Reference Work Entry

Encyclopedia of Molecular Mechanisms of Disease

pp 2228-2230

Von Gierke Disease

  • Janice Y. ChouAffiliated withSection on Cellular Differentiation, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health
  • , Brian C. MansfieldAffiliated withCorrelogic Systems, Inc., Rockville


Glycogen storage disease type I (GSD-I); GSD-Ia (MIM232200); GSD-Ib (MIM232220)

Definition and Characteristics

Von Gierke disease is a group of autosomal recessive disorders of glucose metabolism. The primary defect is in the impaired conversion of glucose-6-phosphate (G6P) to glucose and phosphate due to mutation of either glucose-6-phosphatase-α (G6Pase-α, synonym G6PC) in GSD-Ia, or the G6P transporter (G6PT, synonym SLC37A4) in GSD-Ib [1]. Only a single G6Pase activity, expressed primarily in the liver, kidney and intestine [1], was known until 2003 when a second ubiquitous G6P hydrolase activity was identified. The original G6Pase is now designated G6Pase-α, the second, G6Pase-β (synonym G6PC3). G6Pase-β is not currently implicated in von Gierke disease, although it impacts glucose metabolism in neutrophils. GSD-I patients manifest fasting hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, lactic acidemia, and growth retardation [1]. In the longer term, complications include short stature, osteoporosis, gout, pulmonary hypertension, renal disease, and hepatic adenomas that can become malignant. GSD-Ib patients exhibit the additional complications of neutropenia and myeloid dysfunctions [1]. Untreated, both diseases are fatal in early life.


1:100,000 in GSD-I. Of these, GSD-Ia represents 80% of cases and GSD-Ib 20%.


G6Pase-α is encoded by G6PC, a single copy, ∼12 kb gene, on chromosome 17q21, composed of five exons that encodes a 357 amino acid hydrophobic glycoprotein [2] anchored in the endoplasmic reticulum (ER) by 9-transmembrane helices (Fig. 1). The catalytic center, which includes Arg83, His119, Arg170, and His176, lies within the ER lumen (Fig. 1). His176 is the phosphate acceptor forming the phosphohistidine-G6Pase-α intermediate during catalysis. To hydrolyze G6P, G6Pase-α must couple with G6PT [1,3]. A total of 84 separate G6PC mutations, including 54 missense, 10 nonsense, 17 insertion/deletion, and 3 splicing, spread through the coding and exon–intron junction regions have been associated with GSD-Ia [1]. The R83C mutation has a particularly high prevalence in Ashkenazi Jews with a carrier frequency of 1.4%.
Von Gierke Disease. Figure 1

The primary anabolic and catabolic pathways of G6P in the liver. The G6Pase-α system, an enzyme complex essential for interprandial glucose homeostasis, is comprised of a G6Pase-α catalytic subunit, a G6PT that transports G6P in and phosphate out of the ER, and a putative glucose transporter (T3), shown to anchor in the membrane of the ER in contact with both the cytoplasm and ER lumen. The spatial representation is illustrative only; the proteins probably exist as a multi-protein cluster. Molecular genetic studies have confirmed that inactivating mutations in the G6PC and SLC37A4 genes cause GSD-Ia and GSD-Ib, respectively [1]. Amino acids in G6Pase-α and G6PT altered by missence mutations are marked in black. T3 has not been characterized at the molecular level and its existence is currently unclear. The GLUT2 transporter, responsible for the transport of glucose in and out of the cell, is shown embedded in the plasma membrane.

G6PT is encoded by SLC37A4, a single copy, ∼5 kb gene, on chromosome 11q23, composed of nine exons. The gene is transcribed into two mature RNAs encoding a 429 amino acid G6PT [4] and a 451 amino acid variant G6PT. G6PT (Fig. 1) and variant G6PT are both hydrophobic, ten transmembrane domain ER proteins. G6PT transports cytoplasmic G6P into the ER lumen for hydrolysis and phosphate out [1]. A total of 79 SLC37A4 mutations, including 33 missense, 11 nonsense, 19 insertion/deletion, and 16 splicing, spread through the coding and exon–intron junction regions have been associated with GSD-Ib [1].

Molecular and Systemic Pathophysiology

The G6Pase-α-G6PT complex hydrolyzes G6P to glucose and phosphate in the terminal steps of gluconeogenesis and glycogenolysis (Fig. 1) in the liver, kidney, and small intestine.

These pathways are critical for the maintenance of blood glucose levels between meals. The hallmark of GSD-I patients is hypoglycemia following a short fast [1]. Loss of glucose homeostasis results in the accumulation of elevated levels of G6P in the cytoplasm, driving conversion of G6P to glycogen for storage. Excessive accumulation of glycogen in the liver and kidney promotes progressive hepatomegaly and nephromegaly. Accumulation of fat droplets in the liver also contributes to hepatomegaly. Excess G6P also enters the glycolytic pathway, generating chronic lactic acidemia, hyperuricemia and hyperlipidemia.

The mechanisms for immune deficiency in GSD-Ib are unclear but enhanced neutrophil apoptosis is observed. Neutrophils lacking G6PT also have intrinsic defects in respiratory burst, chemotaxis, and Ca2+ mobilization [5].

Diagnostic Principles

Historically, GSD-I was diagnosed symptomatically, supported by clinical biochemistry, and confirmed by G6Pase activity assays of liver biopsies [1]. Gene-based diagnostic tests for GSD-I are now available and also useful for carrier testing of at-risk families and prenatal diagnosis.

Therapeutic Principles

There is no cure for GSD-Ia or GSD-Ib. Many disease symptoms are managed or improved using a dietary therapy augmented by drugs [1]. Infants receive nocturnal nasogastric infusion of glucose. Older patients eat uncooked cornstarch. GSD-Ib patients also receive granulocyte colony stimulating factor therapy to restore myeloid functions [1]. However, the underlying disease remains untreated and patients continue to suffer hyperlipidemia, hyperuricemia, hypercalciuria, hypocitraturia, and lactic acidemia. Allopurinol and lipid lowering drugs are used to control hyperuricemia and hyperlipidemia, respectively. Angiotensin converting enzyme inhibitors are beneficial in treating microalbuminuria, an early indicator of renal dysfunction in GSD-I patients.

Orthotopic liver transplantation is advocated for patients failing to respond sufficiently to dietary therapy, or with multiple liver adenomas [1]. Patients with, or at risk of, renal failure, may consider combined liver and kidney transplantation.

Animal models of GSD-Ia and GSD-Ib are available and being used to investigate alternative treatments, such as somatic gene therapy, which are showing promise [1].

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© Springer-Verlag GmbH Berlin Heidelberg 2009
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