ubiquinone and Acidosis--Lactic

Mitochondrial encephalomyopathy with lactic acidosis and stroke- like episodes (MELAS) syndrome is caused by mitochondrial respiratory chain dysfunction and oxidative phosphorylation disorder. It is a rare clinical metabolic disease involved with multiple systems.. A 22-year-old patient presented with limb convulsion accompanied by loss of consciousness, headache, partial blindness, blurred vision, and so on.. Brain magnetic resonance imaging showed a high-intensity area in bilateral occipital cortex, left parietal lobe and cerebellum on diffusion-weighted imaging. These focus did not distribute as vascular territory. The pathological examination of skeletal muscle revealed several succinate dehydrogenase reactive vessels with overreaction and increased content of lipid droplets in some muscle fibers. Genetic testing showed that the patient carried m.10158T>C mutation.. She was provided with traditional arginine hydrochloride therapy and orally medication of coenzyme Q (10 mg).. Mitochondrial DNA of blood and hair follicle of patient carried m.10158T>C mutation LESSONS:: For the suspected patients of MELAS syndrome, if the hot-spot mutation test is negative, more detection sites should be selected.

Topics: Acidosis, Lactic; Administration, Oral; Arginine; Awareness; Brain; DNA, Mitochondrial; Female; Humans; Magnetic Resonance Imaging; MELAS Syndrome; Micronutrients; Mitochondrial Encephalomyopathies; Muscle, Skeletal; Mutation; Stroke; Succinate Dehydrogenase; Ubiquinone; Young Adult

Mitochondrial disorders (MDs) are caused by impairment of the mitochondrial electron transport chain (ETC). The ETC is needed for oxidative phosphorylation, which provides the cell with the most efficient energy outcome in terms of ATP production. One of the pathogenic mechanisms of MDs is the accumulation of reactive oxygen species. Mitochondrial dysfunction and oxidative stress appear to also have a strong impact on the pathogenesis of neurodegenerative diseases and cancer. The treatment of MDs is still inadequate. Therapies that have been attempted include ETC cofactors, other metabolites secondarily decreased in MDs, antioxidants, and agents acting on lactic acidosis. However, the role of these dietary supplements in the treatment of the majority of MDs remains unclear. This article reviews the rationale for their use and their role in clinical practice in the context of MDs and other disorders involving mitochondrial dysfunction.

Topics: Acidosis, Lactic; Animals; Antioxidants; Carnitine; Creatine; Dietary Supplements; Electron Transport; Humans; Mitochondrial Diseases; Succinic Acid; Thioctic Acid; Ubiquinone; Vitamin B Complex; Vitamins

An 82 year old woman was admitted with worsening dyspnoea. Arterial blood gases were taken on air and revealed a pH of 7.39, with a partial pressure of CO2 (pCO2) of 1.2 kPa, pO2 of 19.3 kPa, HCO3 of 13.8 mmol/litre, and base excess of -16.3 mmol/litre: a compensated metabolic acidosis with hyperventilation induced hypocapnia, which is known to be a feature of lactic acidosis. There was also an increased anion gap ((Na140 + K4.0) - (Cl 106 + HCO3 13.8) = 24.2 mEq/litre (reference range, 7-16)), consistent with unmeasured cation. Lactate was measured and found to be raised at 3.33 mmol/litre (reference range, 0.9-1.7). After exclusion of common causes of lactic acidosis Atorvastatin was stopped and her acid-base balance returned to normal. Subsequently, thiamine was also shown to be deficient. The acidosis was thought to have been the result of a mitochondrial defect caused by a deficiency of two cofactors, namely: ubiquinone (as a result of inhibition by statin) and thiamine (as a result of dietary deficiency).

Topics: Acidosis, Lactic; Aged; Aged, 80 and over; Anticholesteremic Agents; Atorvastatin; Diet; Female; Heptanoic Acids; Humans; Pyrroles; Thiamine Deficiency; Ubiquinone

Isolated complex III defect is a relatively rare cause of mitochondrial disorder. New genes involved were identified in the last two decades, with only a few cases described for each deficiency. UQCRC2, which encodes ubiquinol-cytochrome c reductase core protein 2, is one of the eleven structural subunits of complex III. We report seven French patients with UQCRC2 deficiency to complete the phenotype reported so far. We highlight the similarities with neoglucogenesis defect during decompensations - hypoglycaemias, liver failure and lactic acidosis - and point out the rapid improvement with glucose fluid infusion, which is a remarkable feature for a mitochondrial disorder. Finally, we discuss the relevance of coenzyme Q10 supplementation in this defect.

Topics: Acidosis, Lactic; Electron Transport Complex III; Humans; Mitochondrial Diseases; Phenotype; 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

Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) are thought to be rarely accompanied by macroangiopathy. We reported a case of MELAS that presented right distal internal carotid arterial (ICA) stenosis and reviewed 12 similar previously reported cases involving intracranial large blood vessels.. A 38-year-old man suffered from recurrent stroke-like episodes (SE) such as alternating hemiparesis (right lesion 3 years ago and current left lesion), cortical blindness and seizure for 3 years, and was previously misdiagnosed as cerebral infarction. Magnetic Resonance Angiography (MRA) and Digital Subtraction Angiography (DSA) revealed right distal ICA stenosis and sparse cortex blood vessels, which were related to the previous SE.. He was diagnosed by genetic screening (a mitochondrial DNA A3243G point mutation) and presence of high lactic acidosis (4.03 mmol/L), which rose to 7.8 mmol/L after exercise.. The patient received Coenzyme Q10, vitamin C, L-arginine for 2 weeks and valproic acid sodium (400 mg bid) to prevent seizures till now.. He is currently less active and intelligent than his peers, with occasional seizures, and needs family care.. Till date, there are 12 reported cases of MELAS combined with major cerebral arteries abnormalities including stenosis, dissection, occlusion, reversible vasoconstriction, aneurysms, and atherosclerosis. Hence, macroangiopathy in MELAS is not very rare. There is correlation between the affected vessels and the lesions in some cases, but not in others, which may increase the misdiagnosis rate. Hence, mitochondrial diseases cannot be excluded due to concurrent macroangiopathic lesions.

Topics: Acidosis, Lactic; Adult; Arginine; Ascorbic Acid; Carotid Stenosis; Humans; Male; MELAS Syndrome; Mitochondrial Encephalomyopathies; Point Mutation; Ubiquinone; Valproic Acid

Coenzyme Q10 (CoQ10) has an important role in mitochondrial energy metabolism by way of its functioning as an electron carrier in the respiratory chain. Genetic defects disrupting the endogenous biosynthesis pathway of CoQ10 may lead to severe metabolic disorders with onset in early childhood. Using exome sequencing in a child with fatal neonatal lactic acidosis and encephalopathy, we identified a homozygous loss-of-function variant in COQ9. Functional studies in patient fibroblasts showed that the absence of the COQ9 protein was concomitant with a strong reduction of COQ7, leading to a significant accumulation of the substrate of COQ7, 6-demethoxy ubiquinone10. At the same time, the total amount of CoQ10 was severely reduced, which was reflected in a significant decrease of mitochondrial respiratory chain succinate-cytochrome c oxidoreductase (complex II/III) activity. Lentiviral expression of COQ9 restored all these parameters, confirming the causal role of the variant. Our report on the second COQ9 patient expands the clinical spectrum associated with COQ9 variants, indicating the importance of COQ9 already during prenatal development. Moreover, the rescue of cellular CoQ10 levels and respiratory chain complex activities by CoQ10 supplementation points to the importance of an early diagnosis and immediate treatment.

Topics: Acidosis, Lactic; Brain; Brain Diseases; Electron Transport Chain Complex Proteins; Fatal Outcome; Homozygote; Humans; Infant, Newborn; Male; Mitochondrial Proteins; Mutation; Ubiquinone; Ultrasonography

Topics: Acidosis, Lactic; Adolescent; Adult; Aged; Aged, 80 and over; Antioxidants; Cells, Cultured; Child; Child, Preschool; DNA, Mitochondrial; Female; Fibroblasts; Humans; Infant; Infant, Newborn; Leigh Disease; Male; Microtubule-Associated Proteins; Middle Aged; Mitochondrial Dynamics; Mitochondrial Membrane Transport Proteins; Mitochondrial Precursor Protein Import Complex Proteins; Mitophagy; Mutation; Neurology; Ubiquinone; Young Adult

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

Although mitochondrial disease research in general is robust, adequate treatment of these life-threatening conditions has lagged, partly because of a persistence of clinical anecdotes as substitutes for scientifically and ethically rigorous clinical trials. Here I summarize the key lessons learned from some of the "first generation" of randomized controlled trials for genetic mitochondrial diseases and suggest how future trials may benefit from both past experience and exciting new resources available for patient-oriented research and training in this field.

Topics: Acidosis, Lactic; Animals; Dichloroacetic Acid; Financing, Government; Humans; MELAS Syndrome; Mitochondrial Diseases; Neglected Diseases; Randomized Controlled Trials as Topic; Rare Diseases; Societies, Medical; Ubiquinone; United States

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

Topics: Acidosis, Lactic; Ascorbic Acid; Blood Pressure; Carnitine; Drug Therapy, Combination; Humans; Reproducibility of Results; Reverse Transcriptase Inhibitors; Survival Rate; Ubiquinone; Vitamin B Complex

Many CoQ trials for mitochondrial encephalomyopathy are reported, however, the action of CoQ in the central nervous system is unknown. We administered CoQ to a patient with MELAS, and decreasing CSF lactate and pyruvate levels were revealed. This reduction in CSF lactate and pyruvate may be evidence that CoQ acts directly on the CNS. There have been no other descriptions of evidence of CoQ effective action in the central nervous system, a finding unique to this report.

Topics: Acidosis, Lactic; Adult; Agnosia; Cerebrovascular Disorders; Delirium; Dose-Response Relationship, Drug; Hemianopsia; Humans; Lactates; Lactic Acid; Magnetic Resonance Imaging; Male; Mitochondria, Muscle; Neurologic Examination; Neuromuscular Diseases; Pyruvates; Pyruvic Acid; Syndrome; Ubiquinone

An 18-year-old male with mitochondrial myopathy, encephalopathy and lactic acidosis was studied by electromyography (EMG) along with histological and biochemical studies on his biopsied muscle. Mitochondrial cytochrome c oxidase deficiency with a decrease in the amounts of the subunits 2, 6, and 7 was discovered. Although no apparent symptoms of peripheral neuropathy were present, EMG revealed high-amplitude motor unit action potentials with a reduced interference pattern and the histochemical study revealed fiber type grouping without grouped atrophy. These findings indicated lower motor neuron damage, probably due to the mitochondrial disorder, followed by reinnervation. Coenzyme Q10 administration was effective in reducing both the lactate and pyruvate levels and for recovering the muscle atrophy.

Topics: Acidosis, Lactic; Adolescent; Biopsy; Brain Diseases; Coenzymes; Cytochrome-c Oxidase Deficiency; Electromyography; Humans; Male; Mitochondria, Muscle; Muscular Diseases; Ubiquinone

Two patients with mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes (MELAS) in one family are reported. Pathological examination of case 1 showed ragged-red fibers, with 7% of the fibers being unstained by cytochrome c oxidase stain, peripheral nerve damage, multiple areas of softening in the cerebrum and midbrain, and spongy changes in the cerebrum, optic nerve and pons. Electron microscopic examination revealed abnormal accumulations of mitochondria in the skeletal muscle, smooth muscle and cardiac muscle. The activity of cytochrome c oxidase in the brain and liver showed a tendency to decrease. In case 2 (maternal aunt of case 1), muscular weakness and peripheral nerve damage improved by treatment with coenzyme Q10. By adding idebenone to the coenzyme Q10 therapy, the EEG and Wechsler's Adult Intelligence Scale (WAIS) improved. Furthermore, in the cerebral spinal fluid (CSF), the protein, lactate, and pyruvate decreased, and the monoamines and monoamine metabolites increased.

Topics: Acidosis, Lactic; Adolescent; Benzoquinones; Brain Diseases; Cerebrovascular Disorders; Female; Humans; Male; Middle Aged; Mitochondria, Muscle; Quinones; Syndrome; Ubiquinone

A patient with severe muscular hypotonia, failure to thrive, a metabolic acidosis and a renal tubular dysfunction is presented. The disease followed a fatal course. Blood lactate and pyruvate levels as well as lactate/pyruvate ratios were strongly elevated. There were a massive excretion of lactate in urine, a generalized hyperaminoaciduria, a proteinuria and a mellituria. The carnitine concentration was diminished in blood and muscle tissue. Biochemical investigations of skeletal muscle and liver tissue revealed a defect in the respiratory chain at the level of succinate: cytochrome c oxidoreductase. The defect could not be demonstrated in cultured fibroblasts.

Topics: Acidosis, Lactic; Carnitine; Fanconi Syndrome; Female; Humans; Infant, Newborn; Lactates; Lactic Acid; Mitochondria, Muscle; Muscular Diseases; Oxidoreductases; Pyruvates; Succinate Cytochrome c Oxidoreductase; Ubiquinone

Topics: Acidosis, Lactic; Benzoquinones; Brain Diseases, Metabolic; Coenzymes; Female; Humans; Middle Aged; Mitochondria, Muscle; Neuromuscular Diseases; Quinones; Syndrome; Ubiquinone

A male with mitochondrial myopathy, encephalopathy, lactic acidemia, and strokelike episodes is reported. He had also recurrent episodes of ileus. Muscle biopsy revealed ragged-red fibres. The cytochemistry of cytochrome c oxidase (CCO) showed scattered nonstained fibres, while all muscle fibres were heavily stained by immunocytochemistry using CCO antibody. These findings suggest that partical CCO deficiency may be present in the skeletal muscles of the patient. NADH cytochrome c reductase in the patient's muscle mitochondria was low compared with normal controls (about 26%), although succinate cytochrome c reductase was normal. Coenzyme Q10 administration (90 mg/day) did not improve CSF lactate levels, but did decrease plasma lactate levels. His muscle weakness slightly improved.

Topics: Acidosis, Lactic; Adult; Brain Diseases; Cerebrovascular Disorders; Coenzymes; Electron Transport Complex IV; Humans; Intestinal Obstruction; Male; Mitochondria, Muscle; Muscular Diseases; Recurrence; Ubiquinone

Topics: Acidosis, Lactic; Adult; Brain Diseases, Metabolic; Coenzymes; Cytochromes; Electron Transport; Humans; Male; Mitochondria, Muscle; Muscular Diseases; Ubiquinone

In a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes [MELAS] who had normal mitochondrial enzyme activity, high doses of coenzyme Q10 (CoQ) were administered. Clinical improvement with decreased serum lactate and pyruvate levels was observed. Though the mechanism of action of CoQ is not known, a trial is worthwhile in patients with MELAS.

Topics: Acidosis, Lactic; Adolescent; Betamethasone; Brain Diseases; Coenzymes; Female; Humans; Mitochondria, Muscle; Muscular Diseases; Prednisolone; Syndrome; Ubiquinone