glycogen and Growth-Disorders

Topics: Adolescent; Alanine; Alanine Transaminase; Aspartate Aminotransferases; Diabetes Mellitus, Type 1; Female; Glycogen; Growth Disorders; Hepatomegaly; Humans; Liver; Syndrome

A mechanistic cause for Mauriac syndrome, a syndrome of growth failure and delayed puberty associated with massive liver enlargement from glycogen deposition in children with poorly controlled type 1 diabetes, is unknown. We discovered a mutation in the catalytic subunit of liver glycogen phosphorylase kinase in a patient with Mauriac syndrome whose liver extended into his pelvis. Glycogen phosphorylase kinase activates glycogen phosphorylase, the enzyme that catalyzes the first step in glycogen breakdown. We show that the mutant subunit acts in a dominant manner to completely inhibit glycogen phosphorylase kinase enzyme activity and that this interferes with glycogenolysis causing increased levels of glycogen in human liver cells. It is known that even normal blood glucose levels physiologically inhibit glycogen phosphorylase to diminish glucose release from the liver when glycogenolysis is not needed. The patient's mother possessed the same mutant glycogen phosphorylase kinase subunit, but did not have diabetes or hepatomegaly. His father had childhood type 1 diabetes in poor glycemic control, but lacked the mutation and had neither hepatomegaly nor growth failure. This case proves that the effect of a mutant enzyme of glycogen metabolism can combine with hyperglycemia to directly hyperinhibit glycogen phosphorylase, in turn blocking glycogenolysis causing the massive liver in Mauriac disease.

Topics: Adolescent; Diabetes Mellitus, Type 1; Glycogen; Glycogen Phosphorylase, Liver Form; Growth Disorders; Hepatomegaly; Humans; Male; Mutation; Phosphorylase Kinase; Puberty, Delayed; Syndrome

Mauriac syndrome is characterised by growth failure, cushingoid appearance and hepatomegaly which occurs in patients with insulin dependent diabetes and was first described shortly after the introduction of insulin as a treatment for the condition.. To describe the clinical features, histological findings and outcome of young people with glycogenic hepatopathy, the hepatic manifestation of Mauriac syndrome (MS).. Retrospective cohort study.. Young people with glycogenic hepatopathy.. Tertiary paediatric hepatology unit.. Thirty-one young people (16 M), median age of 15.1 years (IQR 14-16.2) presented within the study period. Median age of diagnosis of diabetes was 10 years (IQR 8-11). Median insulin requirement was 1.33 units/kg/day; median HbA1c was 96.7 mmol/mol (IQR 84.7-112.0). Growth was impaired: median height z-score was -1.01 (-1.73 to 0.4) and median body mass index (BMI) z-score was 0.28 (-0.12 to 0.67). Hepatomegaly was universal with splenomegaly in 16%. Transaminases were abnormal with a median aspartate aminotransferase (AST) of 76 IU/L and gamma glutamyltransferase of 71 IU/L. Liver biopsy was undertaken in 19 (61%). All showed enlarged hepatocytes with clear cytoplasm with glycogenated nuclei in 17. Steatosis was present in the majority. Inflammation was present in 8 (42%). Fibrosis was seen in 14 (73%) and was generally mild though 2 had bridging fibrosis. Megamitochondria were described in 7. Presence of megamitochondria correlated with AST elevation (p=0.026) and fibrosis on biopsy (p=0.007). At follow-up 17 children had normal or improved transaminases, in 13 there was no change. Transaminases followed the trend of the child's HbA1c.. Despite modern insulin regimens and monitoring in children with type 1 diabetes, MS still exists. Significant steatosis, inflammation and fibrosis were all seen in liver biopsies.

Topics: Adolescent; Biopsy; Diabetes Mellitus, Type 1; Fatty Liver; Female; Glycogen; Growth Disorders; Hepatitis; Hepatomegaly; Humans; Liver; Liver Cirrhosis; Male; Retrospective Studies; Syndrome

We studied the structure and function of the insulin receptor (IR) in two sisters with leprechaunism. The patients had inherited alterations in the IR gene and were compound heterozygotes. Their paternal IR allele carried a major deletion, including exons 10-13, which shifted the reading frame and introduced a premature chain termination codon in the IR sequence. This allele was expressed at a very low level in cultured fibroblasts (< 10% of total IR messenger ribonucleic acid content) and encoded a truncated protein lacking transmembrane and tyrosine kinase domains. The maternal IR allele was deleted of 3 bp in exon 3, causing the loss of Asn281 in the alpha-subunit. This allele generated levels of IR messenger ribonucleic acid and cell surface receptors similar to those seen in control fibroblasts. However, IRs from patients' cells had impaired insulin binding and exhibited in vivo and in vitro constitutive activation of autophosphorylation and tyrosine kinase activity. As a result of this IR-preactivated state, the cells were desensitized to insulin stimulation of glycogen and DNA syntheses. These findings strongly suggest that Asn281 of the IR alpha-subunit plays a critical role in the inhibitory constraint exerted by the extracellular alpha-subunit over the intracellular kinase activity.

Topics: Amino Acid Sequence; Asparagine; Base Sequence; DNA; Electrophoresis; Female; Fibroblasts; Gene Deletion; Glycogen; Growth Disorders; Humans; Infant, Newborn; Insulin; Molecular Sequence Data; Phosphorylation; Polymerase Chain Reaction; Receptor, Insulin; RNA, Messenger; Sequence Analysis, DNA

We studied the biological properties of insulin receptors (IRs) and insulin-like growth factor-I (IGF-I) receptors in cultured fibroblasts from a patient with leprechaunism (leprechaun Par-1). Patient cells displayed normal insulin binding capacity and affinity. Basal in vivo autophosphorylation and in vitro exogenous kinase activity of patient IRs were elevated twofold to threefold compared with control receptors, and insulin had no further effect on these processes. Moreover, patient IRs were unable to promote the stimulation of metabolic and mitogenic pathways. IR substrate-1 (IRS-1) and mitogen-activated protein (MAP) kinase tyrosine phosphorylation and glycogen and DNA synthesis were not increased in the basal state in patient fibroblasts and were also insensitive to the stimulatory effect of insulin. As for IGF-I, although binding and receptor kinase activity were normal, the ability to stimulate glycogen and DNA synthesis was altered in patient cells. Two mutant alleles of the IR gene were detected by denaturing gradient gel electrophoresis (DGGE) and direct sequencing. The maternal allele contained a point mutation in exon 18 encoding the tryptophan-for-arginine substitution at position 1092, and the paternal allele had a point mutation in exon 20 substituting lysine for glutamic acid at codon 1179. Thereby, leprechaun Par-1 was a compound heterozygote for two missense mutations located in the IR beta-subunit. The present investigation provides the first evidence that leprechaunism can be causally related to structural alterations in the tyrosine kinase domain of the IR. These alterations result in severe impairment of insulin and IGF-I action.

Topics: Animals; Cells, Cultured; DNA Replication; Electrophoresis, Polyacrylamide Gel; Female; Glycogen; Growth Disorders; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Insulin-Like Growth Factor I; Male; Pedigree; Phosphoproteins; Phosphorylation; Protein Binding; Protein Kinases; Rats; Receptor, Insulin; Signal Transduction

Seven male members of one family had a form of glycogen storage disease that was inherited in an X-linked recessive pattern. The clinical manifestations included hepatomegaly, delay in growth and sexual maturation, muscular weakness in childhood, and gouty arthritis. The cause of the glycogen accumulation did not appear to be a deficiency of glucose 6-phosphatase, debrancher enzyme, phosphorylase, or phosphorylase kinase. Prognosis appeared to be good although there was significant disability during childhood.

Topics: Adolescent; Adult; Biopsy; Child; Glycogen; Glycogen Debranching Enzyme System; Glycogen Storage Disease; Growth Disorders; Hepatomegaly; Humans; Infant; Liver; Male; Muscle Hypotonia; Pedigree; Phosphorylase Kinase; Uric Acid

Histologic findings are presented of 28 biopsies taken from 19 insulin-dependent children of either sex with long-standing diabetes who developed the Mauriac syndrome or forms frustes of it. Using this comprehensive material, probably the largest series of biopsies related to this problem, a detailed survey is given on morphologic liver findings associated with this rare type of chronic-diabetic decompensation of metabolism. Behaviour and extent of fat and glycogen deposits, including nuclear liver glycogen, showed marked variations. Not in all cases hepatomegaly, the main clinical symptom, was reflected by corresponding histologic findings. Liver glycogenosis alone is not pathognomonic of the Mauriac syndrome. In the decompensation phase of the disease however, liver glycogenosis is found fairly frequently, whereas in the recompensation phase hepatocytic lipid deposits are a common finding.

Topics: Adolescent; Biopsy; Cell Nucleus; Child; Diabetes Mellitus, Type 1; Female; Glycogen; Growth Disorders; Hepatomegaly; Humans; Lipids; Liver; Male; Syndrome

Topics: Allopurinol; Bicarbonates; Blood Glucose; Diazoxide; Gluconeogenesis; Glucose-6-Phosphatase; Glycogen; Glycogen Storage Disease Type I; Growth Disorders; Humans; Hypoglycemia; Liver; Liver Glycogen; Uric Acid

Weanling male Sprague-Dawley rats received bilateral electrolytic lesions in the dorsomedial hypothalamic area by means of a direct cathodal current. Sham-operated rats served as controls. Ponderal and linear growth, obesity index, food intake, and several indices of intermediary metabolism of adipose tissue and muscle were measured. Cathodal lesions, as did anodal lesions reported on previously resulted in retardation of body weight, length, and food intake, while the obesity index remained in the normal range. Similarly, the metabolic data in adipose tissue and muscle are comparable to those from experiments in which dorsomedial lesions were placed by anodal current: incorporation of glucose into CO2 lipid, and glycogen of muscle tissue (diaphragm) were similar in DMN-lesioned rats and controls. The difference between anodal and cathodal lesions in this hypothalamic syndrome is a delay in the onset of hypophagia until about 30 days after the hypothalamic operation. The data support the concept that lesions in the hypothalamus, in general, exert their effect by destruction of neuronal assemblies, i.e., nerve cells and/or fiber tracts passing through the lesioned area.

Topics: Adipose Tissue; Animals; Animals, Newborn; Body Weight; Carbon Dioxide; Diaphragm; Feeding Behavior; Glucose; Glycogen; Growth Disorders; Hypothalamus; Hypothalamus, Middle; Insulin; Lipid Metabolism; Male; Muscles; Proteins; Rats; Syndrome

Bilateral electrolytic lesions were placed in the dorsomedial hypothalamic nuclei (DMN) of weanling male Sprague-Dawley rats. Sham-operated rats served as controls. After 22 days on lab chow and tap water ad libitum, the animals were injected with U-14 C-alanine 0.167 muC/mu moles intraperitoneally (5 muC and 30 mu moles/100 gm body weight) and sacrificed 2 hr later. There was no significant difference, in the incorporation of the label into total lipid, free fatty acids, glycogen, or tissue protein of both liver and diaphragm, between the DMN-lesioned and the sham-operated rats. Similarly, there was no significant difference in the incorporation into plasma glucose or protein. It is concluded that in spite of profound alterations in both ponderal and linear growth and food intake, there is no disruption of normal gluconeogenesis in the weanling rat with DMN lesions.

Topics: Alanine; Animals; Animals, Newborn; Blood Glucose; Body Weight; Diaphragm; Fatty Acids, Nonesterified; Feeding Behavior; Gluconeogenesis; Glycogen; Growth Disorders; Hypothalamus; Lipid Metabolism; Liver; Male; Muscles; Proteins; Rats

Topics: Adult; Basal Metabolism; Body Composition; Body Weight; Chronic Disease; Feeding Behavior; Female; Glycogen; Growth Disorders; Humans; Male; Motivation; Muscles; Nitrogen; Nutrition Disorders; Physical Exertion; Pregnancy; Psychosexual Development; Sleep; Sports Medicine; Twins; Wakefulness

Topics: Abnormalities, Multiple; Age Determination by Skeleton; Bone and Bones; Consanguinity; Developmental Disabilities; Female; Foot; Glycogen; Growth Disorders; Hand; Humans; Infant; Intellectual Disability; Male; Microscopy, Electron; Muscles; Muscular Atrophy; Myofibrils; Nerve Degeneration; Pedigree; Rubinstein-Taybi Syndrome; Sarcoplasmic Reticulum

Topics: Amino Acids; Brain Chemistry; Brain Diseases; Cerebellum; Cerebral Cortex; Cerebrosides; Cholesterol; Electroencephalography; Glycogen; Growth Disorders; Hair; Humans; Infant; Male; Nerve Degeneration; Pedigree; Phenobarbital; Phenytoin; Phospholipids; Plasmalogens; Seizures; Ubiquinone; Vitamin E

Topics: Animals; Blindness; Blood Glucose; Carbon Isotopes; Fasting; Glucose; Glucose Tolerance Test; Glycogen; Growth Disorders; Growth Hormone; Insulin; Lipid Metabolism; Male; Rats; Rats, Inbred Strains

Topics: Female; Fetal Diseases; Glucose; Glycogen; Growth Disorders; Growth Hormone; Humans; Hypoglycemia; Infant Nutritional Physiological Phenomena; Infant, Newborn; Infant, Newborn, Diseases; Jaundice, Neonatal; Male; Placenta Diseases; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Prognosis; Respiratory Distress Syndrome, Newborn

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Animals, Newborn; Body Weight; Diet; Glucose; Glycogen; Growth; Growth Disorders; Hindlimb; Lactates; Male; Muscle Development; Muscles; Organ Size; Oxidoreductases; Pyruvates; Rats; Starvation