glycogen and Neuromuscular-Diseases

Disorders of glycogen metabolism are inborn errors of energy homeostasis affecting primarily skeletal muscle, heart, liver, and, less frequently, the central nervous system. These rare diseases are quite variable in age of onset, symptoms, morbidity, and mortality. This review provides an update on disorders of glycogen metabolism affecting skeletal muscle exclusively or predominantly. From a pathogenetic perspective, we classify these diseases as primary, if the defective enzyme is directly involved in glycogen/glucose metabolism, or secondary, if the genetic mutation affects proteins which indirectly regulate glycogen or glucose processing. In addition to summarizing the most recent clinical reports in this field, we briefly describe animal models of human glycogen disorders. These experimental models are greatly improving the understanding of the pathogenetic mechanisms underlying the muscle degenerative process associated to these diseases and provide in vivo platforms to test new therapeutic strategies.

Topics: Animals; Disease Models, Animal; Glycogen; Glycogen Storage Disease; Humans; Lysosomal Storage Diseases; Muscular Diseases; Neuromuscular Diseases

Phosphorus magnetic resonance spectroscopy monitors muscle energy metabolism by recording the ratio of phosphocreatine to inorganic phosphate at rest, during exercise, and during recovery from exercise. In mitochondrial diseases, abnormalities may appear during some or all these phases. Low phosphocreatine-inorganic phosphate ratios at rest are not disease-specific, but can be increased by drug therapy in several myopathies. Phosphorus magnetic resonance spectroscopy can also record intracellular pH and thus identify disorders of glycogen metabolism in which the production of lactic acid is blocked during ischemic exercise. The measurements of accumulated sugar phosphate intermediates further delineate glycolytic muscle defects. Myophosphorylase deficiency responds to intravenous glucose administration with improved exercise bioenergetics, but no such response is seen in phosphofructokinase deficiency. The muscular dystrophies show no specific bioenergetic abnormality; however, elevation of phospholipids metabolites and phosphodiesters was detected in some cases. While phosphorus magnetic resonance spectroscopy remains primarily a research tool in metabolic myopathies, it will be clinically useful in identifying new therapies and monitoring their effects in a variety of neuromuscular disorders.

Topics: Energy Metabolism; Exercise; Glucose; Glycogen; Glycolysis; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Mitochondria, Muscle; Muscle Contraction; Muscle Relaxation; Muscles; Muscular Dystrophies; Neuromuscular Diseases; Oxidative Phosphorylation; Phosphates; Phosphocreatine; Phosphofructokinase-1; Phosphorus Isotopes; Phosphorylases

Clinical, neurophysiological, morphological and biochemical investigations were performed in 2 patients with the adult form of glycogenosis II and related to the findings of 58 well-documented cases published in the literature. According to these findings three types can be distinguished from each other. The first one is characterized by an involvement of the limb-girdle muscles only. The second type shows the same pattern with additional progressive insufficiency of the respiratory muscles. The third type presents with weakness of the respiratory muscles without any other severe muscle involvement. Our case 1 can be related to the first, our case 2 to the second type. EMG-studies in case 1 showed myopathic changes and myotonic discharges without clinical signs of myotonia. A myotonic pattern was described in one third of the published cases. In case 2 neurogenic changes as well as in 4 cases in the literature were found. The muscle biopsy is the diagnostic clue in the differential diagnosis of progressive myopathy in the adult. Patients with glycogenosis II show glycogen storage specially in type I-fibres. The enzyme defect can be confirmed biochemically in muscle tissue or cultured fibroblasts. Various therapeutic concepts have been tried in patients with glycogenosis II but most of them remain disappointing. A diet with a low carbohydrate and a high protein proportion was observed to be of some benefit. In patients with respiratory muscle involvement artificial ventilation support showed a positive effect on the general condition for some time.

Topics: Adult; Biopsy; Glycogen; Glycogen Storage Disease Type II; Humans; Male; Microscopy, Electron; Muscles; Muscular Atrophy; Neuromuscular Diseases; Reaction Time; Synaptic Transmission; Tibial Nerve

Topics: alpha-Glucosidases; Enzymes; Glycogen; Glycogen Debranching Enzyme System; Glycogen Storage Disease; Glycolysis; Humans; L-Lactate Dehydrogenase; Muscles; Neuromuscular Diseases; Phosphofructokinase-1; Phosphoglycerate Kinase; Phosphoglycerate Mutase; Phosphorylases

Topics: Animals; Blood Glucose; Carbohydrate Metabolism; Catecholamines; Child; Female; Glucose; Glucose Tolerance Test; Glycogen; Hexokinase; Humans; Insulin; Lipids; Mice; Muscles; Muscular Dystrophies; Muscular Dystrophy, Animal; Neuromuscular Diseases

The physiological and anatomical properties of mammalian motor units are discussed, and the results of human and animal studies are compared. A physiological organization of motor units based on the mechanical properties of their associated muscle units is examined. It is concluded that such an organizing principle has broad universal application in both animal and human studies. An anatomical organization of muscle units by their association with their physiological properties and the histochemical profile of their muscle fibers is also considered. The anatomical organizing principle also has broad-ranging applicability. The organization of muscle units according to muscle architecture and innervation patterns is described and its potential applicability to considerations of muscle structure and function is discussed. It is concluded that a number of gaps in our knowledge of muscle unit organization have been identified, especially among human studies, but the potential to fill these gaps rapidly is great.

Topics: Action Potentials; Animals; Cats; Glycogen; Histocytochemistry; Humans; Muscle Contraction; Muscle Proteins; Muscle Spindles; Muscles; Neuromuscular Diseases; Rats

Topics: Autophagy; Basement Membrane; Cell Membrane; Cell Nucleus; Cytoplasmic Granules; Glycogen; Golgi Apparatus; Humans; Lipids; Lipofuscin; Mitochondria, Muscle; Muscles; Myofibrils; Neuromuscular Diseases; Organoids; Sarcoplasmic Reticulum; Vacuoles

Topics: Animals; Biological Transport, Active; Calcium Metabolism Disorders; Glycogen; Humans; Hydrogen-Ion Concentration; Hypernatremia; Hypokalemia; Hyponatremia; Magnesium; Membrane Potentials; Muscles; Myoglobinuria; Neuromuscular Diseases; Phosphorus Metabolism Disorders; Potassium Deficiency; Water-Electrolyte Imbalance

Although androgen receptor (AR) within myocytes is thought to mediate many of the effects of testosterone and other androgens on skeletal muscle, little is known about the functions of AR within these cells. We, therefore, studied the ultrastructure of skeletal muscle of HSA-AR transgenic (Tg) mice that overexpress AR selectively in myocytes and exhibit neuromuscular atrophy. We examined male HSA-AR mice from two different founding lines: L78 (lower copy number and less severe phenotype) and L141 (higher copy number and more severe phenotype) and compared these to wild-type (Wt) brothers. We also examined testosterone-treated female mice from these two lines and compared them both to their Wt sisters and to vehicle-treated controls. Ultrastructural examination of extensor digitorum longus sections using transmission electron microscopy revealed remarkably disorganized myofibrils in male Tg and testosterone-treated female Tg mice. Quantification of ultrastructural pathology indicated reduced myofibril width, hypertrophic and hyperplastic intermyofibrillar mitochondria, and pronounced glycogen accumulation in HSA-AR males of both lines. Reduced myofibrillar width and increases in mitochondrial number, size, and volume density were also observed in testosterone-treated HSA-AR females, although glycogen accumulation was not observed. Structural abnormalities in mitochondria were also associated with increases in electron transport chain activity and systemic resting metabolic rate, indicative of hypermetabolism. We find that overexpression of AR in myocytes of HSA-AR mice results in alterations in myofibrils, mitochondria, and glycogen. Alterations in myofibrils and mitochondria appear to result from acute actions of testosterone, whereas those on glycogen do not. Pathology of myofibrils and/or mitochondria may, therefore, mediate in part the neuromuscular atrophy observed in HSA-AR mice.

Topics: Animals; Atrophy; Basal Metabolism; Electron Transport Chain Complex Proteins; Female; Gene Dosage; Gene Expression; Glycogen; Male; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Mitochondria, Muscle; Muscle Proteins; Muscle, Skeletal; Myofibrils; Neuromuscular Diseases; Receptors, Androgen; Sex Factors; Testosterone

Deficiency of glycogen branching enzyme (GBE) activity causes glycogen storage disease type IV (GSD IV), an autosomal recessive error of metabolism. Abnormal glycogen accumulates in myocytes, hepatocytes, and neurons, causing variably progressive, benign to lethal organ dysfunctions. A naturally occurring orthologue of human GSD IV was described previously in Norwegian forest cats (NFC). Here, we report that while most affected kittens die at or soon after birth, presumably due to hypoglycemia, survivors of the perinatal period appear clinically normal until onset of progressive neuromuscular degeneration at 5 months of age. Molecular investigation of affected cats revealed abnormally spliced GBE1 mRNA products and lack of GBE cross-reactive material in liver and muscle. Affected cats are homozygous for a complex rearrangement of genomic DNA in GBE1, constituted by a 334 bp insertion at the site of a 6.2 kb deletion that extends from intron 11 to intron 12 (g. IVS11+1552_IVS12-1339 del6.2kb ins334 bp), removing exon 12. An allele-specific, PCR-based test demonstrates that the rearrangement segregates with the disease in the GSD IV kindred and is not found in unrelated normal cats. Screening of 402 privately owned NFC revealed 58 carriers and 4 affected cats. The molecular characterization of feline GSD IV will enhance further studies of GSD IV pathophysiology and development of novel therapies in this unique animal model.

Topics: 1,4-alpha-Glucan Branching Enzyme; Alternative Splicing; Animals; Base Sequence; Breeding; Cats; Exons; Female; Glycogen; Glycogen Storage Disease Type IV; Hypoglycemia; Liver; Male; Molecular Sequence Data; Mutation; Neuromuscular Diseases; Pedigree

Topics: Abnormalities, Multiple; Adolescent; Biopsy; Chromosome Deletion; Chromosomes, Human, Pair 22; Craniofacial Abnormalities; Creatine Kinase; Glycogen; Humans; Male; Microscopy, Electron; Muscle, Skeletal; Muscular Atrophy; Neuromuscular Diseases

In the present communication, an investigation is described into the reliability of histochemical methods for the demonstration of alpha-glucan phosphorylase activity in glycogen-depleted skeletal muscle fibres. Human skeletal muscles with glycogen-depleted fibres from patients with diseases of the neuromuscular system and from subjects who had suffered from malignant hyperthermia were used for the study. The location of phosphorylase activity and glycogen was demonstrated with histochemical techniques. Biochemical techniques were used to assay the activity of phosphorylase and the content of glycogen. Biochemical determinations of phosphorylase activity did frequently not reveal significant differences between glycogen-depleted and non-depleted skeletal muscle fibres. In contrast, all histochemical methods investigated, showed little or no phosphorylase activity in the glycogen depleted fibres, indicating that none of the existing histochemical methods revealed reliable staining results in these fibres. Owing to the invalid staining results of the histochemical methods for glycogen-depleted muscle fibres, it is necessary that for metabolic studies a biochemical assay for phosphorylase activity is also to be performed.

Topics: Glycogen; Histocytochemistry; Humans; Malignant Hyperthermia; Muscles; Neuromuscular Diseases; Phosphorylase a; Phosphorylases; Reference Values

We report a 33-yr-old man with an unusual neuromuscular disorder characterized by progressive generalized weakness of 3 yr duration whose muscle biopsy showed a double ring appearance in most muscle fibers. This double ring appearance was due to a peripheral outer sarcoplasmic mass and an inner ring of annular myofibrils surrounding a core of normal longitudinally oriented myofibrils. Nerve conduction studies were normal. Electromyography showed fibrillations, positive waves, and increased brief duration, low amplitude, polyphasic potentials.

Topics: Adult; Electromyography; Exercise; Female; Glycogen; Humans; Microscopy, Electron; Muscles; Myofibrils; Neuromuscular Diseases; Sarcoplasmic Reticulum

Topics: Adult; Age Factors; alpha-Glucosidases; Female; Glucan 1,4-alpha-Glucosidase; Glucosidases; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type II; Humans; Lysosomes; Motor Neurons; Muscles; Muscular Diseases; Neuromuscular Diseases; 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

Biochemical, electron microscopic observations in muscle and liver of an infant dying at 20 months of age of a mitochondrial myopathy are described. Biochemical analysis of tissues revealed low levels of free, esterified and total carnitine and marked decrease of succinic-dehydrogenase activity while cytochrome c-oxidase was normal. Ultrastructural data showed a megaconial myopathy.

Topics: Brain Diseases, Metabolic; Carnitine; Glycogen; Humans; Infant; Lipid Metabolism; Lipid Metabolism, Inborn Errors; Male; Mitochondria; Mitochondria, Liver; Mitochondria, Muscle; Neuromuscular Diseases; Succinate Dehydrogenase

Rimmed vacuoles (Dubowitz and Brooke 1973) have been found in 12 cases with various neuromuscular diseases and are considered to be autophagic in nature. They consisted of multilaminated membranous structures accompanied by glycogen granules, dense bodies, and amorphous, granular, and fibrillar material. The contents of the vacuoles were regarded as having partially dissolved out of the vacuoles in cryostat sections but some were plastered along the walls of the vacuoles and were depicted by the staining procedures for light microscopy. The "lined vacuoles" described by Carpenter et al. (1978) in inclusion body myositis closely agree with the rimmed vacuoles in respect of histochemical and ultrastructural features.

Topics: Adolescent; Adult; Aged; Autophagy; Female; Glycogen; Humans; Male; Microscopy, Electron; Middle Aged; Neuromuscular Diseases; Organoids; Vacuoles

Skeletal muscle samples from the upper and lower extremities of 38 human fetuses (6 to 18 weeks' gestation) of both sexes were studied by histologic, histochemical, and electron microscopic methods. Ultrastructural morphometry was applied. In the different stages of normal development are found regressive changes, ranging from reversible dystrophic to irreversible necrotic alterations, which are characteristic of either primary myogenic myopathies or primary neurogenic muscle atrophies in older age. Several pathologic patterns of so-called congenital myopathies also presented. On the basis of their findings, the authors conclude that in a certain group of congenital myopathies full normal development of muscle is hindered or blocked and that groups of muscles or the whole voluntary musculature is arrested at certain stages of maturation. For example, insufficient or absent innervation of the fetal muscle may be a factor in Werdnig-Hoffmann or Kugelberg-Welander syndromes. The authors' findings suggest that pathologic patterns in muscle diseases have been used physiologically in fetal development to eliminate unnecessary overproduction of muscle fibers.

Topics: Adenosine Triphosphatases; Autophagy; Cytoplasmic Granules; Female; Glycogen; Humans; Male; Mitochondria, Muscle; Muscles; Myofibrils; NADH Tetrazolium Reductase; Neuromuscular Diseases; Sarcoplasmic Reticulum; Vacuoles

Five patients, 4 men and 1 woman, had adult-onset and slowly progressive weakness. There was distal wasting in 2, hepatomegaly in 3, and congestive heart failure in 2. Electromyography showed a mixed pattern with abundant fibrillations. Serum creatine phosphokinase was increased 5- to 45-fold. Blood glucose failed to respond to epinephrine or glucagon, and venous lactate did not rise after ischemic exercise. Muscle biopsy showed vacuolar myopathy affecting both fiber types. By electron microscopy the vacuoles corresponded to large pools of glycogen not limited by a membrane. Glycogen concentration was 3 to 5 times normal in muscle and 7 to 21 times normal in erythrocytes. In the presence of iodine, muscle glycogen showed a spectrum characteristic of phosphorylase-limit-dextrin. Debrancher activity was measured by a spectrophotometric assay and by a radioactive reverse reaction. The activity was lacking in muscle and erythrocytes of 4 patients according to both assays; in 1 patient the reverse reaction was not impaired. Though previously reported in only 5 patients, debrancher deficiency myopathy may not be rare and should be considered in the differential diagnosis of adult-onset hereditary myopathies.

Topics: Adolescent; Adult; Female; Glucosyltransferases; Glycogen; Glycogen Debranching Enzyme System; Glycogen Storage Disease; Glycogen Storage Disease Type III; Histocytochemistry; Humans; Male; Microscopy, Electron; Middle Aged; Muscles; Neuromuscular Diseases; Syndrome

The mild, generalized myopathy (glycogenosis type II) of a 23-year-old male, previously thought to have progressive muscular dystrophy, was studied clinically, electro-myographically, biochemically and with light- and electron microscopes. However, the history and clinical aspects, as well as the registration of high frequency discharges in the electromyogram first made the diagnosis uncertain. This kind of spontaneous activity has been found in nearly all cases reported in the literature. Light microscopic and histochemical examinations show vacular degeneration and glycogen storage in muscle fibres. With the electron microscope we found free dispersed glycogen in the cytoplasm and membrane-bound glycogen, glycogen-filled lysosomes. Biochemical measurements of the muscle enzymes, involved in the glycogen breakdown, were normal except for acid alpha-1,4-glucosidase, which was deficient. The evidence of these findings in this abortive form of glycogenosis type II is discussed and compared with the few cases found in the literature.

Topics: Adult; Diagnosis, Differential; Electromyography; Glucosidases; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type II; Histocytochemistry; Humans; Male; Muscles; Neuromuscular Diseases

A 48 year old woman is described who presented with increasing muscular rigidity and who was found to have a mediastinal tumour. Electrophysiological studies revealed that the muscular stiffness resulted from very high frequency motor unit activity which outlasted voluntary effort, and which was abolished by nerve block. The abnormal activity may have arisen at the anterior horn cell level. Marked improvement followed the administration of diphenylhydantoin.

Topics: Anterior Horn Cells; Electromyography; Electrophysiology; Female; Glycogen; Humans; Lipid Metabolism; Mediastinal Neoplasms; Memory Disorders; Middle Aged; Muscle Contraction; Muscle Rigidity; Muscles; Neural Conduction; Neuromuscular Diseases; Phenytoin

Report on a sporadic case with congenital slowly progressive neuromuscular disease. Light microscopic, ultrastructural and histochemical changes of muscle biopsy reveal the characteristics of central core disease with "structured cores" in type II-fibers.

Topics: Adult; Electromyography; Glycogen; Histocytochemistry; Humans; Male; Mitochondria, Muscle; Neuromuscular Diseases

The authors explored a group of patients suffering from rheumatic pelvispondylitis from the point of view of muscular lesions: clinical muscular examination, anatomo-pathological investigation of the muscle (optical microscopy, histochemistry), electromyographic investigation, and determination of certain serum and muscle enzymes. Some muscular anomalies were observed, which were predominant in the muscles of the lumbar grooves, although there were some lesions of the quadriceps muscle, with a myogenous appearance, but without inflammation. The clearest anomalies were neurogenic and were present particularly in the muscles of the lumbar grooves.

Topics: Adult; Electromyography; Glycogen; Histocytochemistry; Humans; Hyperplasia; Leg; Male; Middle Aged; Motor Activity; Muscles; Muscular Diseases; Neural Conduction; Neurologic Manifestations; Neuromuscular Diseases; Reflex, Monosynaptic; Spine; Spondylitis, Ankylosing

Thick round fibres common in cross sections of muscle biopsies from patients with muscular dystrophy are due to contracted and swollen segments of otherwise normal muscle fibres. This contracture leads to segmental fibre breakdown, which is identical with Zenker's waxy degeneration. In biopsies from 90 patients suspected of neuromuscular disease, segmental contracture was seen in all or nearly all patients with infantile muscular dystrophy, necrotic myopathy or acute alcoholic myopathy. It was present in half of the patients with polymyositis or myotonic dystrophy. In resticted forms of muscular dystrophy it was rare as it was in neurogenic atrophy. In 9 clinically normal patients it was absent. In electron micrographs of the initial stage sarcomeres were moderately shortened, the sarcoplasmic reticulum was distended and the mitochondria were normal. In the plasmalemma holes were found, through which glycogen granules were lost into the interstitial tissue. In later stages myofibrils were overcontracted and homogenized; in large areas the plasmalemma was absent. Based on these findings a hypothesis for the development of waxy degeneration is proposed: locally defects of the plasmamembrane cause segmental contracture, glycogen granules and water soluble enzymes are lost through holes in the plasma membrane, and finally the affected fibre segment becomes necrotic.

Topics: Adolescent; Adult; Aged; Basement Membrane; Child; Child, Preschool; Female; Glycogen; Humans; Infant; Male; Middle Aged; Mitochondria, Muscle; Muscle Contraction; Muscles; Muscular Diseases; Muscular Dystrophies; Myofibrils; Myotonic Dystrophy; Neuromuscular Diseases; Sarcolemma; Sarcoplasmic Reticulum

Topics: Acid Phosphatase; Adenosine Triphosphatases; Adult; Blepharoptosis; Deglutition Disorders; Facial Paralysis; Female; Glycogen; Hearing Disorders; Humans; Lipid Metabolism; Male; Microscopy, Electron; Mitochondria, Muscle; Muscles; Myofibrils; NADH, NADPH Oxidoreductases; Neuromuscular Diseases; Ophthalmoplegia; Pedigree; Speech Disorders; Syndrome

Topics: Glycogen; Histocytochemistry; Humans; Neuromuscular Diseases

Topics: Adenosine Triphosphatases; Adolescent; Adult; Aged; Animals; Cell Differentiation; Chick Embryo; Child; Child, Preschool; Culture Techniques; Female; Glucosyltransferases; Glycogen; Histocytochemistry; Humans; Infant; Infant, Newborn; Male; Middle Aged; Muscles; Myofibrils; Myosins; NAD; Neuromuscular Diseases; Species Specificity

Topics: Basement Membrane; Biopsy; Cell Nucleus; Child, Preschool; Cytoplasm; Extracellular Space; Female; Glycogen; Humans; Intellectual Disability; Microscopy, Electron; Muscles; Muscular Diseases; Myofibrils; Neuromuscular Diseases; Pinocytosis; Reflex, Abnormal; Sarcolemma; Thigh

Topics: Amyloidosis; Carbohydrate Metabolism; Congenital Abnormalities; Endocrinology; Glycogen; Humans; Mitochondria; Muscular Diseases; Muscular Dystrophies; Myositis; Neurology; Neuromuscular Diseases; Paralyses, Familial Periodic

Topics: Disease; Glycogen; Glycogen Storage Disease; Humans; Muscle, Skeletal; Muscles; Muscular Diseases; Neuromuscular Diseases