Hepatic glycogen synthase deficiency: An infrequently recognized cause of ketotic hypoglycemia

Abstract

The glycogen storage diseases comprise several inherited diseases caused by abnormalities of enzymes that regulate the synthesis or degradation of glycogen. In contrast to the classic hepatic glycogen storage diseases that are characterized by fasting hypoglycemia and hepatomegaly, the liver is not enlarged in GSD0. Patients with GSD0 typically have fasting ketotic hypoglycemia without prominent muscle symptoms. Most children are cognitively and developmentally normal. Short stature and osteopenia are common features, but other long-term complications, common in other types of GSD, have not been reported in GSD0. Until recently, the definitive diagnosis of GSD0 depended on the demonstration of decreased hepatic glycogen on a liver biopsy. The need for an invasive procedure may be one reason that this condition has been infrequently diagnosed. Mutation analysis of the GYS2 gene (12p12.2) is a non-invasive method for making this diagnosis in patients suspected to have this disorder. This mini-review discusses the pathophysiology of this disorder, use of mutation analysis to diagnose GSD0, and the clinical characteristics of all reported cases of GSD0.

Multiple Glycogen-binding Sites in Eukaryotic Glycogen Synthase Are Required for High Catalytic Efficiency toward Glycogen

“…Efficient co-localization of enzyme and substrate would facilitate faster responses to the physiological signals that control glucose homeostasis and eliminate any lag period resulting from the reassociation of enzyme and substrate. Consistent with the impact of mutations within site-2 on glycogen association and accumulation, two mutations associated with glycogen storage disease type 0 in humans (T445M and H446D, corresponding to Thr-444 and His-445 in Gsy2p) (29) occur at amino acid positions in close proximity to the site-2 maltodextrin-binding site. Thus, the impaired glycogen synthesis in these patients may be due to reduced association between the enzyme and its substrate.…”

Update on investigating hypoglycaemia in childhood

“…Gluconeogenesis and fatty acid oxidation are unaffected so hypoglycaemia following fasting is initially mild, but becomes severe on prolonged fasting. 29 Treatment consists of avoiding hypoglycaemia through frequent feeds with a high carbohydrate diet.…”

Hypoglycemia as a Pathological Result in Medical Praxis

“…Type 0 glycogen storage disease (GSD0) is caused by deficiency of the hepatic isoform of glycogen synthase (Weinstein et al, 2006). Although GSD0 has been classified as a glycogen storage disease, this is a misnomer.…”

“…In contrast to all other types of glycogenoses, which are characterized by increased glycogen storage, deficiency of glycogen synthase causes a marked decrease in liver glycogen content. GSD0 is the only GSD not associated with hepatomegaly and hypoglycemia typically is m i l d e r t h a n i n t h e o t h e r t y p e s o f G S D (Wolfsdorf & Weinstein, 2003;Weinstein, 2006). Patients with GSD0 have fasting ketotic hypoglycemia.…”