A new caw of hepatic glycogen snthase deficiency. biochemical findings and comparison with reported cases

Abstract

Hepatic glycogen synthase deficiency (GSD-0) is an autosomal recessive disorder first described in 1963. Fifteen cases in seven different families have been reported. Mutations in GYS2, the gene coding for liver glycogen synthase, were found in the four families studied. We report a new case of GSD-0 in a female patient born to healthy non-consanguineous French Canadian parents. She was referred for a family-history of hyperlipidemia at 7 years of age. In addition to increased plasma total cholesterol and triglyceride levels, workup revealed fasting hypoglycemia and ketonuria. Her only complaint was morning headaches. Growth and development were normal Physical exam including neurological exam was normal. Cerebral MRI and EEC were normal Biochemical findings consistent with the diagnosis included fasting hypoglycemia, ketonemia and hypoalaninemia, and postprandial hyperlactatemia and elevated plasma branched chain amino acid levels. Liver biopsy confirmed reduced glycogcn synthase activity. Ratio of active to inactive form of glycogen synthase was normal, suggesting reduced enzyme synthesis rather than synthesis of an inactive protein. Low hepatic glycogen content and mild to moderate liver stealosis were present. Plasma free carnitine concentrations decreased during fasting while esterified carnitine levels remained unchanged. In contrast to other cases, we twice observed an increase in blood glucose levels after administration of glucagon following 15 and 18 hours of fasting respectively (from 2.2 to 3.4 and 2.7 to 4.0 mmol/L respectively) Since her hepatic glycogen content was reduced, this might come from gluconcogenesis At 13 years of age, our patient still has fasting hypoglycemia although to a lesser degree. Her growth and intellectual development remain normal From our patient's clinical course and a review of the literature, we draw the following conclusions (1) non specific symptoms after overnight fasting were the presenting complaint in 6/16, 3 cases were brought to medical attention because of incidental findings, family history led to the diagnosis in 7 cases. (2) fasting hypoglycemia (16/16) and reduced liver glycogen content (8/8) are constant features, (3) other frequent biochemical findings include hyperlactatemia with feeding (13/16) and fasting hyperketonemia (9/16) and hypoalaninemia (8/16); (4) glucagon response after feeding is usually absent (4/6) but can be observed (2/6); (5) liver steatosis was observed in 5/8 cases. (6) growth and development are usually normal (12/16 and 13/16 respectively).