Von Gierke Disease (GSD-1)

What is Von Gierke’s Disease?

Von Gierke’s Disease (GSD-1) is an inheritable and potentially fatal metabolic disease. Early symptoms of GSD-1 are characterized by stunted growth, hyperuricemia, hypertriglyceridemia, hypoglycemia, and lactic acidosis (Chou et al., 2009). If left untreated, further complications will arise such as seizures, gout, increased susceptibility to infections, memory loss, osteoporosis, kidney failure, liver tumors, cardiovascular diseases, and potentially death (Calderaro et al., 2013) (Chou et al., 2009).

What does GSD stand for?

Von Gierke’s Disease (GSD-1) is the most prevalent form of glycogen storage disease (GSD) and approximately 1 out of every 100,000 individuals suffer from GSD-1 (Chou et al., 2009). Glycogen storage diseases are the result of defects in proteins involved in synthesizing or breaking down glycogen in the blood, cells, and tissues (Chou et al., 2009). These protein defects are the result of inborn errors of metabolism due to genetic mutations (Chou et al., 2009). There exists ten different types of GSD’s and each GSD is characterized by the protein defect (Wang et al, 2012). In the case of GSD-1, there are two impacted proteins which are denoted GSD-1a and GSD-1b (Wang et al., 2012). In patients with GSD-1a, glucose-6-phosphatase (G6Pase) is the defective protein and in patients with GSD-1b, glucose-6-phosphatase translocase (a transporter protein for Glucose-6-Phosphate) is the defective protein (Chou et al., 2002). The reason why GSD-1a and GSD-1b are grouped together under GSD-1 is because the overall impact is a deficiency in G6Pase which produces the symptoms of GSD-1.

How is GSD-1 acquired?

GSD-1 is an autosomal recessive disease which means that if both parents are GSD-1 carriers with the affected genes, then there is a chance that their offspring will inherit GSD-1 (Bhattacharya, 2015). The chances of the offspring acquiring GSD-1 is dependent on the genotype of each parents, but for heterozygous/heterozygous parents there is a 25% chance (Figure 1), for heterozygous/homozygous parents there is a 50% chance, and for homozygous/homozygous there is a 100% chance. In patients suffering from GSD-1a, the defect is on the G6PC gene which codes for G6Pase and in patients suffering from GSD-1b, the defect is on the SLC37A4 gene which codes for G6Pase translocase (Chou et al., 2002).

How does GSD-1 affect metabolism?

During a fasting state, the liver is converting a molecule called glycogen (an energy storage molecule) into glucose (usable energy molecule) in a process called gluconeogenesis which is then used to maintain proper blood glucose levels (Bhattacharya, 2015). One of the enzymes involved in this pathway is G6Pase which is involved in converting glucose-6-phosphate into glucose (Figure 2) (Chou et al., 2009). In patients suffering from GSD-1, they are G6Pase deficient because of either the G6PC or SLC37A4 gene mutations (Chou et al., 2002). Since these patients are deficient of G6Pase, then these patients are unable to convert glucose-6-phosphate into glucose.

This interruption in the gluconeogenesis pathway results in low concentrations of glucose being generated due to the G6Pase deficiency which ultimately leads to hypoglycemia. In patients suffering from hypoglycemia they experience fatigue, trouble concentrating or remembering, and seizures (Bhattacharya, 2007). Another result of G6Pase deficiency is the increased concentration of  glucose-6-phosphate as part of gluconeogenesis and its inability to be converted in glucose. Due to the higher concentrations of glucose-6-phopshate, the molecule will then be converted by other enzymes into lactate, uric acid, and triacyglycerides (Bhattacharya, 2015). Ordinarily, these molecules would not have a drastic impact on the body; however, the body is producing more of these molecules as result of glucose synthesis being interrupted which results in excessive amounts of lactate, uric acid, and triacylglycerides and produces conditions known as lactic acidosis, hyperuricemia, and hypertriglyceridemia respectively (Bhattacharya, 2015). Lactic acidosis caused by excessive amounts of lactate can result in a drastic change in bodily pH and cause obesity and kidney failure (Chou et al., 2009). Hyperuricemia caused by excessive amounts of uric acid can result in gout, arthritis, and kidney failure (Chou et al., 2009). Hypertriglyceridemia caused by excessive amounts of triacylglycerides can result in difficulty breathing, memory loss, and gastrointestinal pain (Chou et al., 2009).