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At a glance

Inborn error of metabolism of glucose caused by decreased glycogen synthetase activity and characterized by fasting hypoglycemia, high blood ketones, increased free fatty acids, and low levels of alanine and lactate beginning in early infancy. Conversely, feeding results in hyperglycemia and hyperlactatemia. Unlike other GSDs, GSD 0 does not result in tissue accumulation of normal or abnormal glycogen. Although glycogen synthase deficiency does not result in storage of extra glycogen in the liver, it is often classified as a glycogen storage disease because it is another defect of glycogen storage and can cause similar problems.

Classification

There are two types of glycogen storage disease Type 0 to be considered:

  • Glycogen Storage Disease: Due to liver glycogen synthase deficiency

  • Glycogenosis: Due to muscle and heart glycogen synthase deficiency

Synonym

Glycogen Synthetase Deficiency.

Incidence

The overall incidence for glycogen storage disease is established at approximately 1:20,000 to 25,000 people worldwide. Glycogen-storage disease Type 0 is a rare form that is believed to represent less than 1% of all cases. The identification of asymptomatic and oligosymptomatic siblings in several glycogen-storage disease Type 0 families has suggested that glycogen-storage disease Type 0 is underdiagnosed.

Genetic inheritance

Autosomal recessive trait. Male-to-female ratio is 1:1. Disease is caused by a defect in the gene coding for liver glycogen synthetase (GYS2), which is located on chromosome band 12p12.2.

Pathophysiology

A decrease or absence of hepatic glycogen synthetase, which is the rate-limiting enzyme for glycogen synthesis, by transferring glucose units from UDP-glucose to a glycogen primer. This action depends on phosphorylation/dephosphorylation mechanisms and is regulated by several hormones, including insulin, epinephrine, and glucagon. Secondary to a lack of storage of glycogen, GSD 0 patients develop hypoglycemia in the early stages of fasting, when the main source of glucose is provided by glycogenolysis, while gluconeogenesis is not able to maintain normoglycemia. On the other hand, feeding results in postprandial hyperglycemia and increased blood lactate levels because glycogen synthesis is very limited; excess glucose mainly undergoes lactate conversion through the glycolytic pathway. Muscle glycogen synthetase is coded by a different gene and is not affected in patients with GSD 0.

Diagnosis

After 5 to 7 hours of fasting, patients demonstrate hypoglycemia and ketosis (and ketonuria), while lactate and alanine levels remain normal. Injection of glucagon fails to elicit a rise in plasma glucose in fasted patients, whereas after a meal, it elicits hyperglycemia and decreased levels of plasma lactate and alanine. Oral intake of glucose, fructose, or galactose elicits a consistent rise in blood lactate. Definitive diagnosis of GSD 0 requires a liver biopsy for enzyme assay (defective glycogen synthetase activity) and microscopic analysis (decreased amounts of normal glycogen stores, increased fat accumulation).

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