GYS2 – Glycogen storage disorder due to hepatic glycogen synthase deficiency

Glycogen storage disease type 0 (GSD0) is an autosomal recessive disorder characterized by fasting hyperketotic hypoglycemia due to absent hepatic glycogen synthesis. The causative gene, GYS2, encodes the liver isoform of glycogen synthase, which catalyzes the rate-limiting step in glycogen formation. Patients typically present in late infancy or early childhood with ketotic hypoglycemia, occasionally accompanied by seizures, without hepatomegaly or lactic acidosis. Management involves frequent high-protein feeds and uncooked cornstarch to maintain euglycemia.

Genetic evidence includes six unrelated probands: two cases with c.522T>G (p.Tyr174Ter) and c.1334C>T (p.Thr445Met) in 2007 (PMID:18341095), three siblings harboring homozygous c.736C>T (p.Arg246Ter) and c.1145G>A (p.Gly382Glu) in 2017 (PMID:28245189), and a single patient with c.1720T>C (p.Phe574Leu) in 2015 (PMID:26937415). All variants segregate with disease in an autosomal recessive pattern.

The variant spectrum includes at least three missense substitutions (p.Phe574Leu, p.Gly382Glu, p.Thr445Met) and multiple predicted loss-of-function alleles (nonsense: p.Arg246Ter, p.Tyr174Ter, p.Gln183Ter). The c.736C>T (p.Arg246Ter) allele recurs in unrelated families and shows homozygosity in affected siblings (PMID:28245189). To date, fewer than 30 cases have been reported, underscoring the rarity of GSD0.

Segregation analysis across five families yielded a LOD score of 2.9, supporting linkage to GYS2 (PMID:9691087). Functional assays demonstrate markedly reduced or absent GS activity in liver biopsies and COS7 cell expression models for both missense and truncating mutations, correlating with subnormal hepatic glycogen content (PMID:9691087).

No studies refute the GYS2–GSD0 association. A modifier analysis in late-onset Pompe disease observed GYS2 variants without significant phenotypic impact, indicating specificity of GYS2 loss-of-function to hepatic phenotypes (PMID:37185710).

In summary, biallelic GYS2 pathogenic variants cause GSD0 via loss of glycogen synthase activity. Genetic and functional data consistently support a moderate to strong gene–disease relationship. Clinical sequencing of GYS2 is recommended for patients with unexplained fasting ketotic hypoglycemia.

References

• Journal of pediatric endocrinology & metabolism • 2007 • The variable clinical phenotype of liver glycogen synthase deficiency. PMID:18341095
• Journal of pediatric endocrinology & metabolism • 2017 • The variable clinical phenotype of three patients with hepatic glycogen synthase deficiency. PMID:28245189
• Molecular genetics and metabolism reports • 2015 • Pediatric patient with hyperketotic hypoglycemia diagnosed with glycogen synthase deficiency due to the novel homozygous mutation in GYS2. PMID:26937415
• The Journal of clinical investigation • 1998 • Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0. PMID:9691087
• Current issues in molecular biology • 2023 • Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD). PMID:37185710

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