Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0020473 (hyperlipidemia)
15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycogen storage disease type 1a (GSD-1a), characterized by hypoglycemia, liver and kidney enlargement, growth retardation, hyperlipidemia, and hyperuricemia, is caused by a deficiency in glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis. To evaluate the feasibility of gene replacement therapy for GSD-1a, we have infused adenoviral vector containing the murine G6Pase gene (Ad-mG6Pase) into G6Pase-deficient (G6Pase(-/-)) mice that manifest symptoms characteristic of human GSD-1a. Whereas <15% of G6Pase(-/-) mice under glucose therapy survived weaning, a 100% survival rate was achieved when G6Pase(-/-) mice were infused with Ad-mG6Pase, 90% of which lived to 3 months of age. Hepatic G6Pase activity in Ad-mG6Pase-infused mice was restored to 19% of that in G6Pase(+/+) mice at 7-14 days post-infusion; the activity persisted for at least 70 days. Ad-mG6Pase infusion also greatly improved growth of G6Pase(-/-) mice and normalized plasma glucose, cholesterol, triglyceride, and uric acid profiles. Furthermore, liver and kidney enlargement was less pronounced with near-normal levels of glycogen depositions in both organs. Our data demonstrate that a single administration of a recombinant adenoviral vector can alleviate the pathological manifestations of GSD-1a in mice, suggesting that this disorder in humans can potentially be corrected by gene therapy.
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PMID:Correction of glycogen storage disease type 1a in a mouse model by gene therapy. 1062 14

The clinical manifestations of type 1 glycogen storage disease (GSD-1) in patients deficient in the glucose-6-phosphatase (G6Pase) system (e.g. growth retardation, hepatomegaly, hyperlipidemia, and renal dysfunction) are shared by Hnf1alpha(-/-) mice deficient of a transcriptional activator, hepatocyte nuclear factor 1alpha (HNF1alpha). However, the molecular mechanism is unknown. The G6Pase system, essential for the maintenance of glucose homeostasis, is comprised of glucose 6-phosphate transporter (G6PT) and G6Pase. G6PT translocates G6P from the cytoplasm to the lumen of the endoplasmic reticulum where it is metabolized by G6Pase to glucose and phosphate. Deficiencies in G6Pase and G6PT cause GSD-1a and GSD-1b, respectively. Hnf1alpha(-/-) mice also develop noninsulin-dependent diabetes mellitus caused by defective insulin secretion. In this study, we sought to determine whether there is a molecular link between HNF1alpha deficiency and function of the G6Pase system. Transactivation studies revealed that HNF1alpha is required for transcription of the G6PT gene. Hepatic G6PT mRNA levels and microsomal G6P transport activity are also markedly reduced in Hnf1alpha(-/-) mice as compared with Hnf1alpha(+/+) and Hnf1alpha(+/-) littermates. On the other hand, hepatic G6Pase mRNA expression and activity are up-regulated in Hnf1alpha(-/-) mice, consistent with observations that G6Pase expression is increased in diabetic animals. Taken together, the results strongly suggest that metabolic abnormalities in HNF1alpha-null mice are caused in part by G6PT deficiency and by perturbations of the G6Pase system.
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PMID:A molecular link between the common phenotypes of type 1 glycogen storage disease and HNF1alpha-null mice. 1112 25

A 23-year-old woman was admitted to our hospital with recurrent gouty arthritis. Laboratory findings showed hypoglycemia, lactic acidosis, hyperlipidemia, and hyperuricemia, with normal values of serum alfa-fetoprotein (AFP) and protein induced by vitamin K absence (PIVKA-II). A diagnosis of glycogen storage disease type I (GSD-type I) was made on the basis of the laboratory data, liver biopsy findings, and partially deficient thrombocyte glucose-6-phosphatase (G-6-Pase) activity. Ultrasonography and computed tomography revealed multiple focal hepatic masses. Biopsied specimens of the lesion demonstrated a hepatic adenoma, which changed in appearance in the relatively short period between echography and computed tomography. This interesting phenomenon may highlight the importance for careful follow-up of hepatic adenomas, because of the potential of rupture, hemorrhage, or malignant transformation. During follow-up, the present patient received hemodialysis due to renal failure, and the adenoma regressed spontaneously after 8 years. Included are diagnostic images, demonstrating the association of hepatic adenoma and GSD-type I.
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PMID:Spontaneous regression of hepatic adenoma in a patient with glycogen storage disease type I after hemodialysis: ultrasonographic and CT findings. 1157 51

Mixed hyperlipidaemia is a common finding in glycogen storage disease type Ia (GSD Ia). Although cross-sectional studies have demonstrated increases in intermediate-density lipoproteins (IDLs) and reductions in lipoprotein lipase activity, no studies have investigated the dynamics of apolipoprotein B-100 (apo B) metabolism in GSD Ia. This study investigated apoB turnover in GSD Ia using an exogenous labelling method in one sib from a kinship with established GSD Ia. The study demonstrated normal hepatic secretion of very low-density lipoprotein (VLDL), but hypocatabolism of VLDL, probably due to lack of lipoprotein lipase activity. The production rate of IDL was slightly increased, but the turnover rate of low-density lipoprotein was normal. The findings suggest that, as well as a corn starch diet and dietary fat restriction, treatment of severe mixed hyperlipidaemia in GSD Ia and its attendant risk of pancreatitis should possibly involve fibrates that activate lipoprotein lipase and may enhance the clearance of IDL, rather than omega-3 fatty acids, which principally suppress hepatic secretion of VLDL.
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PMID:Very low-density lipoprotein apolipoprotein B-100 turnover in glycogen storage disease type Ia (von Gierke disease). 1175 80

Glycogen storage disease type 1 (GSD-1), also known as von Gierke disease, is a group of autosomal recessive metabolic disorders caused by deficiencies in the activity of the glucose-6-phosphatase (G6Pase) system that consists of at least two membrane proteins, glucose-6-phosphate transporter (G6PT) and G6Pase. G6PT translocates glucose-6-phosphate (G6P) from cytoplasm to the lumen of the endoplasmic reticulum (ER) and G6Pase catalyzes the hydrolysis of G6P to produce glucose and phosphate. Therefore, G6PT and G6Pase work in concert to maintain glucose homeostasis. Deficiencies in G6Pase and G6PT cause GSD-1a and GSD-1b, respectively. Both manifest functional G6Pase deficiency characterized by growth retardation, hypoglycemia, hepatomegaly, kidney enlargement, hyperlipidemia, hyperuricemia, and lactic acidemia. GSD-1b patients also suffer from chronic neutropenia and functional deficiencies of neutrophils and monocytes, resulting in recurrent bacterial infections as well as ulceration of the oral and intestinal mucosa. The G6Pase gene maps to chromosome 17q21 and encodes a 36-kDa glycoprotein that is anchored to the ER by 9 transmembrane helices with its active site facing the lumen. Animal models of GSD-1a have been developed and are being exploited to delineate the disease more precisely and to develop new therapies. The G6PT gene maps to chromosome 11q23 and encodes a 37-kDa protein that is anchored to the ER by 10 transmembrane helices. A functional assay for the recombinant G6PT protein has been established, which showed that G6PT functions as a G6P transporter in the absence of G6Pase. However, microsomal G6P uptake activity was markedly enhanced in the simultaneous presence of G6PT and G6Pase. The cloning of the G6PT gene now permits animal models of GSD-1b to be generated. These recent developments are increasing our understanding of the GSD-l disorders and the G6Pase system, knowledge that will facilitate the development of novel therapeutic approaches for these disorders.
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PMID:The molecular basis of type 1 glycogen storage diseases. 1189 41

Glycogen storage disease type I (GSD-I) is a group of autosomal recessive disorders with an incidence of 1 in 100,000. The two major subtypes are GSD-Ia (MIM232200), caused by a deficiency of glucose-6-phosphatase (G6Pase), and GSD-Ib (MIM232220), caused by a deficiency in the glucose-6-phosphate transporter (G6PT). Both G6Pase and G6PT are associated with the endoplasmic reticulum (ER) membrane. G6PT translocates glucose-6-phosphate (G6P) from the cytoplasm into the lumen of the ER, where G6Pase hydrolyses the G6P into glucose and phosphate. Together G6Pase and G6PT maintain glucose homeostasis. G6Pase is expressed in gluconeogenic tissues, the liver, kidney, and intestine. However G6PT, which transports G6P efficiently only in the presence of G6Pase, is expressed ubiquitously. This suggests that G6PT may play other roles in tissues lacking G6Pase. Both GSD-Ia and GSD-Ib patients manifest phenotypic G6Pase deficiency, characterized by growth retardation, hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic academia and the current treatment is a dietary therapy. GSD-Ib patients also suffer from chronic neutropenia and functional deficiencies of neutrophils and monocytes, which is treated with granulocyte colony stimulating factor to restore myeloid function. The GSD-Ia and GSD-Ib genes have been cloned. To date, 76 G6Pase and 69 G6PT mutations have been identified in GSD-I patients. A database of the residual enzymatic activity retained by the G6Pase missense mutants is facilitating the correlation of the disease phenotype with the patients' genotype. While the molecular basis for the GSD-I disorders are now known and symptomatic therapies are available, many aspects of the diseases are still poorly understood, and there are no cures. Recently developed animal models of the disorders are now being exploited to delineate the disease more precisely and develop new, more causative therapies.
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PMID:Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex. 1194 31

Oxidative modification of lipoproteins in vessel walls plays a key role in atherogenesis. Patients with glycogen storage disease type Ia (GSD Ia) do not develop premature atherosclerosis despite severe hyperlipidemia. We analyzed antioxidative defense and oxidative stress in plasma and serum of patients with GSD Ia (n = 17) compared to patients with type I diabetes mellitus (DMI, n = 17), familial hypercholesterolemia (FH, n = 18), and healthy controls (n = 20). We measured the total radical-trapping antioxidant parameter (TRAP), single antioxidants (sulfhydryl groups, uric acid, vitamin C, alpha-tocopherol, coenzyme Q10), malondialdehyde, oxidized low density lipoprotein (LDL) antibodies, lipid profile [cholesterol, triglyceride, lipoprotein (a)], homocysteine, and hemoglobin (Hb)A(1C). TRAP levels were elevated in the GSD Ia group (p <.01) and correlated with elevated uric acid levels (r = 0.72, p =.001). None of the other plasma antioxidants correlated with TRAP levels. DMI patients showed decreased sulfhydryl groups (p <.01) and a reduced ubiquinol-10 fraction (p <.01). Malondialdehyde (p <.001) and oxidized LDL autoantibodies (p <.05) were increased in the diabetic group. In FH patients, parameters of oxidative stress and TRAP did not differ from controls. We conclude that in GSD Ia an increased antioxidative defense in plasma may protect against lipid peroxidation and thus against premature atherosclerosis. Furthermore, we demonstrated that in DMI increased oxidative mechanisms are already present in childhood.
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PMID:Plasma antioxidants in pediatric patients with glycogen storage disease, diabetes mellitus, and hypercholesterolemia. 1208 88

Deficiency of glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, causes glycogen storage disease type Ia (GSD-Ia), an autosomal recessive disorder characterized by growth retardation, hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic acidemia. G6Pase is an endoplasmic reticulum-associated transmembrane protein expressed primarily in the liver and the kidney. Therefore, enzyme replacement therapy is not feasible using current strategies, but somatic gene therapy, targeting G6Pase to the liver and the kidney, is an attractive possibility. Previously, we reported the development of a mouse model of G6Pase deficiency that closely mimics human GSD-Ia. Using neonatal GSD-Ia mice, we now demonstrate that a combined adeno virus and adeno-associated virus vector-mediated gene transfer leads to sustained G6Pase expression in both the liver and the kidney and corrects the murine GSD-Ia disease for at least 12 months. Our results suggest that human GSD-Ia would be treatable by gene therapy.
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PMID:Sustained hepatic and renal glucose-6-phosphatase expression corrects glycogen storage disease type Ia in mice. 1218 68

OBJECTIVE: To o present up-to-date knowledge about Glycogen storage disease type I (GSD-type I) - a disease caused by the deposit of glycogen resulting from the deficiency of the enzyme glucose-6- phosphatase - and to provide the pediatricians with the necessary information for a precocious diagnosis and an adequate conduct for those cases where this metabolic disturbance is present. METHODS: Through Medline, the most significant articles published during the last 20 years were selected from national and international journals of medicine, with special attention to dietary treatment of glycogen storage disease type I. RESULTS: The metabolism of glycogen and the metabolic consequences of glycogen storage disease type I were discussed, especially hypoglycemia, the principal metabolic disturbance of the disease. The clinical and laboratory findings are described together with the histopathology. The use of uncooked cornstarch and enteral carbohydrate infusion are the means used for the maintenance of normoglycemia. The control of hyperuricemia, hyperlipidemia and platelet disorders are other aspects of the treatment as well as the prevention of infections and the use of G-CSF for glycogen storage type Ib. Hepatic transplant and its principal indications are commented on. Hepatic adenomae, which always have the potential of malignant transformation, are the results of incomplete treatment. CONCLUSIONS: Although it occurs rarely, glycogen storage type I is an important cause of volumous hepatomegaly which is associated with hypoglycemia among the infants. The dietary treatment of this illness has significantly altered the clinical course and has improved the prognosis. Therefore it is indispensable that the general pediatrician should be familiar with the diagnosis of this clinical state so as to act rigorously in favor of the dietary control.
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PMID:[Glycogenosis type I] 1468 23

The deficiency of glucose-6-phosphatase (G6Pase) underlies life-threatening hypoglycemia and growth retardation in glycogen storage disease type Ia (GSD-Ia). An adeno-associated virus (AAV) vector encoding G6Pase was pseudotyped as AAV8 and administered to 2-week-old GSD-Ia mice (n = 9). Median survival was prolonged to 7 months following vector administration, in contrast to untreated GSD-Ia mice that survived for only 2 weeks. Although GSD-Ia mice were initially growth-retarded, treated mice increased fourfold in weight to normal size. Blood glucose was partially corrected by 2 weeks following treatment, whereas blood cholesterol normalized. Glucose-6-phosphatase activity was partially corrected to 25% of the normal level at 7 months of age in treated mice, and blood glucose during fasting remained lower in treated, affected mice than in normal mice. Glycogen storage was partially corrected in the liver by 2 weeks following treatment, but reaccumulated to pre-treatment levels by 7 months old (m.o.). Vector genome DNA decreased between 3 days and 3 weeks in the liver following vector administration, mainly through the loss of single-stranded genomes; however, double-stranded vector genomes were more stable. Although CD8+ lymphocytic infiltrates were present in the liver, partial biochemical correction was sustained at 7 m.o. The development of efficacious AAV vector-mediated gene therapy could significantly reduce the impact of long-term complications in GSD-Ia, including hypoglycemia, hyperlipidemia and growth failure.
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PMID:Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia. 1667 83


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