glycogen and Metabolism--Inborn-Errors

Metabolic myopathies are a heterogenous group of muscle diseases typically characterized by exercise intolerance, myalgia and progressive muscle weakness. Effective treatments for some of these diseases are available, but while our understanding of the pathogenesis of metabolic myopathies related to glycogen storage, lipid metabolism and β-oxidation is well established, evidence linking treatments with the precise causative genetic defect is lacking.. The objective of this study was to collate all published evidence on pharmacological therapies for the aforementioned metabolic myopathies and link this to the genetic mutation in a format amenable to databasing for further computational use in line with the principles of the "treatabolome" project.. A systematic literature review was conducted to retrieve all levels of evidence examining the therapeutic efficacy of pharmacological treatments on metabolic myopathies related to glycogen storage and lipid metabolism. A key inclusion criterion was the availability of the genetic variant of the treated patients in order to link treatment outcome with the genetic defect.. Of the 1,085 articles initially identified, 268 full-text articles were assessed for eligibility, of which 87 were carried over into the final data extraction. The most studied metabolic myopathies were Pompe disease (45 articles), multiple acyl-CoA dehydrogenase deficiency related to mutations in the ETFDH gene (15 articles) and systemic primary carnitine deficiency (8 articles). The most studied therapeutic management strategies for these diseases were enzyme replacement therapy, riboflavin, and carnitine supplementation, respectively.. This systematic review provides evidence for treatments of metabolic myopathies linked with the genetic defect in a computationally accessible format suitable for databasing in the treatabolome system, which will enable clinicians to acquire evidence on appropriate therapeutic options for their patient at the time of diagnosis.

Topics: Glycogen; Glycogen Storage Disease Type II; Humans; Lipid Metabolism; Metabolism, Inborn Errors; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Muscle Weakness; Mutation

The prevalence of cardiometabolic disease has reached an exponential rate of rise over the last decades owing to high fat/high caloric diet intake and satiety life style. Although the presence of dyslipidemia, insulin resistance, hypertension and obesity mainly contributes to the increased incidence of cardiometabolic diseases, population-based, clinical and genetic studies have revealed a rather important role for inherited myopathies and endocrine disorders in the ever-rising metabolic anomalies. Inherited metabolic and endocrine diseases such as glycogen storage and lysosomal disorders have greatly contributed to the overall prevalence of cardiometabolic diseases. Recent evidence has demonstrated an essential role for proteotoxicity due to autophagy failure and/or dysregulation in the onset of inherited metabolic and endocrine disorders. Given the key role for autophagy in the degradation and removal of long-lived or injured proteins and organelles for the maintenance of cellular and organismal homeostasis, this mini-review will discuss the potential contribution of autophagy dysregulation in the pathogenesis of inherited myopathies and endocrine disorders, which greatly contribute to an overall rise in prevalence of cardiometabolic disorders. Molecular, clinical, and epidemiological aspects will be covered as well as the potential link between autophagy and metabolic anomalies thus target therapy may be engaged for these comorbidities.

Topics: Autophagy; Cardiovascular Diseases; Endocrine System Diseases; Glycogen; Homeostasis; Humans; Insulin Resistance; Lysosomes; Metabolic Syndrome; Metabolism, Inborn Errors; Muscular Diseases; Obesity

Metabolic myopathies comprise a clinically and etiologically diverse group of disorders caused by defects in cellular energy metabolism, including the breakdown of carbohydrates and fatty acids to generate adenosine triphosphate, predominantly through mitochondrial oxidative phosphorylation. Accordingly, the three main categories of metabolic myopathies are glycogen storage diseases, fatty acid oxidation defects, and mitochondrial disorders due to respiratory chain impairment. The wide clinical spectrum of metabolic myopathies ranges from severe infantile-onset multisystemic diseases to adult-onset isolated myopathies with exertional cramps. Diagnosing these diverse disorders often is challenging because clinical features such as recurrent myoglobinuria and exercise intolerance are common to all three types of metabolic myopathy. Nevertheless, distinct clinical manifestations are important to recognize as they can guide diagnostic testing and lead to the correct diagnosis. This article briefly reviews general clinical aspects of metabolic myopathies and highlights approaches to diagnosing the relatively more frequent subtypes (Fig. 1). Fig. 1 Clinical algorithm for patients with exercise intolerance in whom a metabolic myopathy is suspected. CK-creatine kinase; COX-cytochrome c oxidase; CPT-carnitine palmitoyl transferase; cyt b-cytochrome b; mtDNA-mitochondrial DNA; nDNA-nuclear DNA; PFK-phosphofructokinase; PGAM-phosphoglycerate mutase; PGK-phosphoglycerate kinase; PPL-myophosphorylase; RRF-ragged red fibers; TFP-trifunctional protein deficiency; VLCAD-very long-chain acyl-coenzyme A dehydrogenase.

Topics: Algorithms; Glycogen; Humans; Lipid Metabolism Disorders; Metabolic Networks and Pathways; Metabolism, Inborn Errors; Mitochondrial Diseases; Models, Biological; Muscular Diseases

The primary presentations of neuromuscular disease in the newborn period are hypotonia and weakness. Although metabolic myopathies are inherited disorders that present from birth and may present with subtle to marked neonatal hypotonia, a number of these defects are diagnosed classically in childhood, adolescence, or adulthood. Disorders of glycogen, lipid, or mitochondrial metabolism may cause three main clinical syndromes in muscle, namely, (1) progressive weakness with hypotonia (e.g., acid maltase, debrancher enzyme, and brancher enzyme deficiencies among the glycogenoses; carnitine uptake and carnitine acylcarnitine translocase defects among the fatty acid oxidation (FAO) defects; and cytochrome oxidase deficiency among the mitochondrial disorders) or (2) acute, recurrent, reversible muscle dysfunction with exercise intolerance and acute muscle breakdown or myoglobinuria (with or without cramps), e.g., phosphorylase, phosphofructokinase, and phosphoglycerate kinase among the glycogenoses and carnitine palmitoyltransferase II deficiency among the disorders of FAO or (3) both (e.g., long-chain or very long-chain acyl coenzyme A (CoA) dehydrogenase, short-chain L-3-hydroxyacyl-CoA dehydrogenase, and trifunctional protein deficiencies among the FAO defects). Episodes of exercise-induced myoglobinuria tend to present in later childhood or adolescence; however, myoglobinuria in the first year of life may occur in FAO disorders during catabolic crises precipitated by fasting or infection. The following is a survey of genetic disorders of glycogen and lipid metabolism resulting in myopathy, focusing primarily on those defects, to date, that have presented in the neonatal or early infancy period. Disorders of mitochondrial metabolism are discussed in another chapter.

Topics: Fatty Acids; Glycogen; Glycolysis; Humans; Infant, Newborn; Metabolism, Inborn Errors; Mitochondrial Myopathies; Muscle, Skeletal; Muscular Diseases

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: Acidosis, Lactic; Adult; Child; Citric Acid Cycle; Female; Gluconeogenesis; Glycogen; Humans; Infant, Newborn; Lactates; Lactic Acid; Male; Metabolism, Inborn Errors; Mitochondria; Pyruvate Carboxylase Deficiency Disease; Pyruvates

Topics: alpha-Glucosidases; AMP Deaminase; Carnitine; Carnitine O-Palmitoyltransferase; Creatine Kinase; Female; Glucan 1,4-alpha-Glucosidase; Glycogen; Glycogen Storage Disease Type II; Glycogen Storage Disease Type III; Glycogen Storage Disease Type V; Glycogen Storage Disease Type VII; Humans; Lipid Metabolism, Inborn Errors; Male; Metabolism, Inborn Errors; Muscular Diseases; Phosphofructokinase-1; Phosphorylase a

Topics: Animals; Cats; Cattle; Disease Models, Animal; Dogs; G(M2) Ganglioside; Gangliosidoses; Gaucher Disease; Glycogen; Glycogen Storage Disease Type II; Glycopeptides; Humans; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Lipidoses; Lysosomes; Mannosidases; Metabolism, Inborn Errors; Mice; Niemann-Pick Diseases; Rabbits; Sphingolipids

Topics: Catecholamines; Cyclic AMP; Endocrine System Diseases; Fructose-Bisphosphatase; Glucagon; Gluconeogenesis; Glucose-6-Phosphatase; Glycogen; Glycogen Synthase; Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Infant; Infant, Newborn; Infant, Newborn, Diseases; Insulin; Ketosis; Liver; Metabolism, Inborn Errors; Phosphoenolpyruvate Carboxykinase (GTP); Pyruvate Carboxylase

Topics: Animals; Animals, Domestic; Breeding; Cats; Cattle; Dogs; Enzymes; Genes, Recessive; Glycogen; Glycoproteins; Humans; Hydrolases; Leukocytes; Lipidoses; Lysosomes; Metabolism, Inborn Errors; Mink; Sex Chromosomes; Sheep; Sphingolipids; Swine

Mice homozygous for the human GRACILE syndrome mutation (Bcs1l

Topics: Acidosis, Lactic; Animals; Blood Glucose; Cholestasis; Electron Transport; Electron Transport Complex III; Fasting; Female; Fetal Growth Retardation; Gluconeogenesis; Glycogen; Hemosiderosis; Hepatocytes; Homozygote; Hypoglycemia; Lipid Mobilization; Liver; Male; Metabolism, Inborn Errors; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Diseases; Renal Aminoacidurias; Triglycerides

Indications for liver biopsy in children are often specific to this age group, especially in young children for the diagnosis of cholestasis. Since liver biopsies are quite unfrequent in the children population and concern rare but various diseases, it is recommended to entrust the analysis to a specialized liver pathologist, in a laboratory where cryoconservation, specific immuno-stainings, enzymatic studies, and electron microscopy can be performed. Histology is complementary to other methods for the diagnosis, and is valuable for the evaluation of the prognosis, especially the staging of fibrosis and the grading of inflammatory diseases. In cases of co-morbidity or difficult differential diagnosis, histology can also be of great value. For metabolic disorders, the liver tissue can also be used for enzyme detection or evaluation of iron or copper overload. Biopsy is also a key element in the management after liver transplantation. The microscopic images shown here are representative of the most frequent liver diseases in childhood and illustrate the data outlined during the conference.

Topics: Biliary Tract; Biliary Tract Diseases; Biopsy; Child; Glycogen; Hamartoma; Hepatoblastoma; Hepatocytes; Humans; Hyperplasia; Liver; Liver Diseases; Metabolism, Inborn Errors

We consider recent developments in disorders affecting three areas of metabolism: glycogen, fatty acids, and the mitochondrial respiratory chain. Among the glycogenoses, new attention has been directed to defects of glycogen synthesis resulting in absence rather than excess of muscle glycogen ("aglycogenosis"). These include defects of glycogen synthetase and defects of glycogenin, the primer of glycogen synthesis. Considerable progress also has been made in our understanding of alterations of glycogen metabolism that result in polyglucosan storage. Among the disorders of lipid metabolism, mutations in the genes encoding two triglyceride lipases acting hand in hand cause severe generalized lipid storage myopathy, one associated with ichthyosis (Chanarin-Dorfman syndrome), the other dominated by juvenile-onset weakness. For the mitochondrial myopathies, we discuss the importance of homoplasmic mitochondrial DNA mutations and review the rapid progress made in our understanding of the coenzyme Q(10) deficiencies, which are often treatable.

Topics: Animals; Cell Nucleus; DNA; DNA, Mitochondrial; Fatty Acids; Glycogen; Humans; Lipid Metabolism; Metabolism, Inborn Errors; Mitochondrial Diseases; Mitochondrial Myopathies; Muscular Diseases; Mutation

There is little information in the literature regarding the usefulness of ultrastructural examination of axillary skin biopsies in the evaluation of metabolic diseases. This is a retrospective clinicopathologic review of 143 patients who underwent axillary skin biopsies as part of evaluations for metabolic disease. Twenty-three (16%) had abnormalities, classified as follows: mitochondrial (n = 12), lysosomal (n = 6), increased glycogen (n = 3), nonspecific cytoplasmic inclusions (n = 2), ceroid lipofuscinosis (n = 1), and intradermal giant cells containing vacuoles and tubular inclusions (n = 1). Muscle biopsies were performed in 13 of the 23 patients; 11 showed abnormalities, including those related to mitochondria (n = 4) and other nonspecific changes (n = 7). Two patients underwent postmortem examination. Follow-up was available in 21 patients. A clinical or biochemical diagnosis was reached in 11 patients: metachromatic leukodystrophy (n = 2), electron transport chain abnormalities (n = 2), glutaric aciduria type II (n = 1), Unverricht disease (n = 1), Lennox-Gastaut syndrome (n = 1), ketotic hypoglycemia of childhood (n = 1), probable Leigh disease (n = 1), 5-methyl tetrahydrofolate homocystine methyltransferase deficiency (n = 1), and pyruvate dehydrogenase deficiency (n = 1). Of the 120 patients with negative skin biopsy results, 29 had abnormal findings on muscle (n = 27), nerve (n = 7), or brain (n = 3) biopsies. One patient had an abnormal heart biopsy result, and 3 patients underwent postmortem examinations. Follow-up was obtained in 27 of 29 patients. Diagnoses were achieved in 15 patients: electron transport chain abnormalities (n = 5), cortical dysplasia (n = 3), myoclonic epilepsy (n = 1), leukodystrophy (n = 2), Pallister-Killian mosaic syndrome (n = 1), Rett syndrome (n = 1), Landau-Kleffner syndrome (n = 1), and mitochondrial cardiomyopathy (n = 1). In conclusion, axillary skin biopsy is helpful in the evaluation of some causes of metabolic disease, but often the findings are nonspecific. A negative biopsy result does not rule out the possibility of metabolic disease, but a positive result may provide direction for further evaluation.

Topics: Adolescent; Adult; Axilla; Biopsy; Child; Child, Preschool; Female; Glycogen; Humans; Inclusion Bodies; Infant; Lipids; Lysosomes; Male; Metabolism, Inborn Errors; Microscopy, Electron; Middle Aged; Mitochondria; Skin; Vacuoles

Metabolic myopathies are a rare group of disorders. These myopathies reveal a varying severity of a proximal, distal or generalized muscular involvement indicating a progressive myopathy or recurrent episodes of weakness, pain, cramps and stiffness combined with exercise. Some important disorders and their biochemical defects are described. Particular attention is paid to helpful biochemical investigative methods.

Topics: Enzymes; Glycogen; Glycogen Storage Disease; Humans; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Mitochondria, Muscle; Muscles; Muscular Diseases; Neuromuscular Diseases

In the classic view of the control of phosphorylase b to a conversion by catecholamines, cyclic AMP acts as the second messenger stimulating the activity of cyclic AMP-dependent protein kinase to covalently modify phosphorylase kinase. Phosphorylation of phosphorylase kinase converts this enzyme form with a nonactivated to an activated form with a markedly higher activity at pH 7. There is now considerable evidence that the activity of phospphorylase kinase is also regulated by changeds in the Ca-2+ concentration. The activity of both nonactivated and activated phosphorylase kinase is stimulated by Ca-2+ in the range of concentrations that have been reported to occur in the sacroplasm of contracting muscle, with the activated pphosphorylase kinase having a lower K-alpha for Ca-2+. Thus there are at leaset two mechanisms for the regulation of phosphorylase kinase activity in muscle. These mechanisms may act independently or in concert in controlling glycogenolysis stimulated by catecholamines, anoxia, or tetanic electrical stimulation...

Topics: Adenosine Triphosphate; Animals; Anura; Calcium; Catalysis; Chemical Phenomena; Chemistry; Cyclic AMP; Dogs; Enzyme Activation; Glycogen; Guinea Pigs; Magnesium; Metabolism, Inborn Errors; Mice; Models, Biological; Muscle Proteins; Muscles; Myocardium; Phosphoproteins; Phosphorylase Kinase; Rats; Sarcoplasmic Reticulum; Trypsin

Topics: Adenosine Triphosphatases; Adolescent; Glucosamine; Glycogen; Glycosaminoglycans; Hexosamines; Hexoses; Humans; Lyases; Male; Metabolism, Inborn Errors; Microscopy, Electron; Muscles; Muscular Dystrophies; Myofibrils; Neuraminic Acids; Neuraminidase; Periodic Acid; Proteins; Schiff Bases; Staining and Labeling; Uronic Acids

Topics: Amylases; Blood Glucose; Carbon Radioisotopes; Chromatography, Paper; Erythrocytes; Glucose; Glucosephosphate Dehydrogenase; Glucosidases; Glycogen; Glycogen Synthase; Humans; Maltose; Metabolism, Inborn Errors; Microscopy, Electron

Topics: Biopsy; Female; Glycogen; Humans; Leukocytes; Liver; Metabolism, Inborn Errors; Methods; Phosphorylase Kinase; Sex Chromosome Aberrations

Topics: Adolescent; Adult; Agammaglobulinemia; Female; Glycogen; Humans; Lymphocytes; Male; Metabolism, Inborn Errors

Large amounts of glycogen accumulate in rat skeletal muscle fibers during the late fetal stages and are mobilized in the first postnatal days. This glycogen depletion is relatively slow in the immature leg muscles, in which extensive deposits are still found 24 hr after birth and, to some extent, persist until the 3rd day. In the more differentiated psoas muscle and especially in the diaphragm, the glycogen stores are completely mobilized already during the early hours. Section of the sciatic nerve 3 days before birth or within the first 2 hr after delivery does not affect glycogen depletion in the leg muscles. Neonatal glycogenolysis in rat muscle fibers takes place largely by segregation and digestion of glycogen particles in autophagic vacuoles. These vacuoles: (a) are not seen in fetal muscle fibers or at later postnatal stages, but appear concomitantly with the process of glycogen depletion and disappear shortly afterwards; (b) are prematurely formed in skeletal muscles of fetuses at term treated with glucagon; (c) contain almost exclusively glycogen particles and no other recognizable cell constituents; (d) have a double or, more often, single limiting membrane and originate apparently from flattened sacs sequestering glycogen masses; (e) are generally found to contain reaction product in preparations incubated from demonstration of acid phosphatase activity. The findings emphasize the role of the lysosomal system in the physiological process of postnatal glycogen mobilization and appear relevant in the interpretation of type II glycogen storage disease.

Topics: Acid Phosphatase; Animals; Animals, Newborn; Diaphragm; Female; Fetus; Gestational Age; Glucagon; Glycogen; Golgi Apparatus; Histocytochemistry; Inclusion Bodies; Injections, Subcutaneous; Lysosomes; Metabolism, Inborn Errors; Methods; Microscopy, Electron; Muscles; Myofibrils; Pregnancy; Rats; Rats, Inbred Strains; Ribosomes; Sarcolemma; Sarcoplasmic Reticulum; Sciatic Nerve; Time Factors

Topics: Adolescent; Blood Glucose; Child; Child, Preschool; Diagnosis, Differential; Fasting; Female; Galactose; Glucagon; Glucose; Glucose Tolerance Test; Glucosyltransferases; Glycogen; Glycogen Storage Disease Type I; Hexosaminidases; Humans; Hydrocortisone; Hypoglycemia; Infant; Insulin; Liver; Male; Metabolism, Inborn Errors

Topics: Cells, Cultured; Fibroblasts; Glucose; Glycogen; Humans; In Vitro Techniques; Metabolism, Inborn Errors; Skin

Topics: Adult; Biopsy; Diagnosis, Differential; Female; Glucose; Glucosidases; Glycogen; Glycogen Storage Disease; Golgi Apparatus; Histocytochemistry; Humans; In Vitro Techniques; Lactates; Male; Metabolism, Inborn Errors; Microscopy, Electron; Microscopy, Phase-Contrast; Middle Aged; Mitochondria, Muscle; Muscles; Muscular Diseases; Muscular Dystrophies

Topics: Autopsy; Basement Membrane; Cytoplasmic Granules; Gangliosides; Glycogen; Humans; Infant; Kidney; Kidney Glomerulus; Kidney Tubules; Male; Metabolism, Inborn Errors; Microscopy, Electron

Topics: Adenine Nucleotides; Animals; Blood Cells; Female; Glycogen; Heterozygote; Humans; Leukocytes; Liver; Male; Metabolism, Inborn Errors; Mice; Molecular Biology; Muscles; Pedigree; Phosphorylase Kinase; Sex Chromosomes

Topics: Adolescent; Diagnosis, Differential; Fatty Acids; Glycogen; Glycogen Storage Disease; Glycolysis; Humans; Male; Metabolism, Inborn Errors; Muscular Diseases; Pedigree; Phosphofructokinase-1; Phosphorus Metabolism Disorders

Topics: Adenine Nucleotides; Adenosine Triphosphate; Blood Chemical Analysis; Contracture; Electromyography; Glycogen; Humans; In Vitro Techniques; Lactates; Metabolism, Inborn Errors; Muscle Contraction; Muscle Cramp; Muscle Proteins; Muscles; Muscular Diseases; Myoglobinuria; Phosphocreatine; Phosphotransferases; Physical Exertion; Spectrophotometry