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Colonetti K, Pinto E Vairo F, Siebert M, Nalin T, Poloni S, Fernando Wurdig Roesch L, Fischinger Moura de Souza C, Cabral Pinheiro F, Vanessa Doederlein Schwartz I. Cytokine profiling in patients with hepatic glycogen storage disease: Are there clues for unsolved aspects? Cytokine 2023; 162:156088. [PMID: 36462220 DOI: 10.1016/j.cyto.2022.156088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 11/09/2022] [Accepted: 11/12/2022] [Indexed: 12/05/2022]
Abstract
INTRODUCTION Hepatic Glycogen Storage Diseases (GSD) are rare genetic disorders in which the gluconeogenesis pathway is impaired. Cytokines control virtually every aspect of physiology and may help to elucidate some unsolved questions about phenotypes presented by GSD patients. METHODS This was an exploratory study in which 27 GSD patients on treatment (Ia = 16, Ib = 06, III = 02, IXα = 03) and 24 healthy age- and sex-matched subjects had plasma samples tested for a panel of 20 cytokines (G-CSF,GM-CSF, IL-1α,IL-1β, IL-4, IL-6, IL-8, IL-10, IL-13, IL-17A, GRO, IP-10/CXCL10, MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, MDC/CCL22, IFN-γ, TNF-α, TNF-β, VEGF) through a multiplex kit and analyzed in comparison to controls and among patients, regarding to clinical features as anemia, hepatic adenocarcinoma and triglyceride levels. RESULTS Patients (GSD-Ia/III/IX) presented reduced levels of IL-4 (p = 0.040), MIP-1α/CCL3 (p = 0.003), MDC/CCL22 (p < 0.001), TNF-β (p = 0.045) and VEGF (p = 0.043) compared to controls. When different types of GSD were compared, G-CSF was higher in GSD-Ib than -Ia (p < 0.001) and than -III/IX (p = 0.033) patients; IL-10 was higher in GSD-Ib than in GSD-Ia patients (p = 0.019); and GSD-III/IX patients had increased levels of IP-10/CXCL10 than GSD-Ib patients (p = 0.019). When GSD-I patients were gathered into the same group and compared with GSD-III/IX patients, IP10/CXCL10 and MCP-1 were higher in the latter group (p = 0.005 and p = 0.013, respectively). GSD-I patients with anemia presented higher levels of IL-4 and MIP-1α in comparison with patients who had not. Triglyceride level was correlated with neutrophil count and MDC levels on GSD-Ia patients without HCA. CONCLUSION Altogether, altered levels of cytokines in GSD-I patients reflect an imbalance in immunoregulation process. This study also indicates that neutrophils and some cytokines are affected by triglyceride levels, and future studies on the theme should consider this variable.
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Affiliation(s)
- Karina Colonetti
- Post-Graduation Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Laboratory of Basic Research and Advanced Investigations in Neurosciences (BRAIN), Hospital de Clínicas de Porto Alegre, PortoAlegre, RS, Brazil
| | - Filippo Pinto E Vairo
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA
| | - Marina Siebert
- Laboratory of Basic Research and Advanced Investigations in Neurosciences (BRAIN), Hospital de Clínicas de Porto Alegre, PortoAlegre, RS, Brazil; Post-Graduation Program in Sciences of Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Laboratorial Research Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
| | - Tatiéle Nalin
- Ultragenyx Brasil Farmacêutica Ltda, São Paulo, SP, Brazil
| | - Soraia Poloni
- Laboratory of Basic Research and Advanced Investigations in Neurosciences (BRAIN), Hospital de Clínicas de Porto Alegre, PortoAlegre, RS, Brazil
| | - Luiz Fernando Wurdig Roesch
- Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL, USA
| | - Carolina Fischinger Moura de Souza
- Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Post-Graduation Program in Child and Adolescent Health, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Franciele Cabral Pinheiro
- Post-Graduation Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Laboratory of Basic Research and Advanced Investigations in Neurosciences (BRAIN), Hospital de Clínicas de Porto Alegre, PortoAlegre, RS, Brazil; Universidade Federal do Pampa, Itaqui, RS, Brazil
| | - Ida Vanessa Doederlein Schwartz
- Post-Graduation Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Laboratory of Basic Research and Advanced Investigations in Neurosciences (BRAIN), Hospital de Clínicas de Porto Alegre, PortoAlegre, RS, Brazil; Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
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Petrova IO, Smirnikhina SA. Studies on glycogen storage disease type 1a animal models: a brief perspective. Transgenic Res 2022; 31:593-606. [PMID: 36006546 DOI: 10.1007/s11248-022-00325-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 08/09/2022] [Indexed: 01/20/2023]
Abstract
Glycogen storage disease type 1 (GSD1) is a rare hereditary monogenic disease characterized by the disturbed glucose metabolism. The most widespread variant of GSD1 is GSD1a, which is a deficiency of glucose-6-phosphatase-ɑ. Glucose-6-phosphatase-ɑ is expressed only in liver, kidney, and intestine, and these organs are primarily affected by its deficiency, and long-term complications of GSD1a include hepatic tumors and chronic liver disease. This article is a brief overview of existing animal models for GSD1a, from the first mouse model of 1996 to modern CRISPR/Cas9-generated ones. First whole-body murine models demonstrated exact metabolic symptoms of GSD1a, but the animals did not survive weaning. The protocol for glucose treatment allowed prolonged survival of affected animals, but long-term complications, such as hepatic tumorigenesis, could not be investigated. Next, organ-specific knockout models were developed, and most of the metabolic research was performed on liver glucose-6-phosphate-deficient mice. Naturally occuring mutation was also discovered in dogs. All these models are widely used to study GSD1a from metabolic and physiological standpoints and to develop possible treatments involving gene therapy. Research performed using these models helped elucidate the role of glycogen and lipid accumulation, hypoxia, mitochondrial dysfunction, and autophagy impairment in long-term complications of GSD1a, including hepatic tumorigenesis. Recently, gene replacement therapy and genome editing were tested on described models, and some of the developed approaches have reached clinical trials.
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Affiliation(s)
- Irina O Petrova
- Laboratory of Genome Editing, Research Center for Medical Genetics, Moskvorechye 1, Moscow, Russia, 115478.
| | - Svetlana A Smirnikhina
- Laboratory of Genome Editing, Research Center for Medical Genetics, Moskvorechye 1, Moscow, Russia, 115478
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La Rose AM, Bazioti V, Hoogerland JA, Svendsen AF, Groenen AG, van Faassen M, Rutten MGS, Kloosterhuis NJ, Dethmers-Ausema B, Nijland JH, Mithieux G, Rajas F, Kuipers F, Lukens MV, Soehnlein O, Oosterveer MH, Westerterp M. Hepatocyte-specific glucose-6-phosphatase deficiency disturbs platelet aggregation and decreases blood monocytes upon fasting-induced hypoglycemia. Mol Metab 2021; 53:101265. [PMID: 34091064 PMCID: PMC8243524 DOI: 10.1016/j.molmet.2021.101265] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/20/2021] [Accepted: 05/31/2021] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE Glycogen storage disease type 1a (GSD Ia) is a rare inherited metabolic disorder caused by mutations in the glucose-6-phosphatase (G6PC1) gene. When untreated, GSD Ia leads to severe fasting-induced hypoglycemia. Although current intensive dietary management aims to prevent hypoglycemia, patients still experience hypoglycemic events. Poor glycemic control in GSD Ia is associated with hypertriglyceridemia, hepatocellular adenoma and carcinoma, and also with an increased bleeding tendency of unknown origin. METHODS To evaluate the effect of glycemic control on leukocyte levels and coagulation in GSD Ia, we employed hepatocyte-specific G6pc1 deficient (L-G6pc-/-) mice under fed or fasted conditions, to match good or poor glycemic control in GSD Ia, respectively. RESULTS We found that fasting-induced hypoglycemia in L-G6pc-/- mice decreased blood leukocytes, specifically proinflammatory Ly6Chi monocytes, compared to controls. Refeeding reversed this decrease. The decrease in Ly6Chi monocytes was accompanied by an increase in plasma corticosterone levels and was prevented by the glucocorticoid receptor antagonist mifepristone. Further, fasting-induced hypoglycemia in L-G6pc-/- mice prolonged bleeding time in the tail vein bleeding assay, with reversal by refeeding. This could not be explained by changes in coagulation factors V, VII, or VIII, or von Willebrand factor. While the prothrombin and activated partial thromboplastin time as well as total platelet counts were not affected by fasting-induced hypoglycemia in L-G6pc-/- mice, ADP-induced platelet aggregation was disturbed. CONCLUSIONS These studies reveal a relationship between fasting-induced hypoglycemia, decreased blood monocytes, and disturbed platelet aggregation in L-G6pc-/- mice. While disturbed platelet aggregation likely accounts for the bleeding phenotype in GSD Ia, elevated plasma corticosterone decreases the levels of proinflammatory monocytes. These studies highlight the necessity of maintaining good glycemic control in GSD Ia.
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Affiliation(s)
- Anouk M La Rose
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Venetia Bazioti
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Joanne A Hoogerland
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Arthur F Svendsen
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Anouk G Groenen
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Martijn van Faassen
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Martijn G S Rutten
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Niels J Kloosterhuis
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Bertien Dethmers-Ausema
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - J Hendrik Nijland
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Gilles Mithieux
- Université Claude Bernard Lyon 1, Université de Lyon, INSERM UMR-S1213, Lyon, France
| | - Fabienne Rajas
- Université Claude Bernard Lyon 1, Université de Lyon, INSERM UMR-S1213, Lyon, France
| | - Folkert Kuipers
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Michaël V Lukens
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Oliver Soehnlein
- Institute for Experimental Pathology (ExPat), Center for Molecular Biology of Inflammation (ZBME), University of Münster, Münster, Germany; Department of Physiology and Pharmacology (FyFa), Karolinska Institutet, Stockholm, Sweden
| | - Maaike H Oosterveer
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Marit Westerterp
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
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Molares-Vila A, Corbalán-Rivas A, Carnero-Gregorio M, González-Cespón JL, Rodríguez-Cerdeira C. Biomarkers in Glycogen Storage Diseases: An Update. Int J Mol Sci 2021; 22:4381. [PMID: 33922238 PMCID: PMC8122709 DOI: 10.3390/ijms22094381] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 04/10/2021] [Accepted: 04/19/2021] [Indexed: 01/09/2023] Open
Abstract
Glycogen storage diseases (GSDs) are a group of 19 hereditary diseases caused by a lack of one or more enzymes involved in the synthesis or degradation of glycogen and are characterized by deposits or abnormal types of glycogen in tissues. Their frequency is very low and they are considered rare diseases. Except for X-linked type IX, the different types are inherited in an autosomal recessive pattern. In this study we reviewed the literature from 1977 to 2020 concerning GSDs, biomarkers, and metabolic imbalances in the symptoms of some GSDs. Most of the reported studies were performed with very few patients. Classification of emerging biomarkers between different types of diseases (hepatics GSDs, McArdle and PDs and other possible biomarkers) was done for better understanding. Calprotectin for hepatics GSDs and urinary glucose tetrasaccharide for Pompe disease have been approved for clinical use, and most of the markers mentioned in this review only need clinical validation, as a final step for their routine use. Most of the possible biomarkers are implied in hepatocellular adenomas, cardiomyopathies, in malfunction of skeletal muscle, in growth retardation, neutropenia, osteopenia and bowel inflammation. However, a few markers have lost interest due to a great variability of results, which is the case of biotinidase, actin alpha 2, smooth muscle, aorta and fibroblast growth factor receptor 4. This is the first review published on emerging biomarkers with a potential application to GSDs.
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Affiliation(s)
- Alberto Molares-Vila
- Bioinformatics Platform, Health Research Institute in Santiago de Compostela (IDIS), SERGAS-USC, 15706 Santiago de Compostela, Spain;
| | - Alberte Corbalán-Rivas
- Local Office of Health Inspection, Health Ministry at Galician Autonomous Region, 27880 Burela, Spain;
| | - Miguel Carnero-Gregorio
- Department of Molecular Diagnosis (Arrays Division), Institute of Cellular and Molecular Studies (ICM), 27003 Lugo, Spain;
- Efficiency, Quality, and Costs in Health Services Research Group (EFISALUD), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36213 Vigo, Spain;
| | - José Luís González-Cespón
- Efficiency, Quality, and Costs in Health Services Research Group (EFISALUD), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36213 Vigo, Spain;
| | - Carmen Rodríguez-Cerdeira
- Efficiency, Quality, and Costs in Health Services Research Group (EFISALUD), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36213 Vigo, Spain;
- Dermatology Department, Complexo Hospitalario Universitario de Vigo (CHUVI), Meixoeiro Hospital, SERGAS, 36213 Vigo, Spain
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Vernuccio F, Austin S, Meyer M, Guy CD, Kishnani PS, Marin D. "Bull’s eye” appearance of hepatocellular adenomas in patients with glycogen storage disease type I — atypical magnetic resonance imaging findings: Two case reports. World J Clin Cases 2021; 9:871-877. [PMID: 33585634 PMCID: PMC7852632 DOI: 10.12998/wjcc.v9.i4.871] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 12/10/2020] [Accepted: 12/29/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular adenomas are rare tumors that can occur in patients with glycogen storage disease type I.
CASE SUMMARY We herein report two cases of histologically proven hepatocellular adenomas in patients with glycogen storage disease type I. Magnetic resonance imaging (MRI) was performed after bolus injection of gadoxetate disodium, a liver-specific gadolinium-based MRI contrast agent. In the present cases, some of the hepatocellular adenomas showed unexpectedly a “bull’s eye” appearance on T2-weighted and post-contrast images, which was not previously described as imaging findings of hepatocellular adenomas in glycogen storage disease. A bull’s eye appearance on T2-weighted images can be encountered in both benign (i.e., abscess) or malignant (i.e., epithelioid hemangioendothelioma, cholangio-carcinoma, and metastases) hepatic lesions.
CONCLUSION We present two cases of hepatocellular adenomas in patients with glycogen storage disease type 1, in which gadoxetate disodium-MRI showed atypical imaging findings for hepatocellular adenomas. At present there is no systematic study evaluating MRI findings of hepatocellular adenomas in patients with glycogen storage disease, further studies are needed to specifically investigate this issue.
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Affiliation(s)
- Federica Vernuccio
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo 90100, Italy
| | - Stephanie Austin
- Departments of Pediatrics, Duke University Medical Center, Durham, NC 27710, United States
| | - Mathias Meyer
- Department of Radiology, Duke University Medical Hospital, Durham, NC 27708, United States
| | - Cynthia D Guy
- Department of Pathology, Duke University, Durham, NC 27710, United States
| | - Priya S Kishnani
- Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, United States
| | - Daniele Marin
- Department of Radiology, Duke University Medical Center, Durham, NC 27710, United States
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Gjorgjieva M, Mithieux G, Rajas F. Hepatic stress associated with pathologies characterized by disturbed glucose production. Cell Stress 2019; 3:86-99. [PMID: 31225503 PMCID: PMC6551742 DOI: 10.15698/cst2019.03.179] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The liver is an organ with many facets, including a role in energy production and metabolic balance, detoxification and extraordinary capacity of regeneration. Hepatic glucose production plays a crucial role in the maintenance of normal glucose levels in the organism i.e. between 0.7 to 1.1 g/l. The loss of this function leads to a rare genetic metabolic disease named glycogen storage disease type I (GSDI), characterized by severe hypoglycemia during short fasts. On the contrary, type 2 diabetes is characterized by chronic hyperglycemia, partly due to an overproduction of glucose by the liver. Indeed, diabetes is characterized by increased uptake/production of glucose by hepatocytes, leading to the activation of de novo lipogenesis and the development of a non-alcoholic fatty liver disease. In GSDI, the accumulation of glucose-6 phosphate, which cannot be hydrolyzed into glucose, leads to an increase of glycogen stores and the development of hepatic steatosis. Thus, in these pathologies, hepatocytes are subjected to cellular stress mainly induced by glucotoxicity and lipotoxicity. In this review, we have compared hepatic cellular stress induced in type 2 diabetes and GSDI, especially oxidative stress, autophagy deregulation, and ER-stress. In addition, both GSDI and diabetic patients are prone to the development of hepatocellular adenomas (HCA) that occur on a fatty liver in the absence of cirrhosis. These HCA can further acquire malignant traits and transform into hepatocellular carcinoma. This process of tumorigenesis highlights the importance of an optimal metabolic control in both GSDI and diabetic patients in order to prevent, or at least to restrain, tumorigenic activity during disturbed glucose metabolism pathologies.
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Affiliation(s)
- Monika Gjorgjieva
- Institut National de la Santé et de la Recherche Médicale, U1213, Lyon, F-69008, France.,Université de Lyon, Lyon, F-69008 France.,Université Lyon I, Villeurbanne, F-69622 France
| | - Gilles Mithieux
- Institut National de la Santé et de la Recherche Médicale, U1213, Lyon, F-69008, France.,Université de Lyon, Lyon, F-69008 France.,Université Lyon I, Villeurbanne, F-69622 France
| | - Fabienne Rajas
- Institut National de la Santé et de la Recherche Médicale, U1213, Lyon, F-69008, France.,Université de Lyon, Lyon, F-69008 France.,Université Lyon I, Villeurbanne, F-69622 France
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Gjorgjieva M, Oosterveer MH, Mithieux G, Rajas F. Mechanisms by Which Metabolic Reprogramming in GSD1 Liver Generates a Favorable Tumorigenic Environment. JOURNAL OF INBORN ERRORS OF METABOLISM AND SCREENING 2016. [DOI: 10.1177/2326409816679429] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Affiliation(s)
- Monika Gjorgjieva
- Institut National de la Santé et de la Recherche Médicale, U1213 “Nutrition, Diabetes and the Brain”, Lyon, France
- Université de Lyon, Lyon, France
- Université Lyon 1, Villeurbanne, France
| | - Maaike H. Oosterveer
- Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Gilles Mithieux
- Institut National de la Santé et de la Recherche Médicale, U1213 “Nutrition, Diabetes and the Brain”, Lyon, France
- Université de Lyon, Lyon, France
- Université Lyon 1, Villeurbanne, France
| | - Fabienne Rajas
- Institut National de la Santé et de la Recherche Médicale, U1213 “Nutrition, Diabetes and the Brain”, Lyon, France
- Université de Lyon, Lyon, France
- Université Lyon 1, Villeurbanne, France
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Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med 2015; 16:e1. [PMID: 25356975 DOI: 10.1038/gim.2014.128] [Citation(s) in RCA: 281] [Impact Index Per Article: 28.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Accepted: 08/12/2014] [Indexed: 12/11/2022] Open
Abstract
PURPOSE Glycogen storage disease type I (GSD I) is a rare disease of variable clinical severity that primarily affects the liver and kidney. It is caused by deficient activity of the glucose 6-phosphatase enzyme (GSD Ia) or a deficiency in the microsomal transport proteins for glucose 6-phosphate (GSD Ib), resulting in excessive accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa. Patients with GSD I have a wide spectrum of clinical manifestations, including hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, and growth retardation. Individuals with GSD type Ia typically have symptoms related to hypoglycemia in infancy when the interval between feedings is extended to 3–4 hours. Other manifestations of the disease vary in age of onset, rate of disease progression, and severity. In addition, patients with type Ib have neutropenia, impaired neutrophil function, and inflammatory bowel disease. This guideline for the management of GSD I was developed as an educational resource for health-care providers to facilitate prompt, accurate diagnosis and appropriate management of patients. METHODS A national group of experts in various aspects of GSD I met to review the evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management. RESULTS This management guideline specifically addresses evaluation and diagnosis across multiple organ systems (hepatic, kidney, gastrointestinal/nutrition, hematologic, cardiovascular, reproductive) involved in GSD I. Conditions to consider in the differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, hepatic and renal transplantation, and prenatal diagnosis, are also addressed. CONCLUSION A guideline that facilitates accurate diagnosis and optimal management of patients with GSD I was developed. This guideline helps health-care providers recognize patients with all forms of GSD I, expedite diagnosis, and minimize adverse sequelae from delayed diagnosis and inappropriate management. It also helps to identify gaps in scientific knowledge that exist today and suggests future studies.
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Resaz R, Vanni C, Segalerba D, Sementa AR, Mastracci L, Grillo F, Murgia D, Bosco MC, Chou JY, Barbieri O, Varesio L, Eva A. Development of hepatocellular adenomas and carcinomas in mice with liver-specific G6Pase-α deficiency. Dis Model Mech 2015; 7:1083-91. [PMID: 25147298 PMCID: PMC4142728 DOI: 10.1242/dmm.014878] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Glycogen storage disease type 1a (GSD-1a) is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α), and is characterized by impaired glucose homeostasis and a high risk of developing hepatocellular adenomas (HCAs). A globally G6Pase-α-deficient (G6pc(-/-)) mouse model that shows pathological features similar to those of humans with GSD-1a has been developed. These mice show a very severe phenotype of disturbed glucose homeostasis and rarely live beyond weaning. We generated liver-specific G6Pase-α-deficient (LS‑G6pc(-/-)) mice as an alternative animal model for studying the long-term pathophysiology of the liver and the potential treatment strategies, such as cell therapy. LS‑G6pc(-/-) mice were viable and exhibited normal glucose profiles in the fed state, but showed significantly lower blood glucose levels than their control littermates after 6 hours of fasting. LS‑G6pc(-/-) mice developed hepatomegaly with glycogen accumulation and hepatic steatosis, and progressive hepatic degeneration. Ninety percent of the mice analyzed developed amyloidosis by 12 months of age. Finally, 25% of the mice sacrificed at age 10-20 months showed the presence of multiple HCAs and in one case late development of hepatocellular carcinoma (HCC). In conclusion, LS‑G6pc(-/-) mice manifest hepatic symptoms similar to those of human GSD-1a and, therefore, represent a valid model to evaluate long-term liver pathogenesis of GSD-1a.
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Affiliation(s)
- Roberta Resaz
- Laboratory of Molecular Biology, Istituto Gannina Gaslini, 16147 Genova, Italy
| | - Cristina Vanni
- Laboratory of Molecular Biology, Istituto Gannina Gaslini, 16147 Genova, Italy
| | - Daniela Segalerba
- Laboratory of Molecular Biology, Istituto Gannina Gaslini, 16147 Genova, Italy
| | - Angela R Sementa
- Department of Pediatric Pathology, Istituto Gannina Gaslini, 16147 Genova, Italy
| | - Luca Mastracci
- Department of Surgical and Diagnostic Sciences (DISC), Anatomic Pathology Unit, University of Genova, 16132 Genova, Italy IRCCS AOU San Martino-IST, National Cancer Research Institute, 16132 Genova, Italy
| | - Federica Grillo
- Department of Surgical and Diagnostic Sciences (DISC), Anatomic Pathology Unit, University of Genova, 16132 Genova, Italy IRCCS AOU San Martino-IST, National Cancer Research Institute, 16132 Genova, Italy
| | - Daniele Murgia
- Department of Pediatric Pathology, Istituto Gannina Gaslini, 16147 Genova, Italy
| | - Maria Carla Bosco
- Laboratory of Molecular Biology, Istituto Gannina Gaslini, 16147 Genova, Italy
| | - Janice Y Chou
- Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1830, USA
| | - Ottavia Barbieri
- IRCCS AOU San Martino-IST, National Cancer Research Institute, 16132 Genova, Italy Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy
| | - Luigi Varesio
- Laboratory of Molecular Biology, Istituto Gannina Gaslini, 16147 Genova, Italy
| | - Alessandra Eva
- Laboratory of Molecular Biology, Istituto Gannina Gaslini, 16147 Genova, Italy
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Rajas F, Clar J, Gautier-Stein A, Mithieux G. Lessons from new mouse models of glycogen storage disease type 1a in relation to the time course and organ specificity of the disease. J Inherit Metab Dis 2015; 38:521-7. [PMID: 25164786 PMCID: PMC5522669 DOI: 10.1007/s10545-014-9761-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2014] [Revised: 08/05/2014] [Accepted: 08/07/2014] [Indexed: 12/12/2022]
Abstract
Patients with glycogen storage diseases type 1 (GSD1) suffer from life-threatening hypoglycaemia, when left untreated. Despite an intensive dietary treatment, patients develop severe complications, such as liver tumors and renal failure, with aging. Until now, the animal models available for studying the GSD1 did not survive after weaning. To gain further insights into the molecular mechanisms of the disease and to evaluate potential treatment strategies, we have recently developed novel mouse models in which the catalytic subunit of glucose-6 phosphatase (G6pc) is deleted in each glucose-producing organ specifically. For that, B6.G6pc(ex3lox/ex3lox) mice were crossed with transgenic mice expressing a recombinase under the control of the serum albumin, the kidney androgen protein or the villin promoter, in order to obtain liver, kidney or intestine G6pc(-/-) mice, respectively. As opposed to total G6pc knockout mice, tissue-specific G6pc deficiency allows mice to maintain their blood glucose by inducing glucose production in the other gluconeogenic organs. Even though it is considered that glucose is produced mainly by the liver, liver G6pc(-/-) mice are perfectly viable and exhibit the same hepatic pathological features as GSD1 patients, including the late development of hepatocellular adenomas and carcinomas. Interestingly, renal G6pc(-/-) mice developed renal symptoms similar to the early human GSD1 nephropathy. This includes glycogen overload that leads to nephromegaly and morphological and functional alterations in the kidneys. Thus, our data suggest that renal G6Pase deficiency per se is sufficient to induce the renal pathology of GSD1. Therefore, these new mouse models should allow us to improve the strategies of treatment on both nutritional and pharmacological points of view.
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Affiliation(s)
- Fabienne Rajas
- Institut National de la Santé et de la Recherche Médicale, U855, Lyon, 69008, France,
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Multiple roles of glucose-6-phosphatases in pathophysiology. Biochim Biophys Acta Gen Subj 2013; 1830:2608-18. [DOI: 10.1016/j.bbagen.2012.12.013] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Revised: 12/11/2012] [Accepted: 12/13/2012] [Indexed: 12/28/2022]
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Lee YM, Jun HS, Pan CJ, Lin SR, Wilson LH, Mansfield BC, Chou JY. Prevention of hepatocellular adenoma and correction of metabolic abnormalities in murine glycogen storage disease type Ia by gene therapy. Hepatology 2012; 56:1719-29. [PMID: 22422504 PMCID: PMC3477505 DOI: 10.1002/hep.25717] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Accepted: 02/29/2012] [Indexed: 12/07/2022]
Abstract
UNLABELLED Glycogen storage disease type Ia (GSD-Ia), which is characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA), is caused by deficiencies in the endoplasmic reticulum (ER)-associated glucose-6-phosphatase-α (G6Pase-α or G6PC) that hydrolyzes glucose-6-phosphate (G6P) to glucose. G6Pase-α activity depends on the G6P transporter (G6PT) that translocates G6P from the cytoplasm into the ER lumen. The functional coupling of G6Pase-α and G6PT maintains interprandial glucose homeostasis. We have shown previously that gene therapy mediated by AAV-GPE, an adeno-associated virus (AAV) vector expressing G6Pase-α directed by the human G6PC promoter/enhancer (GPE), completely normalizes hepatic G6Pase-α deficiency in GSD-Ia (G6pc(-/-) ) mice for at least 24 weeks. However, a recent study showed that within 78 weeks of gene deletion, all mice lacking G6Pase-α in the liver develop HCA. We now show that gene therapy mediated by AAV-GPE maintains efficacy for at least 70-90 weeks for mice expressing more than 3% of wild-type hepatic G6Pase-α activity. The treated mice displayed normal hepatic fat storage, had normal blood metabolite and glucose tolerance profiles, had reduced fasting blood insulin levels, maintained normoglycemia over a 24-hour fast, and had no evidence of hepatic abnormalities. After a 24-hour fast, hepatic G6PT messenger RNA levels in G6pc(-/-) mice receiving gene therapy were markedly increased. Because G6PT transport is the rate-limiting step in microsomal G6P metabolism, this may explain why the treated G6pc(-/-) mice could sustain prolonged fasts. The low fasting blood insulin levels and lack of hepatic steatosis may explain the absence of HCA. CONCLUSION These results confirm that AAV-GPE-mediated gene transfer corrects hepatic G6Pase-α deficiency in murine GSD-Ia and prevents chronic HCA formation.
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Affiliation(s)
- Young Mok Lee
- Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
| | - Hyun Sik Jun
- Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
| | - Chi-Jiunn Pan
- Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
| | - Su Ru Lin
- Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
| | - Lane H. Wilson
- Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
| | - Brian C. Mansfield
- Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892,Foundation Fighting Blindness, Columbia, MD 21046
| | - Janice Y. Chou
- Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892,Correspondence should be addressed to: Janice Y. Chou, Building 10, Room 9D42, NIH, 10 Center Drive, Bethesda, MD 20892-1830, Tel: 301-496-1094, Fax: 301-402-6035,
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Sakellariou S, Al-Hussaini H, Scalori A, Samyn M, Heaton N, Portmann B, Tobal K, Quaglia A. Hepatocellular adenoma in glycogen storage disorder type I: a clinicopathological and molecular study. Histopathology 2012; 60:E58-65. [PMID: 22372484 DOI: 10.1111/j.1365-2559.2011.04153.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
AIMS Glycogen storage disease type I is a metabolic disorder resulting from deficiency of the glucose-6-phosphate complex. Long-term complications include the development of hepatocellular adenoma (HCA). In this retrospective study, our aim was to reclassify according to geno-phenotypic characteristics nodular lesions identified in hepatectomy specimens of such patients transplanted between 1998 and 2008 at our institution. METHODS AND RESULTS Clinicopathological data of seven consecutive transplanted patients with glycogen storage disease type I were reviewed. Liver nodules were re-examined histologically and by immunohistochemistry. Molecular analysis was performed additionally in a case with specific features. Four patients had multiple tumours. We concluded that 26 of 38 nodules available for study had features of inflammatory hepatocellular adenomas, seven comprised adenomas not otherwise specified and five were found to be focal nodular hyperplasia. CONCLUSIONS Further studies are needed to clarify the pathogenesis of hepatocellular adenomas in glycogen storage disease; in particular to determine whether they share abnormal metabolic pathways with inflammatory adenomas in the general population. Testing for acute phase proteins may be a helpful tool in the early detection of HCA in such patients. Finally, there is a need to further define their risk of malignant transformation, in relation to age and possible cofactors.
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Abstract
INTRODUCTION Glycogen storage disease (GSD) type Ia and Ib are disorders of impaired glucose homeostasis affecting the liver and kidney. GSD-Ib also affects neutrophils. Current dietary therapies cannot prevent long-term complications. In animal studies, recombinant adeno-associated virus (rAAV) vector-mediated gene therapy can correct or minimize multiple aspects of the disorders, offering hope for human gene therapy. AREAS COVERED A summary of recent progress in rAAV-mediated gene therapy for GSD-I; strategies to improve rAAV-mediated gene delivery, transduction efficiency and immune avoidance; and vector refinements that improve expression. EXPERT OPINION rAAV-mediated gene delivery to the liver can restore glucose homeostasis in preclinical models of GSD-I, but some long-term complications of the liver and kidney remain. Gene therapy for GSD-Ib is less advanced than for GSD-Ia and only transient correction of myeloid dysfunction has been achieved. A question remains as to whether a single rAAV vector can meet the expression efficiency and tropism required to treat all aspects of GSD-I, or if a multi-pronged approach is needed. An understanding of the strengths and weaknesses of rAAV vectors in the context of strategies to achieve efficient transduction of the liver, kidney and hematopoietic stem cells is required for treating GSD-I.
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Affiliation(s)
- Janice Y Chou
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Bethesda, MD 20892 1830, USA.
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Glycogen storage disease type Ia in canines: a model for human metabolic and genetic liver disease. J Biomed Biotechnol 2011; 2011:646257. [PMID: 21318173 PMCID: PMC3027000 DOI: 10.1155/2011/646257] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2010] [Accepted: 11/24/2010] [Indexed: 11/17/2022] Open
Abstract
A canine model of Glycogen storage disease type Ia (GSDIa) is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose-6-phosphatase-α. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including “lactic acidosis”, larger size, and longer lifespan compared to other animal models. Use of this model in preclinical trials of gene therapy is described and briefly compared to the murine model. Although the canine model offers a number of advantages for evaluating potential therapies for GSDIa, there are also some significant challenges involved in its use. Despite these challenges, the canine model of GSDIa should continue to provide valuable information about the potential for generating curative therapies for GSDIa as well as other genetic hepatic diseases.
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Abstract
Glycogen storage disease type I (GSD-I) consists of two subtypes: GSD-Ia, a deficiency in glucose-6-phosphatase-α (G6Pase-α) and GSD-Ib, which is characterized by an absence of a glucose-6-phosphate (G6P) transporter (G6PT). A third disorder, G6Pase-β deficiency, shares similarities with this group of diseases. G6Pase-α and G6Pase-β are G6P hydrolases in the membrane of the endoplasmic reticulum, which depend on G6PT to transport G6P from the cytoplasm into the lumen. A functional complex of G6PT and G6Pase-α maintains interprandial glucose homeostasis, whereas G6PT and G6Pase-β act in conjunction to maintain neutrophil function and homeostasis. Patients with GSD-Ia and those with GSD-Ib exhibit a common metabolic phenotype of disturbed glucose homeostasis that is not evident in patients with G6Pase-β deficiency. Patients with a deficiency in G6PT and those lacking G6Pase-β display a common myeloid phenotype that is not shared by patients with GSD-Ia. Previous studies have shown that neutrophils express the complex of G6PT and G6Pase-β to produce endogenous glucose. Inactivation of either G6PT or G6Pase-β increases neutrophil apoptosis, which underlies, at least in part, neutrophil loss (neutropenia) and dysfunction in GSD-Ib and G6Pase-β deficiency. Dietary and/or granulocyte colony-stimulating factor therapies are available; however, many aspects of the diseases are still poorly understood. This Review will address the etiology of GSD-Ia, GSD-Ib and G6Pase-β deficiency and highlight advances in diagnosis and new treatment approaches, including gene therapy.
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Affiliation(s)
- Janice Y Chou
- Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Building 10, Room 9D42, 10 Center Drive, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1830, USA.
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Neonatal gene therapy of glycogen storage disease type Ia using a feline immunodeficiency virus-based vector. Mol Ther 2010; 18:1592-8. [PMID: 20571544 DOI: 10.1038/mt.2010.119] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Glycogen storage disease type Ia (GSD-Ia), also known as von Gierke disease, is caused by a deficiency of glucose-6-phosphatase-alpha (G6Pase), a key enzyme in glucose homeostasis. From birth, affected individuals cannot maintain normal blood glucose levels and suffer from a variety of metabolic disorders, leading to life-threatening complications. Gene therapy has been proposed as a possible option for treatment of this illness. Vectors have been constructed from feline immunodeficiency virus (FIV), a nonprimate lentivirus, because the wild-type virus does not cause disease in humans. Previously, we have shown that these vectors are capable of integrating stably into hepatocyte cell lines and adult murine livers and lead to long-term transgene expression. In the current work, we have assessed the ability to attenuate disease symptoms in a murine model of GSD-Ia. Single administration of FIV vectors containing the human G6Pase gene to G6Pase-alpha(-/-) mice did not change the biochemical and pathological phenotype. However, a double neonatal administration protocol led to normalized blood glucose levels, significantly extended survival, improved body weight, and decreased accumulation of liver glycogen associated with the disease. This approach shows a promising paradigm for treating GSD-Ia patients early in life thereby avoiding long-term consequences.
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Yiu WH, Lee YM, Peng WT, Pan CJ, Mead PA, Mansfield BC, Chou JY. Complete normalization of hepatic G6PC deficiency in murine glycogen storage disease type Ia using gene therapy. Mol Ther 2010; 18:1076-84. [PMID: 20389290 DOI: 10.1038/mt.2010.64] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Glycogen storage disease type Ia (GSD-Ia) patients deficient in glucose-6-phosphatase-alpha (G6Pase-alpha or G6PC) manifest disturbed glucose homeostasis. We examined the efficacy of liver G6Pase-alpha delivery mediated by AAV-GPE, an adeno-associated virus (AAV) serotype 8 vector expressing human G6Pase-alpha directed by the human G6PC promoter/enhancer (GPE), and compared it to AAV-CBA, that directed murine G6Pase-alpha expression using a hybrid chicken beta-actin (CBA) promoter/cytomegalovirus (CMV) enhancer. The AAV-GPE directed hepatic G6Pase-alpha expression in the infused G6pc(-/-) mice declined 12-fold from age 2 to 6 weeks but stabilized at wild-type levels from age 6 to 24 weeks. In contrast, the expression directed by AAV-CBA declined 95-fold over 24 weeks, demonstrating that the GPE is more effective in directing persistent in vivo hepatic transgene expression. We further show that the rapid decline in transgene expression directed by AAV-CBA results from an inflammatory immune response elicited by the AAV-CBA vector. The AAV-GPE-treated G6pc(-/-) mice exhibit normal levels of blood glucose, blood metabolites, hepatic glycogen, and hepatic fat. Moreover, the mice maintained normal blood glucose levels even after 6 hours of fasting. The complete normalization of hepatic G6Pase-alpha deficiency by the G6PC promoter/enhancer holds promise for the future of gene therapy in human GSD-Ia patients.
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Affiliation(s)
- Wai Han Yiu
- Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1830, USA
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Kishnani PS, Chuang TP, Bali D, Koeberl D, Austin S, Weinstein DA, Murphy E, Chen YT, Boyette K, Liu CH, Chen YT, Li LH. Chromosomal and genetic alterations in human hepatocellular adenomas associated with type Ia glycogen storage disease. Hum Mol Genet 2009; 18:4781-90. [PMID: 19762333 DOI: 10.1093/hmg/ddp441] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular adenoma (HCA) is a frequent long-term complication of glycogen storage disease type I (GSD I) and malignant transformation to hepatocellular carcinoma (HCC) is known to occur in some cases. However, the molecular pathogenesis of tumor development in GSD I is unclear. This study was conducted to systematically investigate chromosomal and genetic alterations in HCA associated with GSD I. Genome-wide SNP analysis and mutation detection of target genes was performed in ten GSD Ia-associated HCA and seven general population HCA cases for comparison. Chromosomal aberrations were detected in 60% of the GSD Ia HCA and 57% of general population HCA. Intriguingly, simultaneous gain of chromosome 6p and loss of 6q were only seen in GSD Ia HCA (three cases) with one additional GSD I patient showing submicroscopic 6q14.1 deletion. The sizes of GSD Ia adenomas with chromosome 6 aberrations were larger than the sizes of adenomas without the changes (P = 0.012). Expression of IGF2R and LATS1 candidate tumor suppressor genes at 6q was reduced in more than 50% of GSD Ia HCA that were examined (n = 7). None of the GSD Ia HCA had biallelic mutations in the HNF1A gene. These findings give the first insight into the distinct genomic and genetic characteristics of HCA associated with GSD Ia. These results strongly suggest that chromosome 6 alterations could be an early event in the liver tumorigenesis in GSD I, and may be in general population. These results also suggest an interesting relationship between GSD Ia HCA and steps to HCC transformation.
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Affiliation(s)
- Priya S Kishnani
- Division of Medical Genetics, Duke University Medical Center, Durham, NC 27710, USA
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Kim SY, Bae YS. Cell death and stress signaling in glycogen storage disease type I. Mol Cells 2009; 28:139-48. [PMID: 19756389 DOI: 10.1007/s10059-009-0126-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2009] [Accepted: 08/19/2009] [Indexed: 12/19/2022] Open
Abstract
Cell death has been traditionally classified in apoptosis and necrosis. Apoptosis, known as programmed cell death, is an active form of cell death mechanism that is tightly regulated by multiple cellular signaling pathways and requires ATP for its appropriate process. Apoptotic death plays essential roles for successful development and maintenance of normal cellular homeostasis in mammalian. In contrast to apoptosis, necrosis is classically considered as a passive cell death process that occurs rather by accident in disastrous conditions, is not required for energy and eventually induces inflammation. Regardless of different characteristics between apoptosis and necrosis, it has been well defined that both are responsible for a wide range of human diseases. Glycogen storage disease type I (GSD-I) is a kind of human genetic disorders and is caused by the deficiency of a microsomal protein, glucose-6-phosphatase-α (G6Pase-α) or glucose-6-phosphate transporter (G6PT) responsible for glucose homeostasis, leading to GSD-Ia or GSD-Ib, respectively. This review summarizes cell deaths in GSD-I and mostly focuses on current knowledge of the neutrophil apoptosis in GSD-Ib based upon ER stress and redox signaling.
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Affiliation(s)
- So Youn Kim
- Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul, Korea.
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Koeberl DD, Kishnani PS, Bali D, Chen YT. Emerging therapies for glycogen storage disease type I. Trends Endocrinol Metab 2009; 20:252-8. [PMID: 19541498 DOI: 10.1016/j.tem.2009.02.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2008] [Revised: 02/10/2009] [Accepted: 02/11/2009] [Indexed: 10/20/2022]
Abstract
Glycogen storage disease type I (GSD I) is caused by deficiency of the glucose-6-phosphatase catalytic subunit in type Ia or of glucose-6-phosphate transporter in type Ib. The cellular bases for disruptions of homeostasis have been increasingly understood in GSD I, including those for anemia, renal failure and neutropenia. Advances in the understanding of cellular abnormalities in GSD I have provided rationales for new therapy, and recent developments in gene therapy have led to potential curative treatments for GSD I. These advances will benefit patients with GSD I in the future, improving both quality of life and survival, as well as illuminating the molecular effects of altered metabolism upon multiple organ systems.
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Affiliation(s)
- D D Koeberl
- Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
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