Glucose-6-phosphatase mutation G188R confers an atypical glycogen storage disease type 1b phenotype

Glycogen storage disease type 1a (GSD 1a) is caused by a deficiency in microsomal glucose-6-phosphatase (G6Pase). A variant (GSD 1b) is caused by a defect in the transport of glucose-6-phosphate (G6P) into the microsome and is associated with chronic neutropenia and neutrophil dysfunction. Mutually exclusive mutations in the G6Pase gene and the G6P transport gene establish GSD la and GSD 1b as independent molecular processes and are consistent with a multicomponent translocase catalytic model. A modified translocase/catalytic unit model based on biochemical data in a G6Pase knockout mouse has also been proposed for G6Pase catalysis. This model suggests coupling of G6Pase activity and G6P transport. A 5-mo-old girl with hypoglycemia, hepatomegaly, and lactic acidemia was diagnosed with GSD 1a. She also developed neutropenia, neutrophil dysfunction, and recurrent infections characteristic of GSD 1b. Homozygous G188R mutations of the G6Pase gene were identified, but no mutations in the G6P translocase gene were found. We have subsequently identified a sibling and two unrelated patients with similar genotypic/phenotypic characteristics. The unusual association of neutrophil abnormalities in patients with homozygous G188R mutations in the G6Pase gene supports a modified translocase/catalytic unit model.     

Glycogen storage disease type Ib

Glycogen storage disease type Ib has all the clinical manifestations of glycogen storage disease type Ia such as hepatomegaly, growth retardation, bleeding tendency, hypoglycemia, hyperlactacidemia, hyperuricemia, hyperlipidemia, impaired platelet function plus neutropenia. The overall glucose-6-phosphatase activity in disrupted microsomes from liver is normal whereas glucose-6-phosphate translocase, the first enzyme in the glucose-6-phosphate transport system is absent. There is no glucose-6-phosphatase activity in vivo. Recent results show that in granulocytes the glucose-6-phosphate-dependent hexosemonophosphate-shunt is impaired.Prof. Horst Bickel on the occasion of his 65th birthday     

Glycogen storage disease type Ib without neutropenia

We report 2 patients with atypical glycogen storage disease type Ib without neutropenia or infectious complications. Neither patient was deficient in hepatic glucose-6-phosphatase activities in microsome-disrupted homogenates; both had mutations in the glucose-6-phosphate transporter gene, suggesting an allelic variant of glycogen storage disease type Ib.     

Glycogen storage disease type I: diagnosis and phenotype/genotype correlation

Glycogen storage disease type Ia (GSD Ia) is caused by mutations in theG6PC gene encoding the phosphatase of the microsomal glucose-6-phosphatase system. GSD Ia is characterized by hepatomegaly, hypoglycemia, lactic acidemia, hyperuricemia, hyperlipidemia and short stature. Other forms of GSD I (GSD I non-a) are characterized by the additional symptom of frequent infections caused by neutropenia and neutrophil dysfunction. GSD I non-a is caused by mutations in a gene encoding glucose-6-phosphatase translocase (G6PT1). We report on the molecular genetic analyses of G6PC and G6PT 1 in 130 GSD Ia patients and 15 GSD I non-a patients, respectively, and provide an overview of the current literature pertaining to the molecular genetics of GSD I. Among the GSD Ia patients, 34 different mutations were identified, two of which have not been described before (A65P; F117C). Seventeen different mutations were detected in the GSD I non-a patients. True common mutations were identified neither in GSD Ia nor in GSD I non-a patients,Conclusion: Glycogen storage disease type Ia and and type I non-a are genetically heterogenous disorders. For the diagnosis of the various forms of glycogen storage disease type I, molecular genetic analyses are reliable and convenient alternatives to the enzyme assays in liver biopsy specimens. Some genotype-phenotype correlations exist, for example, homozygosity for oneG6PC mutation, G188R, seems to be associated with a glycogen storage disease type I non-a phenotype and homozygosity for the 727G>T mutation may be associated with a milder phenotype but an increased risk for hepatocellular carcinoma. Published online: 27 July 2002     

How many forms of glycogen storage disease type I?

 Glucose-6-phosphatase is a multicomponent enzymatic system of the endoplasmic reticulum, which catalyses the terminal steps of gluconeogenesis and glycogenolysis by converting glucose-6-phosphate to glucose and inorganic phosphate. Glycogen storage diseases type I (GSD I) are a group of metabolic disorders arising from a defect in a component of this enzymatic system, i.e. the glucose-6-phosphate hydrolase (GSD Ia), the glucose-6-phosphate translocase (GSD Ib) and possibly also the translocases for inorganic phosphate (GSD Ic) or glucose (GSD Id). The genes encoding the glucose-6-phosphate hydrolase and the glucose-6-phosphate translocase have both been cloned and assigned to human chromosomes 17q21 and 11q23, respectively. Investigation of patients with GSD I shows that those with GSD Ia are mutated in the glucose-6-phosphate hydrolase gene, whereas those diagnosed as GSD Ib, GSD Ic or GSD Id are mutated in the glucose-6-phosphate translocase gene, and are therefore GSD Ib patients, in agreement with the fact that they all have neutropenia or neutrophil dysfunction. This suggests that the biochemical assays used to differentiate GSD Ic and GSD Id from GSD Ib are not reliable. Conclusion In practice therefore appears to be only two types of GSD I (Ia and Ib), which can be differentiated by (1) measurement of glucose-6-phosphatase activity in fresh and detergent-treated homogenates and (2) by mutation search in the genes encoding the glucose-6-phosphate hydrolase and the glucose-6-phosphate translocase. Received: 20 July 1999 and in revised form: 1 October 1999 / Accepted: 1 October 1999     

Improved neutrophil function in a glycogen storage disease type 1b patient after liver transplantation

Patients with glycogen storage disease type 1b (GSD1b) not only show hepatomegaly, hypoglycaemia and lactic acidosis, but also neutropenia and neutrophil dysfunction. Here, we report improvement of neutropenia and neutrophil function in a 22-year-old male GSD1b patient who had undergone living-related partial liver transplantation (LT) at 18 years of age. After LT, the patients infectious episodes decreased, gastrointestinal symptoms ameliorated, neutrophil counts increased, and neutrophil function tests normalised. Conclusion:although it is not known whether this improvement was causally related to liver transplantation, this may be the first recorded case of restoration of neutrophil dysfunction in a glycogen storage disease type 1b patient.Abbreviations G6PT glucose-6-phosphate translocase - GSD glycogen storage disease - GSD1b glycogen storage disease type 1b - LT liver transplantation - PMA phorbol-12-myristate-13-acetate - rhGCSF recombinant human granulocyte colony stimulating factor     

Acute myelogenous leukemia and glycogen storage disease 1b

Glycogen storage disease 1b (GSD 1b) is caused by a deficiency of glucose-6-phosphate translocase and the intracellular accumulation of glycogen. The disease presents with failure to thrive, hepatomegaly, hypoglycemia, lactic acidosis, as well as neutropenia causing increased susceptibility to pyogenic infections. We present a case of a young woman with GSD 1b who developed acute myelogenous leukemia while on long-term granulocyte colony-stimulating factor therapy. The presence of two rare diseases in a single patient raises suspicion that GSD 1b and acute myelogenous leukemia are linked. Surveillance for acute myelogenous leukemia should become part of the long-term follow-up for GSD 1b.     

Development of the rat hepatic microsomal glucose-6-phosphatase system and its glucocorticoid inducibility

Rat liver glucose-6-phosphatase activity was determined in both fully activated and intact microsomal preparations during perinatal development. Activities increased rapidly in both preparations following birth, then gradually fell to adult values. The latency of the glucose-6-phosphatase system also increased neonatally whereas hepatic glycogen concentrations decreased postnatally. The effect of dexamethasone pretreatment on the hepatic glucose-6-phosphatase system was also investigated. Dexamethasone pretreatment failed to decrease the latency of glucose-6-phosphatase in microsomes from neonatal rats but decreased the latency of the enzyme in adult female rat liver from 44 to 12% of total activity.     

Studies on a patient with in vivo evidence of type I glycogenosis and normal enzyme activities in vitro.

Biochemical and clinical studies on a patient with hepatic glycogen storage disease are reported. The patient showed many of the clinical and biochemical features of type I glycogenosis (glucose-6-phosphatase deficiency), but had normal activities of the following enzymes in liver tissue: glucose-6-phosphatase (EC3.1.3.9); amylo-1,6-glucosidase (EC3.2.1.33); glycogen phosphorylase (EC2.4.1.1); fructose-1,6-diphosphatase (EC3.1.3.11). The urinary excretion of 2-oxoglutaric acid was greatly increased in this patient and in a case of enzymologically proven type I glycogenosis. Abnormal 2-oxoglutaric aciduria has not been previously reported in the glycogen storage diseases. The results are discussed in relation to the possible nature of the underlying biochemical defect in patients of this type.     

STUDIES ON A PATIENT WITH IN VIVO EVIDENCE OF TYPE I GLYCOGENOSIS AND NORMAL ENZYME ACTIVITIES IN VITRO

ABSTRACT. Biochemical and clinical studies on a patient with hepatic glycogen storage disease are reported. The patient showed many of the clinical and biochemical features of type I glycogenosis (glucose-6-phosphatase deficiency), but had normal activities of the following enzymes in liver tissue: glucose-6-phosphatase (EC3.1.3.9); amylo-1,6-glucosidase (EC3.2.1.33); glycogen phosphorylase (EC2.4.1.1); fructose-1,6-diphosphatase (EC3.1.3.11). The urinary excretion of 2-oxoglutaric acid was greatly increased in this patient and in a case of enzymologically proven type I glycogenosis. Abnormal 2-oxoglutaric aciduria has not been previously reported in the glycogen storage diseases. The results are discussed in relation to the possible nature of the underlying biochemical defect in patients of this type.     

Impaired monocyte function in glycogen storage disease type Ib

Phagocyte (neutrophil and monocyte) function was evaluated in a boy with glycogen storage disease type Ib. Neutrophils were found to be defective in motility and respiratory burst and monocytes showed a defect in respiratory burst but not in motility. These results suggested that the glucose-6-phosphate transport system plays a role in the function of neutrophils and monocytes and that these two phagocytes are different from each other in their energy metabolism for motility.Abbreviations GSD Ia Glycogen storage disease type Ia - GSD Ib glycogen storage disease type Ib - G6P glucose-6-phosphate - G6Pase glucose-6-phosphatase - PHA phytohemagglutinin - CL chemiluminescence - ZAS zymosan-activated serum - FMLP N-formylmethionyl-leucyl-phenylalanine - CSA colony-stimulating activity     

Glycogen storage disease type Ib: familial bleeding tendency

A mild bleeding tendency with characteristics of the von Willebrand disease was documented in family members of a girl with glycogen storage disease type Ib (GSD) Ib). It was assumed that a defective glucose-6-phosphate dependent microsomal glycoprotein synthesis was involved in the bleeding disorder of the patient and the GSD Ib heterozygotes.Abbreviations GSD Ia glycogen storage disease type Ia - GSD Ib glycogen storage disease type Ib - G6P glucose-6-phosphate - G6P-ase glucose-6-phosphatase     

Glycogen storage disease type 1b: microsomal glucose-6-phosphatase system in two patients with different clinical findings

The basic defect in glycogen storage disease (GSD) type 1b was investigated in two patients: one, (Y.S.), a severely affected infant and the other, (Y.M.), an adult with mild clinical symptoms. The enzymatic studies on liver needle biopsy specimens from the two patients indicated that glucose-6-phosphate (G-6-P) phosphohydrolase activity of the "intact microsomes" was partially deficient (20% of that in controls) in Y.M. and undetectable in Y.S. Activities of G-6-P phosphohydrolase in the disrupted microsomes of Y.S. and Y.M. are higher than those in the disrupted microsomes of controls (12.60 mumole/min/g liver in Y.S., 9.18 in Y.M. and 6.26 +/- 1.22, mean +/- S.D. in controls). Our study also shows that PPi phosphohydrolase activities of the "intact microsomes" from both patients (6.07 mumol/min/g liver in Y.S. and 5.36 in Y.M.) were greater than those of the controls (3.23 +/- 0.77 mumole/min/g wet weight liver). These results indicate that the G-6-P translocase was the locus of the defect in both patients with GSD type 1b. Clinical symptoms and enzymatic studies suggest that the clinical severity of this disorder depends on the level of residual activities of G-6-P translocase. Kinetic studies showed an abnormally high Km of the residual G-6-P translocase in Y.M., suggesting a structural gene mutation. The systematic assay method for glucose-6-phosphatase system, which requires only 15 mg of liver tissues, is also described.     

Type Ib glycogenosis

Type Ib glycogenosis is a rare glycogen storage disorder resulting from a defect in the enzyme, glucose-6-phosphatase microsomal translocase. We report a case of Type Ib glycogenosis in an 18 month-old male child who presented with a history of hypoglycemic seizures and recurrent infections and had a massive hepatomegaly, recurrent hypoglycemia, hyperuricemia, hypertriglyceridemia, neutropenia and fasting lacticacidemia which decreased sharply on glucose administration.     

Genotype/phenotype correlation in glycogen storage disease type 1b: a multicentre study and review of the literature

We studied the genotype/phenotype correlation in a cohort of glycogen storage disease type (GSD) 1b patients. A total of 25 GSD1b patients, 13 females and 12 males, age range: 4.3–28.4 years, mean:14.6±6.8 years; median: 15 years, representing the entire case load of Italian GSD1b patients, were enrolled in the study. Molecular analysis of the glucose 6-phosphate translocase (G6PT1) gene was performed in all patients. We analysed the presence of a correlation among both the clinical features associated with GSD1b (neutropenia, frequency of admission to the hospital for severe infections) and the presence of systemic complications (liver adenomas, nephropathy, bone mineral density defect, polycystic ovaries, short stature, inflammatory bowel disease) and the mutations detected in each patient. Nine patients were homozygous or compound heterozygous for mutations causing stop codons. In particular, three patients were homozygous for the same mutation (400X); of these patients, one showed chronic neutropenia with severe and frequent infections and severe inflammatory bowel disease, another patient cyclic neutropenia associated with rare bacterial infections and mild bowel involvement and the last one normal neutrophil count. Two patients were homozygous for the mutation 128X; one of these patients did not show neutropenia, whereas the other one had severe neutropenia needing frequent hospital admission and was under granulocyte-colony stimulating factor treatment. In three patients no mutations were detected. Conclusion:no correlation was found between individual mutations and the presence of neutropenia, bacterial infections and systemic complications. These results suggest that different genes and proteins modulate neutrophil differentiation, maturation and apoptosis and thus the severity and frequency of infections. The absence of detectable mutations in three patients could suggest that a second protein plays a role in microsomal phosphate transport.     

Glucose-6-phosphatase and type 1 glycogen storage disease: Some critical considerations

There now is compelling evidence that hydrolysis of glucose-6-phosphate (Glc-6-P) in intact hepatic endoplasmic reticulum (ER) membrane preparations involves four integral components of the membrane: a Glc-6-P specific transporter (T₁), a nonspecific enzyme (E) with its active site facing the lumen, and two other transport systems to mediate rapid and reversible fluxes of the hydrolytic products, inorganic phosphate (P_i) and glucose, i.e. (T₂) and (T₃), respectively. T₂ also mediates transport of inorganic pyrophosphate (PP_i) and carbamylphosphate. This concept readily and completely reconciles all known characteristics of the glucose-6-phosphatase (Glc-6-P'ase) system provided appropriate considerations are given to: (1) the quantitative contribution of E residing in membranes lacking a permeability barrier; (2) the kinetic restrictions imposed by T₁ and T₂; and (3) the influences of the endocrine, developmental and nutritional state on the kinetic relationship between the capacities to transport and hydrolyze. A broaderbased understanding and application of these principles in the study of Glc-6-P'ase is needed to ensure accurate diagnosis of type 1 glycogen storage disease (GSD) and minimize unnecessary controversy. The view that the enzyme in native ER membranes is conformationally constrained is not supported by direct measurements of the catalytic turnover number. Finally, we describe the marked deficiencies of rapid filtration assays of Glc-6-P and PP_i uptake as a direct method of diagnosis of types 1b and 1c GSD.     

Induction in utero of hepatic glucose-6-phosphatase by fetal hypoinsulinemia

The effect of fetal hypoglycemia and hypoinsulinemia on fetal rat hepatic glucose-6-phosphatase activity was studied. Fetal hypoglycemia and hypoinsulinemia were produced by inducing maternal hyperinsulinemia and hypoglycemia secondary to the exogenous administration of insulin via implantation of osmotically driven minipumps on day 15 of gestation into 15 experimental animals. 13 animals served as sham-operated controls. Cesarean sections were performed on day 20 or 21 of gestation under pentobarbital anesthesia. Liver glucose-6-phosphatase activity was increased in the hypoinsulinemic fetuses. In contrast, the hyperinsulinemic mothers had suppressed hepatic glucose-6-phosphatase activity. Hypoinsulinemia would appear to be the primary stimulus for enhanced fetal glucose-6-phosphatase in this model.