Glycogen Storage Diseases Are Caused by Inherited

Glycogen storage diseases are caused by inherited mutations that alter the enzymatic activity of enzymes involved in gluconeogenesis (Wolfsdorf and Weinstein, 2003). The disorders can be roughly divided into those that primarily affect glycogen storage in the liver, resulting in the prototypical symptom of hypoglycemia, and those that affect glycogen storage in muscle tissue and therefore causing muscle weakness.

Glycogen Storage Disease Type-I (von Gierke Disease)

Glycogen storage disease type-I (GSD-I) can be broken down into at least two distinct autosomal recessive diseases (Wolfsdorf and Weinstein, 2003). Type-Ia disease involves mutations in the gene encoding the enzyme glucose-6-phosphatase (G6Pase or SLC37A4) and type-Ib involves mutations in the glucose-6-phosphate transporter-1 (G6PT1 or MIM232220) gene. Type-Ia is by far the most common, representing 80% of all GDS-I patients. Over 70 mutations in gene encoding G6Pase have been identified that impair its function and therefore the ability of the liver to mobilize glycogen stores to produce blood glucose. The type-Ic, -Id, and -- Isp are less well-characterized and common and affect the function of either G6Pase or G6PT1 as well.

Since the main source of glycogen is glucose-6-phosphate, and G6Pase is critical for both glucogenolysis and gluconeogenesis, mutations causing a G6Pase deficiency result in the more severe symptoms experienced by patients with glycogen storage disease. The symptoms of GSD-Ia include hypoglycemia, growth retardation, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, lactic academia, hypoglycemic seizures, and coma (Kim and Bae, 2009). GSD-1b patients also suffer from neutropenia and myeloid dysfunctions, and defects in neutrophils respiratory bursts, chemotaxis, and calcium flux . The latter renders these patients susceptible to bacterial infections, inflammatory bowel disease, and aphtous stomatitis.

The major product of glycogen metabolism is glucose-1-phosphate, which is reversibly converted to glucose-6-phosphate by phosphoglucomutase (G6P; see Figure 1). G6P can then by hydrolyzed into glucose and inorganic phosphorus by the multi-component G6Pase enzymatic complex located on the luminal surface of the endoplasmic reticulum (ER) (Rake et al., 2000). The structure of the catalytic unit (G6Pase) consists of a nine-transmembrane helical structure, with the N-terminus and four loops positioned on the ER luminal surface. One of these transmembrane sections is home to 25 missense mutations that cause GSD type Ia, suggesting the resulting amino acid changes and this transmembrane section are critical to the catalytic activity of G6Pase. Another disease-linked missense mutation is located in the N-terminus and the remaining seven missense mutations that have been identified are located in two of the four loops. The only regions not linked to disease-causing mutations are the cytoplasmic loops and one luminal loop.