| Arginine:Glycine Amidinotransferase Deficiency: The Third Inborn Error of Creatine Metabolism in Humans (PDF Format) Arginine:glycine amidinotransferase (AGAT) catalyzes the first step of creatine synthesis, resulting in the formation of guanidinoacetate, which is a substrate for creatine formation. In two female siblings with mental retardation who had brain creatine deficiency that was reversible by means of oral creatine supplementation and had low urinary guanidinoacetate concentrations, AGAT deficiency was identified as a new genetic defect in creatine metabolism. |
| Guanidinoacetate methyltransferase (GAMT) deficiency (PDF Format) Guanidinoacetate methyltransferase (GAMT, EC 2.1.1.2) deficiency is a newly recognized inborn error of creatine synthesis. The clinical phenotype is variable including a spectrum of neurological involvement from progressive extrapyramidal movement disorder and severe muscular hypotonia, to epilepsy and mental retardation. Biochemical findings include high urinary excretion of guanidinoacetate (immediate precursor of creatine and substrate to the deficient enzyme activity), low urinary excretion of creatinine, and depletion of creatine in brain and muscle. |
| Mitochondrial cytopathy in adults: What we know so far (PDF Format) Mitochondrial cytopathies are a diverse group of inherited and acquired disorders that result in inadequate energy production. They can be caused by inheritable genetic mutations, acquired somatic mutations, exposure to toxins (including some prescription medications), and the aging process itself. In addition, a number of well-described diseases can decrease mitochondrial energy production; these include hyperthyroidism, hypothyroidism, and hyperlipidemia. |
| Mitochondrial Encephalomyopathy With Lactic Acidosis and Strokelike Episodes (MELAS): A Mitochondrial Disorder Presents as Fibromyalgia (PDF Format) This case report describes a patient who presented with symptoms and signs of longstanding fibromyalgia. Routine laboratory tests revealed an elevated anion gap. Evaluation of the elevated anion gap demonstrated elevated lactate and pyruvate levels and a lactate-to-pyruvate ratio greater than 20:1. A muscle biopsy was performed, exhibiting red ragged fibers, pathognomonic for a mitochondrial disorder. The patient was diagnosed with mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS). This is the first report describing fibromyalgia as the initial presentation of MELAS. This article outlines the diagnostic process that can assist the physician in distinguishing mitochondrial disorders from other muscular diseases, particularly fibromyalgia. |
| Mitochondrial DNA-Associated Leigh Syndrome and NARP (PDF Format) Mitochondria! DNA-associated (mtDNA-associated) Leigh syndrome and NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) are part of a continuum of progressive neurodegenerative disorders caused by abnormalities of mitochondria! energy generation. Leigh syndrome or subacute necrotizing encephalomyelopathy is characterized by onset of symptoms typically between three to 12 months of age, often following a viral infection. Decompensation (often with lactic acidosis) during an intercurrent illness is typically associated with psychomotor retardation or regression. |
| A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease (PDF Format) Creatine and minocycline were prioritized for testing in Phase II clinical trials based on a systematic evaluation of potentially disease modifying compounds for Parkinson disease (PD). Objective: To test whether creatine and minocycline alter the course of early PD relative to a predetermined futility threshold for progression of PD in a randomized, double-blind, Phase II futility clinical trial. Agents that do not perform better than the futility threshold are rejected as futile and are not considered for further study. |
| Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2=dG (PDF Format) In a randomized, double-blind, placebo-controlled study in 64 subjects with Huntington disease (HD), 8 g/day of creatine administered for 16 weeks was well tolerated and safe. Serum and brain creatine concentrations increased in the creatine-treated group and returned to baseline after washout. Serum 8-hydroxy-2=-deoxyguanosine (8OH2=dG) levels, an indicator of oxidative injury to DNA, were markedly elevated in HD and reduced by creatine treatment. |
| Creatine monohydrate enhances strength and body composition in Duchenne muscular dystrophy (PDF Format) Objective: To determine whether creatine monohydrate (CrM) supplementation increases strength and fat-free mass (FFM) in boys with Duchenne muscular dystrophy (DD). Methods: Thirty boys with DD (50% were taking corticosteroids) completed a double-blind, randomized, cross-over trial with 4 months of CrM (about 0.10 g/kg/day), 6-week wash-out, and 4 months of placebo. Measurements were completed of pulmonary function, compound manual muscle and handgrip strength, functional tasks, activity of daily living, body composition, serum creatine kinase and γ-glutamyl transferase activity and creatinine, urinary markers of myofibrillar protein breakdown (3-methylhistidine), DNA oxidative stress (8-hydroxy-2-deoxyguanosine [8-OH-2-dG]), and bone degradation (N-telopeptides). |
Letter to President Barack Obama (HTML Format) Dear President Obama:
We represent a broad spectrum of physicians, scientists and researchers and are
writing to express our strong support for your commitment to expand scientific
research. As you consider this increased investment in science, we want to highlight a
very important and potentially far-reaching area of inquiry. Specifically, greater
understanding of the mitochondria could provide insights into treatments for a wide
range of diseases and conditions that affect millions of Americans. Also available in PDF format. |
| Mitochondrial Disease in Autism Spectrum Disorder Patients: A Cohort Analysis (PDF Format) Previous reports indicate an association between autism spectrum disorders (ASD) and disorders of mitochondrial oxidative phosphorylation. One study suggested that children with both diagnoses are clinically indistinguishable from children with idiopathic autism. There are, however, no detailed analyses of the clinical and laboratory findings in a large cohort of these children. Therefore, we undertook a comprehensive review of patients with ASD and a mitochondrial disorder. |
| Mitochondrial Nanomedicine (PDF Format) The ongoing merger of nanoscience with mitochondrial medicine gives rise to novel strategies for diagnosis and therapy of mitochondrial disorders. Significant progress has been made in elucidating the central role of mitochondria in influencing the life and death of a cell. Yet, effective therapies for mitochondrial diseases remain elusive. However, the ongoing merger of nanoscience with mitochondrial medicine gives rise to novel strategies for diagnosis and therapy of mitochondrial disorders. |
| Delivery of Drugs and Macromolecules to Mitochondria
(PDF Format) Mitochondria is where the bulk of the cell’s ATP is produced. Mutations occur to genes coding for members of the complexes involved in energy production. Some are a result of damages to nuclear coded genes and others to mitochondrial coded genes. This review describes approaches to bring small molecules, proteins and RNA/DNA into mitochondria. The purpose is to repair damaged genes as well as to interrupt mitochondrial function including energy production, oxygen radical formation and the apoptotic pathway. |
| Human Coenzyme Q10 Deficiency(PDF Format) Abstract Ubiquinone (coenzyme Q10 or CoQ10) is a lipid-soluble component of virtually all cell membranes and has multiple metabolic functions. Deficiency of CoQ10 (MIM 607426) has been associated with five different clinical presentations that suggest genetic heterogeneity, which may be related to the multiple steps in CoQ10 biosynthesis. Patients with all forms of CoQ10 deficiency have shown clinical improvements after initiating oral CoQ10 supplementation. Thus, early diagnosis is of critical importance in the management of these patients. This year, the first molecular defect causing the infantile form of primary human CoQ10 deficiency has been reported. The availability of genetic testing will allow for a better understanding of the pathogenesis of this disease and early initiation of therapy (even presymptomatically in siblings of patients) in this otherwise life-threatening infantile encephalomyopathy. |
Lipophilic antioxidants in patients with phenylketonuria1-3 (PDF Format) Background: Low serum ubiquinone-10 concentrations have been described in phenylketonuric patients fed natural-proteinrestricted diets. Such low concentrations may be related to increased free radical damage.
Objective: We evaluated the relation between low serum ubiquinone-10 concentrations and other lipophilic antioxidants (tocopherol and retinol), selenium, glutathione peroxidase activity, and malondialdehyde concentrations as a marker of lipid peroxidation. |
DrugDigest - Coenzyme Q10 Coenzyme Q-10 is used extensively in Japan, and its use is more common in Europe and western Asia than it is in the United States. However, specific coenzyme Q-10 products have been given orphan drug status in the United States. An orphan drug has received FDA approval because it shows effectiveness for treating severe or rare diseases that usually have few other treatment options. |
Coenzyme Q10 Coenzyme Q10 is a vitamin-like substance used in the treatment of a variety of disorders primarily related to suboptimal cellular energy
metabolism and oxidative injury. Studies supporting the efficacy of
coenzyme Q10 appear most promising for neurodegenerative disorders
such as Parkinson’s disease and certain encephalomyopathies
for which coenzyme Q10 has gained orphan drug status. |
The Spectrum of Mitochondrial DiseaseThis article is a brief update on mitochondrial biology for primary care physicians, genetic counselors, and other health care professionals who may find themselves involved in the care of children with mitochondrial disease and their families. |
The Role of Nutrition in Mitochondrial and Metabolic DiseasesNutrition plays a vital role in the multidisciplinary management of mitochondrial and metabolic diseases. Depending on the pathophysiology and biochemistry of the disease, nutritional therapy can encompass single nutrient manipulations, vitamin supplementation and/or alternative routes of feeding. |
Mitochondrial cytopathy in adults: What we know so far Mitochondrial cytopathies are a diverse group of inherited and acquired disorders that result in inadequate energy production. They can be caused by inheritable genetic mutations, acquired somatic mutations, exposure to toxins (including some prescription medications), and the aging
process itself. In addition, a number of well-described
diseases can decrease mitochondrial energy production;
these include hyperthyroidism, hypothyroidism, and
hyperlipidemia. |
| Diagnosis and Treatment of Childhood Mitochondrial DiseasesMitochondria are important in cellular metabolism and transport, and function in a variety of degradative and synthetic
functions. Mitochondria participate in the process of
oxidative phosphorylation (OXPHOS), the transformation
of energy (from the breakdown of nutrients) in the presence
of oxygen to adenosine triphosphate (ATP). |
