 4) a minimal contribution from movement artifact on the detected signals. We also demonstrate the ability of this system to detect abnormal patterns of tissue oxygenation in a well-characterized patient with a deficiency of skeletal muscle coenzyme Q(10). We conclude that this is a valid system design for the precise, accurate, and sensitive detection of changes in bulk skeletal muscle oxygenation, can be constructed economically, and can be used diagnostically in patients with disorders of skeletal muscle energy metabolism.

Topics: Coenzymes; Electronics; Equipment Design; Exercise; Hemoglobins; Humans; Hyperemia; Ischemia; Kinetics; Metabolism, Inborn Errors; Movement; Muscle, Skeletal; Myoglobin; Neuromuscular Diseases; Oxygen; Oxygen Consumption; Plethysmography; Reproducibility of Results; Sensitivity and Specificity; Spectroscopy, Near-Infrared; Ubiquinone

3-Methylglutaconic aciduria is an organic aciduria with diverse phenotypic presentations. In more than half of the cases it is a 'neurologic or silent organic aciduria', and, except for one subtype, the biochemical defect is unknown. This report describes 10 new patients. Four of them presented with early global neurologic involvement and arrested development. They rapidly became demented, developed myoclonus or tonic-clonic seizures, spastic quadriplegia, deafness and blindness, and died. Three had acidosis and hypoglycemia neonatally; later, myoclonus and deafness, and eventually severe mental retardation and spastic quadriplegia developed. One patient died. In three children who presented with sudden onset of extrapyramidal tract symptoms, with or without optic atrophy, the clinical presentation was significantly different from that described either for 'unspecified' type or for Costeff syndrome. All three patients showed clinical improvement soon after treatment with coenzyme Q.

Topics: Acidosis; Basal Ganglia Diseases; Child, Preschool; Female; Glutarates; Humans; Infant; Male; Metabolism, Inborn Errors; Nervous System Diseases; Phenotype; Ubiquinone

Patients with mevalonate kinase deficiency suffer from psychomotor retardation, ataxia with progredient cerebellar atrophy, and myopathy. The pathophysiology of the disease remains unclear. The mevalonate kinase product, cholesterol, is within the normal range in patient plasma and fibroblasts. In search of the pathophysiology of this disorder, another mevalonate kinase product, ubiquinone-10, was studied. The concentrations of ubiquinone-10 in patient plasma (n = 6) and ubiquinol-10 in patient LDL (n = 2) and the synthesis of ubiquinone-10 in patient fibroblasts (n = 4) were determined. After oxidative modification of LDL by copper in vitro, the concentrations of alpha-tocopherol and polyunsaturated fatty acids in LDL and the relative electrophoretic mobility of LDL were measured to determine the antioxidant capacity of LDL samples of two affected siblings. The ubiquinone-10 concentrations in plasma samples (median = 508 micrograms/L, range = 488-642 micrograms/L) versus controls (median = 613 micrograms/L, range = 564-809 micrograms/L; p < 0.005) were decreased. In LDL samples of two affected siblings, the concentration of ubiquinol-10 and the resistance to oxidation in vitro were found decreased during intercurrent patient crisis condition. In patient fibroblasts (median = 533 dpm/mg protein, range = 399-1,047 dpm/mg protein) versus controls (median = 40,731 dpm/mg protein, range = 12,774-54,739 dpm/mg protein), the synthesis of ubiquinone was found to be decreased. We conclude that mevalonate kinase deficiency leads to a decreased synthesis of ubiquinone-10 and that ubiquinone-10 deficiency is responsible for the clinical progression of this disease characterized by increased lipid peroxidation, cerebellar atrophy, cataract development, and myopathy with increased creatine kinase activity.

Topics: Cells, Cultured; Child; Child, Preschool; Creatine Kinase; Dolichols; Female; Fibroblasts; Humans; Infant; Lipoproteins, LDL; Male; Metabolism, Inborn Errors; Mevalonic Acid; Oxidation-Reduction; Phosphotransferases (Alcohol Group Acceptor); Ubiquinone; Vitamin E

The electron transport system of muscle mitochondria was examined in a familial syndrome of lactacidemia, mitochondrial myopathy, and encephalopathy. The propositus, a 14-year-old female, and her 12-year-old sister had suffered from progressive muscle weakness, abnormal fatigability, and central nervous system dysfunction since early childhood. In the propositus, the state 3 respiratory rate of muscle mitochondria with NADH-linked substrates and with succinate was markedly reduced. The levels of cytochromes a + a3, b, and c + c1 were normal. The activities of complexes I, II, III, and IV of the electron transport chain were normal or increased. By contrast, the activities of complex I-III and of complex II-III, both of which need coenzyme Q10 (CoQ10), were abnormally low. On direct measurement, the mitochondrial CoQ10 content was 3.7% of the mean value observed in 10 controls. Serum and cultured fibroblasts of the propositus had normal CoQ10 contents. In the younger sister, the respiratory activities and CoQ10 level of muscle mitochondria were similar to those observed in the propositus. The findings establish CoQ10 deficiency as a cause of a familial mitochondrial cytopathy and suggest that the disease results from a tissue-specific defect of CoQ10 biosynthesis.

Topics: Adolescent; Child; Coenzyme A; Cytochromes; Electron Transport; Female; Humans; Metabolism, Inborn Errors; Mitochondria, Muscle; Neuromuscular Diseases; Oxygen Consumption; Reference Values; Ubiquinone

Topics: Animals; Antibody Formation; Antineoplastic Agents; Chick Embryo; Cricetinae; Haplorhini; Humans; Lipid Metabolism; Metabolism, Inborn Errors; Mice; Neoplasms; Peroxides; Phenylalanine; Rabbits; Rats; Sarcoma 180; Succinate Dehydrogenase; Turkeys; Tyrosine; Ubiquinone

Topics: Aortic Aneurysm; Heart Diseases; Heart Septal Defects, Ventricular; Humans; Metabolism, Inborn Errors; Mitochondria, Muscle; Myocardium; Oxidoreductases; Spectrophotometry; Succinate Dehydrogenase; Ubiquinone

Topics: Animals; Electron Transport; Hindlimb; Metabolism, Inborn Errors; Mice; Movement; Muscular Dystrophies; Ubiquinone