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Glycogen storage disease type I (GSD I)

Written2012-06Alix Mollet Boudjemline, François Petit, Aurélie Hubert Buron, Pascale Trioche Eberschweiler, Vincent Gajdos, Philippe Labrune
APHP, Centre de References Maladies Hereditaires du Metabolisme Hepatique, Service de pediatrie, Hopital Antoine Beclere, BP 405, 92141 Clamart cedex,, Univ Paris Sud (VG, PL), France

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Other namesvon Gierke disease
Atlas_Id 10071
Genes implicated inAGL   G6PC   GAA   GBE1   GYS1   GYS2   PFKM   PHKA2   PHKB   PHKG2   PYGL   PYGM   SLC37A4  
Note The disease comprises two sub-types: type Ia (glucose-6-phosphatase deficiency), type Ib (glucose-6-phosphate translocase deficiency).
Inheritance Autosomal recessive. Incidence around 1/100 000 births.


Note Most of clinical manifestations are common to both sub-types of GSD I. Patients with type Ib have neutropenia.
Phenotype and clinics Patients have poor tolerance to fasting (with hypoglycemia and hyperlactacidemia after 3 to 4 hours of fasting), marked hepatomegaly, full-cheeked round face, growth retardation (small stature and delayed puberty), generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, enlarged kidneys and platelet dysfunctions leading to frequent epistaxis (Chen, 2000; Matern et al., 2002; Rake et al., 2002). In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphthous gingivostomatitis, parodontitis, and enterocolitis. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma (Talente et al., 1994; Labrune et al., 1997; Franco et al., 2005; Reddy et al., 2007) and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency, stones) (Talente et al., 1994; Rake et al., 2002; Scales et al., 2010) rare cases of pulmonary hypertension have been reported (Humbert et al., 2002).
  CT: liver tomodensitometry showing an important heterogeneous tumor (white arrows) - MRI: liver MRI illustrating the same hepatic tumor. Liver after hepatectomy: picture of the liver after liver transplantation, showing hepatocarcinoma.
Neoplastic risk Hepatocellular adenomas are at risk of malignant transformation, even though this risk is weak. Patients with such adenomas must be regularly followed-up, with clinical, biological, and MRI evaluations. Several studies have been performed to understand the physiopathology of adenomas development in GSD patients, and the transformation into hepatocellular carcinomas, but the precise mechanisms remain unknown (Kishnani et al., 2009).
Treatment Diet is the basis of the treatment (Rake et al., 2002). It aims at avoiding hypoglycemia, combining, in infants, frequent meals and quite often nocturnal enteral feeding. Later, oral uncooked starch is introduced. Fructose and galactose intakes are restricted. Many patients are given allopurinol (hyperuricemia frequently occurs), fibrates and/or statins (hypertriglyceridemia may have to be treated), converting enzyme inhibitors (should increased glomerular filtration rate and/or microalbuminuria be detected) (Melis et al., 2005). G-CSF may be used in type Ib patients, to correct neutropenia. Liver transplantation, performed on the basis of poor metabolic control and/or hepatocarcinoma, corrects hypoglycemia, but renal involvement may continue to progress and neutropenia is not always corrected in type Ib (Rake et al., 2002; Rake et al., 2002). Kidney transplantation can be performed in case of severe renal insufficiency. Combined liver-kidney grafts have been performed in a few cases.
Prognosis Prognosis is usually good: late hepatic and renal complications may occur, however, with adapted management, patients have almost normal life span.

Genes involved and Proteins

Gene NameG6PC (glucose-6-phosphatase catalytic subunit)
Location 17q21.31
Note GSD type Ia. Not imprinted, maternally and paternally expressed.
Description The human G6PC gene is 12,6 kb long and includes 5 coding exons (1071 bp for the coding region) (Lei et al., 1993).
Description 357 amino acids, trans-membrane protein.
Expression The G6PC protein is constituted by 357 aminoacids and is expressed in liver, kidney and intestine. This protein is not expressed in neutrophils, explaining the absence of neutropenia in GSD type Ia.
Localisation The protein is located in the endoplasmic reticulum membrane with its catalytic site on the internal side.
Function G6PC hydrolyses glucose-6-phosphate to glucose in the endoplasmic reticulum. The enzyme forms with the glucose-6-phosphate transporter (SLC37A4) the complex responsible for glucose production and homeostatic regulation of blood glucose levels.
Somatic The G6PC mutations are responsible for the glycogen storage disease type Ia (Von Gierke disease). More than 90 mutations have been described affecting the whole coding sequence (Matern et al., 2002; Shieh et al., 2002; Chou and Mansfield, 2008).

Gene NameSLC37A4 (solute carrier family 37 member 4)
Location 11q23.3
Note GSD type Ib. Not imprinted, maternally and paternally expressed.
Description The human SLC37A4 gene is 6,4 kb long and includes 9 coding exons (3870 bp for the coding region, exon 7bis being exclusively expressed in neutrophils (Hiraiwa et al., 1999; Veiga-da-Cunha et al., 1999).
Description 1290 amino acids, trans-membrane protein.
Expression The SLC37A4 protein is constituted of 1290 aminoacids and is co-expressed with G6PC gene in liver, kidney and intestine, and with G6PC3 in neutrophils (probably required for normal neutrophil function).
Localisation The protein is located in the endoplasmic reticulum membrane.
Function SLC37A4 transfers glucose-6-phosphate from cytoplasm to internal endoplasmic reticulum. This activity associated with glucose-6-phosphatase activity (G6PC or G6PC3) regulates glucose production from glycogenolysis and gluconeogenesis (Van Schaftingen and Gerin, 2002).
Somatic The SLC37A4 mutations are responsible for the glycogen storage disease type Ib (Von Gierke disease). More than 80 mutations have been described affecting the whole coding sequence (Veiga-da-Cunha et al., 1999).


The gene for glycogen-storage disease type 1b maps to chromosome 11q23.
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Chen YT.
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Mutations in the glucose-6-phosphatase-alpha (G6PC) gene that cause type Ia glycogen storage disease.
Chou JY, Mansfield BC.
Hum Mutat. 2008 Jul;29(7):921-30. (REVIEW)
PMID 18449899
Hepatocellular carcinoma in glycogen storage disease type Ia: a case series.
Franco LM, Krishnamurthy V, Bali D, Weinstein DA, Arn P, Clary B, Boney A, Sullivan J, Frush DP, Chen YT, Kishnani PS.
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J Biol Chem. 1999 Feb 26;274(9):5532-6.
PMID 10026167
Pulmonary arterial hypertension and type-I glycogen-storage disease: the serotonin hypothesis.
Humbert M, Labrune P, Sitbon O, Le Gall C, Callebert J, Herve P, Samuel D, Machado R, Trembath R, Drouet L, Launay JM, Simonneau G.
Eur Respir J. 2002 Jul;20(1):59-65.
PMID 12166582
Chromosomal and genetic alterations in human hepatocellular adenomas associated with type Ia glycogen storage disease.
Kishnani PS, Chuang TP, Bali D, Koeberl D, Austin S, Weinstein DA, Murphy E, Chen YT, Boyette K, Liu CH, Chen YT, Li LH.
Hum Mol Genet. 2009 Dec 15;18(24):4781-90. Epub 2009 Sep 16.
PMID 19762333
Hepatocellular adenomas in glycogen storage disease type I and III: a series of 43 patients and review of the literature.
Labrune P, Trioche P, Duvaltier I, Chevalier P, Odievre M.
J Pediatr Gastroenterol Nutr. 1997 Mar;24(3):276-9. (REVIEW)
PMID 9138172
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Lei KJ, Shelly LL, Pan CJ, Sidbury JB, Chou JY.
Science. 1993 Oct 22;262(5133):580-3.
PMID 8211187
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Matern D, Seydewitz HH, Bali D, Lang C, Chen YT.
Eur J Pediatr. 2002 Oct;161 Suppl 1:S10-9. Epub 2002 Jul 27.
PMID 12373566
Efficacy of ACE-inhibitor therapy on renal disease in glycogen storage disease type 1: a multicentre retrospective study.
Melis D, Parenti G, Gatti R, Casa RD, Parini R, Riva E, Burlina AB, Vici CD, Di Rocco M, Furlan F, Torcoletti M, Papadia F, Donati A, Benigno V, Andria G.
Clin Endocrinol (Oxf). 2005 Jul;63(1):19-25.
PMID 15963056
Guidelines for management of glycogen storage disease type I - European Study on Glycogen Storage Disease Type I (ESGSD I).
Rake JP, Visser G, Labrune P, Leonard JV, Ullrich K, Smit GP; European Study on Glycogen Storage Disease Type I (ESGSD I).
Eur J Pediatr. 2002b Oct;161 Suppl 1:S112-9. Epub 2002 Aug 24. (REVIEW)
PMID 12373584
Resection of hepatocellular adenoma in patients with glycogen storage disease type Ia.
Reddy SK, Kishnani PS, Sullivan JA, Koeberl DD, Desai DM, Skinner MA, Rice HE, Clary BM.
J Hepatol. 2007 Nov;47(5):658-63. Epub 2007 Jun 18.
PMID 17637480
Stone forming risk factors in patients with type Ia glycogen storage disease.
Scales CD Jr, Chandrashekar AS, Robinson MR, Cantor DA, Sullivan J, Haleblian GE, Leitao VA, Sur RL, Borawski KM, Koeberl D, Kishnani PS, Preminger GM.
J Urol. 2010 Mar;183(3):1022-5. Epub 2010 Jan 21.
PMID 20092831
The molecular basis of glycogen storage disease type 1a: structure and function analysis of mutations in glucose-6-phosphatase.
Shieh JJ, Terzioglu M, Hiraiwa H, Marsh J, Pan CJ, Chen LY, Chou JY.
J Biol Chem. 2002 Feb 15;277(7):5047-53. Epub 2001 Dec 5.
PMID 11739393
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Talente GM, Coleman RA, Alter C, Baker L, Brown BI, Cannon RA, Chen YT, Crigler JF Jr, Ferreira P, Haworth JC, Herman GE, Issenman RM, Keating JP, Linde R, Roe TF, Senior B, Wolfsdorf JI.
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PMID 8273986
The putative glucose 6-phosphate translocase gene is mutated in essentially all cases of glycogen storage disease type I non-a.
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PMID 10482962
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PMID 11879177


This paper should be referenced as such :
Mollet, Boudjemline A ; Petit, F ; Hubert, Buron A ; Trioche, Eberschweiler P ; Gajdos, V ; Labrune, P
Glycogen storage disease type I (GSD I)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(11):860-863.
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