Recent development and gene therapy for glycogen storage disease type Ia

Abstract

Glycogen storage disease type Ia (GSD-Ia) is an autosomal recessive metabolic disorder caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC) that is expressed primarily in the liver, kidney, and intestine. G6Pase-α catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate in the terminal step of gluconeogenesis and glycogenolysis, and is a key enzyme for endogenous glucose production. The active site of G6Pase-α is inside the endoplasmic reticulum (ER) lumen. For catalysis, the substrate G6P must be translocated from the cytoplasm into the ER lumen by a G6P transporter (G6PT). The functional coupling of G6Pase-α and G6PT maintains interprandial glucose homeostasis. Dietary therapies for GSD-Ia are available, but cannot prevent the long-term complication of hepatocellular adenoma that may undergo malignant transformation to hepatocellular carcinoma. Animal models of GSD-Ia are now available and are being exploited to both delineate the disease more precisely and develop new treatment approaches, including gene therapy.

A case of glycogen storage disease type 1a mimicking familial chylomicronemia syndrome

“…Treatment includes dietary fat restriction (<15.0% of daily caloric intake), avoidance of high glycemic index foods, supplementation with omega-3 and medium-chain TGs. Fibrates and niacin may be used that are somewhat effective [ 1 ].…”

“…Hypertriglyceridemia may also occur due to glycogen storage diseases, of which GSD1a is the most frequent, and the incidence is estimated to be 1/100,000 births [ 1 ]. The disease occurs due to the defects on the G6PC gene, which is located on chromosome 17q21.31.…”

“…Disturbed glucose homeostasis, leads to secondary metabolic derangement causing hyperlipidemia and hepatosteatosis due to TG accumulation in the liver. Patients display lactic acidosis, a protruded abdomen due to hepatomegaly, anemia and bleeding tendency due to platelet dysfunction, a round doll-like face, muscle weakness, osteopenia and short stature [ 1 ].…”

“…Due to the deficient activity of this enzyme, excessive accumulation of glycogen occurs in the liver, kidney, skeletal muscles and intestinal mucosa. As glucose homeostasis cannot be maintained during fasting, life-threatening hypoglycemia episodes may be seen [ 1 ].…”

DBS Screening for Glycogen Storage Disease Type 1a: Detection of c.648G>T Mutation in G6PC by Combination of Modified Competitive Oligonucleotide Priming-PCR and Melting Curve Analysis

“…Serious long-term complications are hepatocellular adenoma [ 15 , 16 ] and renal diseases such as focal segmental glomerulosclerosis [ 17 ]. Hepatocellular adenoma may undergo malignant transformation [ 18 ]. Dietary therapies to prevent fasting hypoglycemia are currently available, but cannot prevent the long-term complications of hepatic tumors [ 18 ].…”