Background

Glycogen-storage disease type 0 (GSD-0), or glycogen synthetase deficiency, commonly appears in infancy and early childhood with fasting hypoglycemia accompanied by ketosis and low normal reference range blood levels of lactate and alanine. Although feeding relieves symptoms, it results in postprandial hyperglycemia and hyperlacticacidemia. Unlike other forms of glycogen-storage disease, glycogen-storage disease type 0 does not involve the storage of excessive or abnormal glycogen and is characterized by moderately decreased glycogen stores in the liver. Recent reports suggest that patients with glycogen-storage disease type 0 present with symptoms that range from asymptomatic hyperglycemia to recurrent hypoglycemic seizures.^[1]

Glycogen is most abundant in the liver and muscle. In the liver, glycogen is a storage form of glucose. During periods of fasting, when little to no glucose is taken in enterally, glycogen releases glucose to be used by tissues that need them to function. In the muscle, glycogen is the source of energy for muscle activity. Thus, glycogen storage disorders can manifest as hypoglycemia, ketosis, lethargy, fatigue, weakness, muscle cramping, and exercise intolerance.

There are two isoforms of the glycogen synthase enzyme. GYS1 is expressed in the skeletal and cardiac muscle. GYS2 is expressed in the liver. GSD-0 is caused by a defect in the gene that encodes for the liver GYS2. It is an autosomal-recessive condition.

Pathophysiology

In the early stages of fasting, the liver provides a steady source of glucose from glycogen breakdown (or glycogenolysis). With prolonged fasting, glucose is generated in the liver from noncarbohydrate precursors through gluconeogenesis. Such precursors include alanine (derived from the breakdown of proteins in skeletal muscle) and glycerol (derived from the breakdown of triacylglycerols in fat cells). In patients with glycogen-storage disease type 0, fasting hypoglycemia occurs within a few hours after a meal because of the limited stores of hepatic glycogen and inadequate gluconeogenesis to maintain normoglycemia. Feeding characteristically results in postprandial hyperglycemia and glucosuria, in addition to increased blood lactate levels, because glycogen synthesis is limited, and excess glucose is preferentially converted to lactate by means of the glycolytic pathway.

Frequency

International

The overall frequency of glycogen-storage disease is approximately 1 case per 20,000-25,000 people. Glycogen-storage disease type 0 is a rare form, representing 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.

Mortality/Morbidity

The major morbidity is a risk of fasting hypoglycemia, which can vary in severity and frequency. Major long-term concerns include growth delay, osteopenia, and neurologic damage resulting in developmental delay, intellectual deficits, and personality changes.

Sex

No sexual predilection is observed because the deficiency of glycogen synthetase activity is inherited as an autosomal recessive trait.

Age

Glycogen-storage disease type 0 is most commonly diagnosed during infancy and early childhood.

Clinical Presentation

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