coenzyme-q10 and MELAS-Syndrome

Topics: Coenzymes; Deafness; Diabetes Mellitus, Type 2; Diagnosis, Differential; DNA, Mitochondrial; Hypoglycemic Agents; Insulin; Insulin Secretion; MELAS Syndrome; Mitochondria; Mutation; Prognosis; Ubiquinone

Topics: Coenzymes; Diagnosis, Differential; DNA, Mitochondrial; Humans; MELAS Syndrome; Migraine Disorders; Mutation; Prognosis; RNA; RNA, Mitochondrial; RNA, Transfer; Thiamine; Ubiquinone

This paper briefly summarizes the results of a long-term, open pharmacotherapy trial in 16 patients with well-characterized mitochondrial disease. Outcome measures included repeated clinical evaluation, 31P-NMR spectroscopy and near-infrared spectroscopy. Treated patients appeared to survive longer with less functional disability and medical complications than typically seen in clinical practice.

Topics: Adolescent; Adult; Age of Onset; Antioxidants; Ascorbic Acid; Child; Coenzymes; Female; Humans; Kearns-Sayre Syndrome; Male; MELAS Syndrome; MERRF Syndrome; Methylprednisolone; Middle Aged; Mitochondrial Myopathies; Oxidative Phosphorylation; Oxygen Consumption; Treatment Outcome; Ubiquinone; Vitamin E; Vitamin K; Vitamins

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

MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) is a mitochondrial disease most usually caused by point mutations in tRNA genes encoded by mitochondrial DNA (mtDNA). Approximately 80% of cases of MELAS syndrome are associated with a m.3243A > G mutation in the MT-TL1 gene, which encodes the mitochondrial tRNALeu (UUR). Currently, no effective treatments are available for this chronic progressive disorder. Treatment strategies in MELAS and other mitochondrial diseases consist of several drugs that diminish the deleterious effects of the abnormal respiratory chain function, reduce the presence of toxic agents or correct deficiencies in essential cofactors.. We evaluated the effectiveness of some common pharmacological agents that have been utilized in the treatment of MELAS, in yeast, fibroblast and cybrid models of the disease. The yeast model harbouring the A14G mutation in the mitochondrial tRNALeu(UUR) gene, which is equivalent to the A3243G mutation in humans, was used in the initial screening. Next, the most effective drugs that were able to rescue the respiratory deficiency in MELAS yeast mutants were tested in fibroblasts and cybrid models of MELAS disease.. According to our results, supplementation with riboflavin or coenzyme Q(10) effectively reversed the respiratory defect in MELAS yeast and improved the pathologic alterations in MELAS fibroblast and cybrid cell models.. Our results indicate that cell models have great potential for screening and validating the effects of novel drug candidates for MELAS treatment and presumably also for other diseases with mitochondrial impairment.

Topics: Autophagy; Cell Line; Cells, Cultured; Drug Evaluation, Preclinical; Fibroblasts; Genes, Mitochondrial; Humans; MELAS Syndrome; Models, Biological; Mutation; Reactive Oxygen Species; Riboflavin; RNA, Transfer, Leu; Saccharomyces cerevisiae; Ubiquinone

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disease most usually caused by point mutations in tRNA genes encoded by mtDNA. Here, we report on how this mutation affects mitochondrial function in primary fibroblast cultures established from 2 patients with MELAS who harbored the A3243G mutation. Both mitochondrial respiratory chain enzyme activities and coenzyme Q(10) (CoQ) levels were significantly decreased in MELAS fibroblasts. A similar decrease in mitochondrial membrane potential was found in intact MELAS fibroblasts. Mitochondrial dysfunction was associated with increased oxidative stress and the activation of mitochondrial permeability transition (MPT), which triggered the degradation of impaired mitochondria. Furthermore, we found defective autophagosome elimination in MELAS fibroblasts. Electron and fluorescence microscopy studies confirmed a massive degradation of mitochondria and accumulation of autophagosomes, suggesting mitophagy activation and deficient autophagic flux. Transmitochondrial cybrids harboring the A3243G mutation also showed CoQ deficiency and increased autophagy activity. All these abnormalities were partially restored by CoQ supplementation. Autophagy in MELAS fibroblasts was also abolished by treatment with antioxidants or cyclosporine, suggesting that both reactive oxygen species and MPT participate in this process. Furthermore, prevention of autophagy in MELAS fibroblasts resulted in apoptotic cell death, suggesting a protective role of autophagy in MELAS fibroblasts.

Topics: Autophagy; Autophagy-Related Protein 5; Base Sequence; Cells, Cultured; DNA Primers; DNA, Mitochondrial; Electron Transport; Fibroblasts; Gene Knockdown Techniques; Humans; MELAS Syndrome; Microtubule-Associated Proteins; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Point Mutation; Reactive Oxygen Species; RNA, Small Interfering; RNA, Transfer, Leu; 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

Topics: Coenzymes; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; MELAS Syndrome; Middle Aged; Neurologic Examination; Ubiquinone

We studied free radical, lipid peroxide (LPO) and antioxidant levels of blood in three cases with mitochondrial encephalomyopathy. Case 1 was a 17-year-old man with MELAS. Serum vitamin E levels were decreased and LPO levels were increased after stroke-like episodes in case 1. Case 2 was a 68-year-old woman with MELAS and a maternal elder aunt of case 1. She showed an elevated serum LPO levels (6.58 nmol/ml) in the absence of stroke-like episode and serum CoQ10 level was 0.54 microgram/ml before therapy. By CoQ10, idebenone and tocopherol nicotinate therapy, serum LPO levels decreased gradually in parallel with the decrease of lactate and pyruvate levels. Free radicals were measured in case 2 and controls by spin trapping method. Hydroxyl radical and C center radical were increased and H radical was normal in blood. But these free radicals in serum were all normal. Her serum antioxidants revealed an elevated percent inhibition of SOD and a decreased transfferin level. Case 3 was a 52-year-old woman with MERRF. She showed an elevation of serum LPO (12.8 nmol/ml). Her serum antioxidants revealed an elevated vitamin E and ceruloplasmin levels and percent inhibition of SOD.

Topics: Adolescent; Aged; Coenzymes; Female; Free Radicals; Humans; Lipid Peroxides; Male; MELAS Syndrome; MERRF Syndrome; Superoxide Dismutase; Ubiquinone; Vitamin E