Practice Essentials
Glycogen storage disease type 0 (GSD 0) is a rare autosomal recessive disorder characterized by decreased liver glycogen stores, leading to a predisposition to fasting hypoglycemia. [1, 2] As patients cannot efficiency synthesize glycogen, carbohydrates from diet can lead to post-prandial hyperglycemia, hyperlactatemia, and hyperalaninemia. The main manifestations of GSD 0 stem from the fasting hypoglycemia, with symptoms such as drowsiness, tremor, abnormal mental status, and seizures. Treatment is dietary-based and focused on providing frequent meals with enough protein to sustain gluconeogenesis and complex, low-glycemic index carbohydrates to extend fasting times. Uncooked cornstarch may be used in some circumstances, especially to prevent nocturnal hypoglycemia. Emergency treatment involves prompt reversal of hypoglycemia with enteral fast-absorption carbohydrates or, when blood glucose is critically low, parental dextrose-containing fluids. Long-term complications include sequelae of hypoglycemic episodes (eg, developmental delays, focal neurological signs), growth delays, and osteopenia.
Background
Glycogen storage disease type 0 (GSD 0), or liver glycogen synthase 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. [1, 2] Although feeding rescues hypoglycemia, it results in postprandial hyperglycemia and hyperlactatemia since glucose from diet cannot be incorporated into glycogen. Unlike other forms of glycogen storage disease, glycogen storage disease type 0 does not involve the storage of excessive or abnormal glycogen - on the contrary, it is characterized by decreased glycogen stores in the liver (ie, aglycogenosis). [1, 2] Reports suggest that patients with glycogen storage disease type 0 present with symptoms that range from asymptomatic hyperglycemia to recurrent hypoglycemic seizures. [3]
Glycogen is most abundant in the liver and muscle. In the liver, glycogen is a storage form of glucose. During periods of fasting, glycogen releases glucose to be used by other tissues, maintaining euglycemia. In the muscle, glycogen is the source of energy for muscle activity; muscle tissue lacks the enzymes to release glucose into the circulation, and thus does not contribute to maintaining euglycemia. Glycogen storage disorders can manifest as hypoglycemia, ketosis, lethargy, fatigue, weakness, muscle cramping, or exercise intolerance, depending on which aspect of liver or muscle glycogen synthesis or glycogenolysis are affected.
There are two isoforms of the glycogen synthase enzyme, each encoded by a different gene. 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 GYS2. It is a a rare 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 non-carbohydrate precursors through gluconeogenesis. Such precursors include alanine (derived from the breakdown of proteins in skeletal muscle) and glycerol (derived from the breakdown of triacylglycerols [aka, triglycerides] in fat cells). The energy to transform amino acids and glycerol into glucose comes mostly from the breakdown of fatty acids in the β-oxidation pathway. 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 euglycemia. Feeding characteristically results in postprandial hyperglycemia and glucosuria, in addition to increased blood lactate and alanine levels, because glycogen synthesis is limited, and excess glucose is converted to lactate and alanine from pyruvate, at the end of the glycolytic pathway. [1, 2]
Epidemiology
Frequency
International
The overall frequency of glycogen-storage disease is theoretically as high as 1 case per 20,000-25,000 people, although fewer than 50 cases have been reported in the literature, which likely reflects a great number of undiagnosed individuals. [4] Glycogen storage disease type 0 is a rare form, representing less than 1% of all cases of glycogen storage disorders. 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 and is incompletely penetrant. There are no described founder effects with high prevalence in specific populations.
Mortality/Morbidity
The major morbidity is a risk for fasting hypoglycemia, which can vary in severity and frequency. Major long-term concerns include growth delay and osteopenia. Neurologic damage from hypoglycemia is rare, but may result in hypoglycemic seizures, developmental delays, intellectual deficits, and personality changes after a major hypoglycemic episode.
Sex
No sex differences are 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. Symptoms usually become apparent once infants begin to fast for longer periods (eg, when overnight feeds end).
