Glycogen Storage Disease 0, Liver

A number sign (#) is used with this entry because of evidence that liver glycogen storage disease-0 (GSD0A) is caused by homozygous or compound heterozygous mutation in the GYS2 gene (138571), which encodes glycogen synthase-2, on chromosome 12p12.

See 611556 for a description of muscle glycogen storage disease caused by mutation in the GYS1 gene (138570).

Clinical Features

In a well-studied family, Lewis et al. (1963) demonstrated that infantile hypoglycemia was due to a deficiency of glycogen synthetase in the liver. The cases were probably of the same type as those reported by Broberger and Zetterstrom (1961) because urinary excretion of catecholamines was not influenced by hypoglycemia. The observations of Lewis et al. (1963) are particularly convincing evidence for autosomal recessive inheritance of this one form, although iron-clad proof awaits demonstration of a partial deficiency in both parents. See hepatic deficiency of fructose-1,6-phosphatase (229700), another cause of hypoglycemia. Howell (1972) doubted that the deficiency of glycogen synthetase is primary. He suggested that the low level of glycogen synthetase is due to low levels of insulin, which normally stimulates the enzyme. He pointed out that, with feeding, glycogen is synthesized and glucagon is effective. Dykes and Spencer-Peet (1972) restudied the family. They pointed out that elevation of blood lactate after administration of glucose or more particularly of galactose is a useful diagnostic test. The level of enzyme activity in cultured fibroblasts was not commented on. Aynsley-Green et al. (1977, 1977) did metabolic and enzyme studies on a 9-year-old girl who first presented with hypoglycemic convulsions at the age of 7 years. They found that the 13-year-old brother of the proband had the same 'metabolic profile' but was asymptomatic. With fasting, there is hypoglycemia and hyperketonemia; with feeding, there is hyperglycemia and hyperlactatemia. Gitzelmann et al. (1983) reported that cultured skin fibroblasts from 2 sibs with hepatic glycogen synthetase deficiency and from their parents contained glycogen synthetase activity that was within the range of the controls. Thus, this mutation was not expressed in fibroblasts, a finding that further supports the presumed existence of genetically different forms of glycogen synthetase.

Gitzelmann et al. (1996) described 3 children with liver glycogen synthase deficiency from 2 German families and compared the observations with the previously published 3 families comprising 8 patients. The 2 index cases presented with morning fatigue, had ketotic hypoglycemia when fasting which rapidly disappeared after eating, and hepatic glycogen deficiency with absent or very low hepatic glycogen synthase activity. Metabolic profiles comprising glucose, lactate, alanine, and ketones in blood were typical for hepatic glycogen synthase deficiency. Symptoms were rapidly relieved and chemical signs corrected by introducing frequent protein-rich meals and nighttime feedings of suspensions of uncooked corn starch. The discovery of oligosymptomatic and asymptomatic sibs suggested that there are persons with undiagnosed hepatic glycogen synthase deficiency. Gitzelmann et al. (1996) stated that the disorder should be sought in children who, before the first meal of the day, present with drowsiness, lack of attention, pallor, uncoordinated eye movements, disorientation, or convulsions, and who have hypoglycemia and acetone in the urine. Gitzelmann (1996) stated that he is aware of 2 additional families with affected members.

Rutledge et al. (2001) reported an additional patient with liver glycogen synthase deficiency. In the first year of life she ate every 3 to 4 hours and never slept through the night, awakening spontaneously to feed. At 15 months she slept through the night for the first time. She was found at 6 o'clock the following morning in a generalized tonic-clonic seizure. Blood glucose was 27 mg/dL, and urinary ketones were present.

Laberge et al. (2003) described hepatic glycogen synthase deficiency in a French Canadian girl referred at 7 years of age for a family history of hyperlipidemia. Initial evaluation incidentally revealed fasting hypoglycemia and ketonuria after a 10-hour fast with normal growth, development, and physical examination. Additional biochemical findings included fasting hypoalaninemia with elevated plasma branched chain amino acids and postprandial hyperlactatemia. Liver glycogen synthase activity was reduced. Unlike most other reported patients, the patient showed an increase in fasting plasma glucose levels after glucagon administration during episodes of hypoglycemia. At 13 years of age, growth and intellect were normal; however, she still had hypoglycemia after 18 hours of fasting.

Mapping

Orho et al. (1998) established linkage of glycogen storage disease 0 to intragenic and flanking polymorphic markers of the GYS2 gene on chromosome 12p12.2.

Molecular Genetics

In affected members of 5 families with liver glycogen storage disease 0, Orho et al. (1998) identified homozygous or compound heterozygous mutations in the GYS2 gene (138571.0001-138571.0008)