Glycogen storage disease type I: Genetic etiology, clinical manifestations, and conventional and gene therapies

Abstract

Glycogen storage disease type I (GSDI) is an inherited metabolic disorder characterized by a deficiency of enzymes or proteins involved in glycogenolysis and gluconeogenesis, resulting in excessive intracellular glycogen accumulation. While GSDI is classified into four different subtypes based on molecular genetic variants, GSDIa accounts for approximately 80%. GSDIa and GSDIb are autosomal recessive disorders caused by deficiencies in glucose-6-phosphatase (G6Pase-α) and glucose-6-phosphate-transporter (G6PT), respectively. For the past 50 years, the care of patients with GSDI has been improved following elaborate dietary managements. GSDI patients currently receive dietary therapies that enable patients to improve hypoglycemia and alleviate early symptomatic signs of the disease. However, dietary therapies have many limitations with a risk of calcium, vitamin D, and iron deficiency and cannot prevent long-term complications, such as progressive liver and renal failure. With the deepening understanding of the pathogenesis of GSDI and the development of gene therapy technology, there is great progress in the treatment of GSDI. Here, we review the underlying molecular genetics and the current clinical management strategies of GSDI patients with an emphasis on promising experimental gene therapies.

Keywords: dietary therapy; drug therapy; gene therapy; glycogen storage disease type I; molecular genetics mechanism.

FIGURE 1

Potential targets of disrupted glucose homeostasis. Glucose‐6‐phosphatase‐α (G6Pase‐α) and glucose‐6‐phosphate transporter (G6PT) are shown embedded within the membrane of the endoplasmic reticulum (ER). In gluconeogenic organs, such as liver, kidney, and intestine, G6PT couples with G6Pase‐α to maintain interprandial blood glucose homeostasis. G6PT transports glucose‐6‐phosphate (G6P) from the cytoplasm to the lumen of the ER, where G6Pase‐α hydrolyzes G6P into glucose and inorganic phosphate. (A) Glycogen storage disease type Ia (GSDIa) is a glycogen metabolic disorder and manifests hypoglycemia and secondary metabolic symptoms. (B) Glycogen storage disease type Ib (GSDIb) is a metabolic and immune disorder. GSDIb manifests overlapping and distinct phenotypes compared with GSDIa.

FIGURE 2

The essential role of G6P metabolism in gluconeogenesis. G6P can be hydrolyzed into glucose and inorganic phosphate in the terminal rate‐limiting step of gluconeogensis and glycogenolysis by G6Pase‐α. They are responsible for maintaining glucose homeostasis. Furthermore, G6P can be hydrolyzed to produce energy through glycolysis and TCA cycle. G6P can also provide ribose 5‐phosphate via the pentose phosphate pathway for nucleotide and nucleic acid biosynthesis. Conversely, G6P can be synthesized into glycogen via glycogenesis for energy storage.