Glycogen Storage Disease Ib Research Articles

Glycogen storage disease type Ib: Infectious complications and measures for prevention

A patient with glycogen storage disease (GSD) type Ib, neutrophenia, chronic inflammatory bowel disease and recurrent abscesses was treated with recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF). GM-CSF (and also granulocyte colony stimulating factor) therapy markedly increased the neutrophil counts and reduced the frequency of infections and inflammation. We conclude that myeloid growth factors are effective for the treatment and prevention of acute infections and chronic inflammatory complications in patients with GSD Ib.

Defective neutrophil and monocyte functions in glycogen storage disease type Ib: a literature review.

A summary review of leukocyte function in 42 published cases of glycogen storage disease Ib is presented. Polymorphonuclear and monocyte dysfunctions were evidenced in the majority of cases, whereas lymphocytes appeared to be unaffected. Phagocyte dysfunctions comprised in vivo mobilization and motility, in vitro random and directed migration, and one or several component functions of the "metabolic" ("respiratory") burst. On the basis of the available data it is impossible to know whether a primary functional deficit of the glucose 6-phosphate transport protein of the microsomal glucose 6-phosphatase system, as demonstrated in liver, also exists in these phagocytic cells and is responsible for this dysfunction.

Neutrophil dysfunction in glycogen storage disease Ib: Association with Crohn's-like colitis

Two cases of patients with Crohn's-like colitis and glycogen storage disease Ib have been reported previously. In the current report, chronic inflammatory bowel disease that developed in another adolescent with this glycogenosis is described, thereby corroborating the association. The neutrophil dysfunction observed in glycogen storage disease Ib is the most likely predisposing factor. Neutrophil function was investigated in our patient in an attempt to shed light on the pathogenesis of his intestinal inflammation. The patient displayed reduced neutrophil chemotaxis to zymosan-activated serum, N-formyl-methionine-phenylalanine, and Escherichia coli bacteria-derived factor and reduced intracellular killing of Staphylococcus aureus 502A. Others have found this defective bacteriocidal activity to be caused by impaired oxidative metabolism. The recent recognition of chronic inflammatory bowel disease in glycogen storage disease Ib, as well as in chronic granulomatous disease, suggests that further study of respiratory burst activity of neutrophils in Crohn's disease is warranted.

129 GRANULOCYTE/MACROPHAGE COLONY STIMULATING FACTOR (GM-CSF) FOR TREATMENT IN GLYCOGEN STORAGE DISEASE TYPE IB

Type Ib glycogen storage disease is caused by a defect in the glucose-6-phosphatase translocase of the microsomal glucose-6-phosphatase system. In addition to metabolic problems patients exhibit a predisposition for infections which is related to neutropenia. Various degrees of impairment of the neutrophil function have been observed including reduced chemotaxis and superoxide (O2−) production. In vitro, GM-CSF stimulates growth of myeloic progenitor cells and improves functions of mature neutrophils such as formation of oxygen radicals and chemotaxis. In clinical trials, GM-CSF has been shown to increase the neutrophil count in a dose-dependent manner.A 13 year old girl with type Ib glycogen storage disease, inflammatory bowel disease (resembling Crohn's disease), and obstinate neutropenia (neutrophil counts below 500/μl) sufferd from severe oral mucosal lesions. The girl was treated with human recombinant GM-CSF at a daily dose of 250 μg/m2 subcutaneously during a 2 week course with the parents' informed consent. From the third day of treatment the neutrophil count increased continuously from 216/μl to 6052/μl at day 14. At the same time, normal superoxide production was measured in the isolated granulocytes activated by PMA or zymosan. Oral ulcers resolved completely. Except for some painful hyperemic areas at the sites of injections no side effects appeared. After GM-CSF administration was discontinued leucocyte counts decreased to pre-treatment levels within 7 days.From the results of this limited clinical trial we conclude that GM-CSF can increase the neutrophil count and normalize specific granulocyte functions in glycogen storage disease Ib. GM-CSF might be of clinical benefit in managing severe inflammatory complications in neutropenic patients with this disorder.

Hexose Uptake and Transport in Polymorphonuclear Leukocytes from Patients with Glycogen Storage Disease Ib

Neutrophil functions and glucose metabolism are known to be impaired in glycogen storage disease (GSD) Ib patients. The uptake of nonmetabolizing glucose analogues into polymorphonuclear leukocytes (PMN) of GSD Ib patients was studied. 2-Deoxyglucose (2-DOG) and 3-O-methylglucose are transported across the cell membrane by facilitated diffusion mediated by the glucose transporter. Because 2-DOG is phosphorylated within the cell, its uptake rate reflects hexose transport as long as phosphorylation is not rate-limiting. These conditions prevail only at low 2-DOG concentrations. Transport of 5 microM DOG into GSD Ib patient PMN was found to be similar to controls (4.3 +/- 0.5 and 4.65 +/- 1.77 pmol/min X 10(6), respectively). In contrast, 2-DOG uptake at high concentrations (2 mM) decreased by 70% in patient PMN compared with control cells (0.17 +/- 0.06 and 0.51 +/- 0.11 nmol/min X 10(6), for patients and controls, respectively). Transport of 3-O-methylglucose (a glucose analogue that does not undergo intracellular phosphorylation) was not different in patient PMN compared with controls (1.86 +/- 0.53 and 2.19 +/- 0.30 nmol/min X 10(6), respectively). Hexose monophosphate shunt activity in PMN of GSD Ib patients at a glucose concentration of 2 mM was 43% of control values, whereas at 10 microM it was similar to controls. Taken together, these results suggest that the defect in glucose uptake and metabolism found in GSD Ib patient PMN is due to an impairment in hexose phosphorylation rather than in a reduction in the transmembrane glucose transport activity.

Glycogen storage disease Ib: modification of alpha 1-antitrypsin glycoprotein microheterogeneity.

Upon isoelectric focusing, alpha 1-antitrypsin shows a characteristic major band pattern caused by glycoprotein isoforms with different oligosaccharide side chains. In ten apparently healthy individuals with the Pi type MM the ratio of isoforms I, II, and III was 5.2:3.9:1.0. In six patients with glycogen storage disease Ib the ratio of isoforms in the Pi type MM was 3.6:5.5:1.9 suggesting a shift from the biantennary to triantennary oligosaccharide side chains. This shift may result from the limited availability of glucose or glucose derivatives for the synthesis of N-glycosidic glycoproteins.

Impaired carbohydrate metabolism of polymorphonuclear leukocytes in glycogen storage disease Ib.

This study measures hexose monophosphate (HMP) shunt activity, glycolytic rate, and glucose transport in PMN and lymphocytes of patients with glycogen storage disease (GSD) type Ib as compared with controls and with GSD Ia patients. HMP shunt activity and glycolysis were significantly lower in intact PMN cells of GSD Ib patients as compared with GSD Ia patients and with controls. These activities were above normal levels in disrupted GSD Ib PMN. HMP shunt activity and glycolytic rates in lymphocytes were similar in all three groups studied. The rate of 2-deoxyglucose transport into GSD Ib PMN was 30% of that into cells of normal controls. In GSD Ib lymphocytes or in GSD Ia PMN and lymphocytes transport was normal. The striking limitation of glucose transport across the cell membrane of the PMN of GSD Ib patients may account for the impairment of leukocyte function that is characteristic of GSD Ib, but not found in GSD Ia patients.

Impaired glucose transport in polymorphonuclear leukocytes in glycogen storage disease Ib.

A study of 2-deoxyglucose transport into polymorphonuclear leukocytes (PMN) was performed in three patients with glycogen storage disease (GSD) type Ib. The rate of 2-deoxyglucose transport into GSD Ib PMN was 30% of that of cells of normal controls. In GSD Ib lymphocytes, transport was normal. Km for 2-deoxyglucose in the PMN of one patient was within the normal range. The reduced transport was not due to the elevation in Km for 2-deoxyglucose nor to the decreased rate of phosphorylation of 2-deoxyglucose. The striking limitation of glucose transport across the cell membrane may account for the impairment of leukocyte function which is characteristic of GSD Ib.

The dietary treatment of children with type I glycogen storage disease with slow release carbohydrate.

The effect of ingestion of uncooked cornstarch (2 g/kg body weight) in water, uncooked starch (1 g/kg) added to a meal, and glucose (2 g/kg) in water, was studied in eight patients with type IA glycogen storage disease (GSD) and one patient with type IB GSD. Blood glucose concentrations were determined at 30-min intervals during each tolerance test; blood lactate, blood insulin, and expiratory hydrogen were determined at 60-min intervals. The glucose levels remained in the normal range (greater than or equal to 1.8 mM) during approximately 6.5-9.0 h, 3.5-6.5 h, and 2.25-4.0 h during the three tolerance tests, respectively. The lactate levels differed markedly for the different tests per patient, and for the same type of test between the patients. Blood insulin concentrations after starch administration did not exceed values of 50 mU/liter above fasting levels and were markedly lower than those after glucose administration (maximum levels of 280 mU/liter). The expiratory hydrogen excretion did not increase or only slightly increased after cornstarch administration (less than 20 ppm).