Type I glycogen storage disease

Glucose-6-phosphate (G6P) is the central metabolite where the major pathways of the endogenous glucose production (i.e., glycogenolysis and gluconeogenesis) come together. The enzyme glucose-6-phosphatase (G6Pase) is encoded by the G6PC1 gene. The transporter protein encoded by the SLC37A4 gene, allows transport of G6P across the endoplasmic reticulum membrane. In the lumen of the endoplasmic reticulum, the G6Pase active site is responsible for the hydrolysis of G6P into glucose and phosphate, the terminal step in glycogenolysis and gluconeogenesis.[4]Chou JY, Jun HS, Mansfield BC. Glycogen storage disease type 1 and G6Pase-beta deficiency: etiology and therapy. Nat Rev Endocrinol. 2010 Dec;6(12):676-88. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178929 http://www.ncbi.nlm.nih.gov/pubmed/20975743?tool=bestpractice.com ​ Biallelic G6PC1 variants are associated with GSD 1a and biallelic SLC37A4 variants are associated with GSD Ib. Over 80 pathogenic variants have been reported in each gene.[4]Chou JY, Jun HS, Mansfield BC. Glycogen storage disease type 1 and G6Pase-beta deficiency: etiology and therapy. Nat Rev Endocrinol. 2010 Dec;6(12):676-88. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178929 http://www.ncbi.nlm.nih.gov/pubmed/20975743?tool=bestpractice.com ​ Importantly, SLC37A4 is also expressed in the neutrophil, while G6PC1 is not.[Figure caption and citation for the preceding image starts]: Simplified scheme of glycogen synthesis and degradation in the liver. Key to scheme: UDP-glucose, uridine diphosphoglucose; 1. hexokinase/glucokinase; 2. glucose 6-phosphatase; 3. phosphoglucomutase; 4. glycogen synthase; 5. branching enzyme; 6. glycogen phosphorylase; 7. debranching enzyme; 8. phosphofructokinase; 9. fructose 1,6-bisphosphatase; 10. acid maltase; 11. pyruvate dehydrogenaseCreated by Dr Joseph I. Wolfsdorf; used with permission [Citation ends].

Key to scheme: UDP-glucose, uridine diphosphoglucose; 1. hexokinase/glucokinase; 2. glucose 6-phosphatase; 3. phosphoglucomutase; 4. glycogen synthase; 5. branching enzyme; 6. glycogen phosphorylase; 7. debranching enzyme; 8. phosphofructokinase; 9. fructose 1,6-bisphosphatase; 10. acid maltase; 11. pyruvate dehydrogenase.

GSD I results from lack of activity of the hepatic enzyme complex consisting of glucose-6-phosphate transporter (G6PT) and glucose-6-phosphatase-alpha, which is essential for glycogen breakdown in the liver, kidney, and intestine. Inability to convert glucose-6-phosphate to glucose results in hypoglycemia between meals. Glucose-6-phosphate is shunted into alternative pathways resulting in 3 major metabolic consequences:[4]Chou JY, Jun HS, Mansfield BC. Glycogen storage disease type 1 and G6Pase-beta deficiency: etiology and therapy. Nat Rev Endocrinol. 2010 Dec;6(12):676-88. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178929 http://www.ncbi.nlm.nih.gov/pubmed/20975743?tool=bestpractice.com

• Hyperlacticacidemia, which develops as a byproduct of enhanced glycolysis

• Hyperuricemia, which arises due to shunting of glucose-6-phosphate into the pentose phosphate pathway

• Hypertriglyceridemia, which arises due to both increased production and decreased clearance of triglycerides.

Glycogen storage disease (GSD) I

• Deficient catalytic activity of the glucose-6-phosphatase enzyme system (GSD type Ia)

• Deficient transport of glucose-6-phosphate into the endoplasmic reticulum (GSD type Ib)