coenzyme-q10 and Acidosis--Lactic

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

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 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

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

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