Glycogen Storage Disease Type I (GSD-I) or Von Gierke’s disease the most common form of glycogen storage disease (GSD) in the world with a prevalence rate of 1:1000,000 individuals with a higher prevalence in Ashkenazi Jews (1:20,000) (Eckstein, 2004). GSD-I is an autosomal recessive disorder of glucose metabolism where the primary defect is in the impaired conversion of glucose-6-phosphate (G6P) to glucose and phosphate during gluconeogenesis. This impairment of glucose production results in a decrease in blood glucose concentrations during fasting conditions. As a result of the increase in G6P, there is increased flux down the glycolytic pathway which generates lactate by anaerobic respiration, increased flux via acetyl CoA which generates lipids, and increased flux via the pentose phosphate shunt to generate 5-carbon glucose molecules. The build-up of 5-carbon glucose molecules eventually results in the formation of nucleic acids, which when catabolized, generate uric acid. It is also observed that GSD-I can result in the excessive buildup of glycogen in body tissues such as the kidneys and liver and can be visible under a microscope. This build-up of glycogen will result in an increased risk of enlarged liver, liver/kidney failure, and liver tumors (benign and malignant).
Early onset of GSD-I include:
- Hypoglycemia in newborns
- Increased hunger
- Stunted growth
Advanced onset of GSD-I include:
- Increased susceptibility to infections (GSD-Ib only)
- Enlarged kidenys
- Kidney failure
- Seizures and confusion
- Kidney tumors (benign and malignant)
- Brain damage
The initial discovery of GSD-I was by Dr. von Gierke in 1929 who was the first to characterize the disease after performing an autopsy of 2 children suffering from chronic nosebleeds prior to their death. Dr. von Gierke discovered that both the children had accumulated excessive glycogen in both their kidneys and their enlarged livers. Then, in 1950’s a similar case was observed with 6 patients by Dr. Cori and Dr. Cori. After performing a through autopsy, Dr. Cori and Dr. Cori discovered that 2 of the children were complete deficient in G6Pase while the other 4 were not (Cori and Cori, 1952). Curious about these cases, Dr. Cori and Dr. Cori homogenized deceased patients’ frozen liver samples, filtered the homogenate through gauzes, and incubated various dilutions of the flow through in G6P to test substrate to enzyme proportionality. These results were then compared to ordinary liver samples with normal G6Pase and Dr. Cori and Dr. Cori successfully demonstrated that hepatic G6Pase was the defective protein resulting in these conditions and linked it back to Dr. von Gierke’s 1929 observations (Cori and Cori, 1952). Unbeknowst to Dr. Cori and Dr. Cori, they had actually discovered GSD-Ia which is a deficient G6Pase protein resulting from a G6PC mutation. Although G6Pase was determined to be the affected enzyme in GSD-I, the mechanism was still unknown despite knowledge that a hydroxylation was performed. It was then in 1960 when Hass and Bryne observed that G6Pase catalyzed an exchange reaction between G6P and glucose that it was confirmed a phosphoenzyme intermediate was being generated (Hass and Bryne, 1960). This observation by Hass and Bryne was consistent with phosphotransferase activity. Building off of this development, Feldman et al. in 1972 was able to demonstrate through the analysis of isotope exchange reactions and labeling patterns of a radioactive phosphate incubated with G6Pase that a phosphohistidine bond was being generated (Feldman et al., 1972). Although Dr. Cori and Dr. Cori successfully identified the protein responsible for GSD, they both could not figure out why the other 4 children also had the same condition, but demonstrated normal G6Pase function. This observation remained a mystery until 1978 when Narisawa et al. discovered that a deficiency to the G6Pase translocase protein which transport G6P into the cell resulted in the same conditions observed by Dr. von Gierke, Dr. Cori, and Dr. Cori (Narisawa et al., 1978). The authors performed a G6Pase assay with deceased patients’ liver samples both in the presence of detergent and without detergents. The purpose of the detergents was to destroy the cell membrane and that would tell the authors G6Pase function was consistent both inside and outside the cell. When the assay determined that G6Pase activity was higher with the detergent than without the detergent, that suggests that the complication does not lie with the G6Pase, but with a transport protein. The discovery by Narisawa et al. highlighted the GSD-Ib aspect of GSD-I where a G6Pase translocase defect results in GSD-I symptoms (Narisawa et al., 1978).
Fortunately with the advances in modern medicine, it is very easy to diagnose GSD-I. Since GSD-I can result in hypoglycemia, hyperuricemia, and hyperglyceridemia, lactic acidosis, testing a pateint’s blood serum for abnormal blood glucose (<60mg/dL), lactate (>2.5 mmol,L), uric acid (>5.0 mg/dL), and glyceride (>250 mg/dL) concentrations is a reliable method to determine if a patient has GSD-I (Fernandes et al., 1972). A GSD-I diagnosis is further strengthened by a glucagon/epinephrine test (adminstrating glucagon or epinephrine does not increase blood glucose levels, but increases blood lactate levels) and liver histology (surgical dissection and analysis of liver tissue for excessive buildup of glycogen). For definitive tests which confirm GSD-I, then a G6Pase and/or G6Pase translocase activity assay and genetic test will confirm the results. For a G6Pase/G6Pase translocase activity assay, the enzyme’s activity level is tested and compared to standard enzyme activity levels. In GSD-I patients, the G6Pase activity is 10% of the standard enzyme and G6Pase translocase activity is 15% of the standard enzyme. The genetic test is the most definitive and accurate diagnostic tool available to determine GSD-I because it will allow doctors and scientists to scan a patient’s G6PC and SLC37A4 regions of the DNA for mutations. If there is 1 of the known 80 mutation at either of these two locations, then the patient can accurately be diagnosis with GSD-I.
Full Context of GSD-I Disease-Free System
GSD-I is a disease resulting from a deficiency of G6Pase (either from the enzyme itself or the translocase protein). In a disease free system, G6Pase function would be normal and enzymatically activity at standard levels in the liver and kidneys. During fasting periods, glycogen would be broken down and converted via gluconeogenesis into G6P. The G6Pase translocase would transport G6P to the membrane bound G6Pase where G6P is converted into glucose via a hydrolysis reaction and removing a phosphate (Chou et al., 2002). The mechanism of G6Pase begins with a nucleophilic attack on the phosphate by His176 which results in a phosphohistidine bond and the destablization of the carbonyl (Chou et al., 2002). The negatively charged oxygen transfers its electrons in order to restore the carbonyl and eliminating the negatively charged glucose (Chou et al., 2002). The negative charged glucose is then protonated by His119 and generating glucose (Chou et al., 2002). The newly produced glucose is then exported out of the cell via glucose transporter proteins. This conversion of G6P into glucose is a normal process of gluconeogenesis and occurs during fasting periods in order to elevate blood glucose levels and maintain homeostasis. Due to maintained levels of blood glucose, glucose travels to vital areas such as the brain and tissues resulting improved neurological function and growth. Due to the fact that there is no buildup of G6P, excessive amounts of G6P are not being converted into excessive amounts of lactate, uric acid, and glycerides (Chou et al., 2002).