Glycogen-Storage Disease Type 0 (GSD-0) (Glycogen Synthetase Deficiency)

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.

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.

The most common clinical history in patients with glycogen-storage disease type 0 (GSD-0) is that of an infant or child with symptomatic hypoglycemia or seizures that occur before breakfast or after an inadvertent fast. In affected infants, this event typically begins after they outgrow their nighttime feeds. In children, this event may occur during acute GI illness or periods of poor enteral intake.

Mild hypoglycemic episodes may be clinically unrecognized, or they may cause symptoms such as drowsiness, sweating, lack of attention, or pallor. Uncoordinated eye movements, disorientation, seizures, and coma may accompany severe episodes.

Glycogen-storage disease type 0 affects only the liver. Growth delay may be evident with height and weight percentiles below average. Abdominal examination findings may be normal or reveal only mild hepatomegaly, if any. Other glycogen storage disorders present with significant hepatomegaly.

Signs of acute hypoglycemia may be present, including the following:

• Lethargy

• Apathy

• Jitteriness

• Diaphoresis

• Tachycardia

• Pallor

• Nausea and vomiting

• Headache

• Mental confusion

• Visual disturbances

• Dysarthria

• Hypotonia

• Ataxia

• Seizures

• Coma

• Death

Glycogen-storage disease type 0 is caused by genetic defects in the gene that codes for liver glycogen synthetase (GYS2), which is located on chromosome band 12p12.2.[2]

Glycogen synthetase catalyzes the rate-limiting reaction for glycogen synthesis in the liver by transferring glucose units from uridine 5'-diphosphate (UDP)-glucose to a glycogen primer. Its action is highly regulated by a mechanism of phosphorylation and dephosphorylation and modulated by counter-regulatory hormones including insulin, epinephrine, and glucagon.

Mutations in the gene for liver glycogen synthetase (GYS2, 138571) result in decreased or absent activity of liver glycogen synthetase and moderately decreased amounts of structurally normal glycogen in the liver. Mutational studies of patients with glycogen-storage disease type 0 do not demonstrate correlations between genotype and phenotype.[3] A different gene (GYS1, 138570) encodes muscle glycogen synthetase, which has normal activity in patients with glycogen-storage disease type 0.

Serum glucose levels are measured to document the degree of hypoglycemia. Serum electrolytes calculate the anion gap to determine presence of metabolic acidosis; typically, patients with glycogen-storage disease type 0 (GSD-0) have an anion gap in the reference range and no acidosis. See the Anion Gap calculator.

Serum lipids (including triglyceride and total cholesterol) may be measured. In patients with glycogen-storage disease type 0, hyperlipidemia is absent or mild and proportional to the degree of fasting.

Urine (first voided specimen with dipstick test for ketones and reducing substances) may be analyzed. In patients with glycogen-storage disease type 0, urine ketones findings are positive, and urine-reducing substance findings are negative. However, urine-reducing substance findings are positive (fructosuria) in those with fructose 1-phosphate aldolase deficiency (fructose intolerance).

Serum lactate is in reference ranges in fasting patients with glycogen-storage disease type 0. Serum lactate is elevated in the postprandial state of patients with glycogen-storage disease type 0.

Liver function studies provide evidence of mild hepatocellular damage in patients with mild elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels.

Plasma amino-acid analysis shows plasma alanine levels as in reference ranges or low during a fast.

Skeletal radiography may reveal osteopenia.

Evaluation of a patient with suspected glycogen-storage disease type 0 requires monitored assessment of fasting adaptation in an inpatient setting.

Patients typically have hypoglycemia and ketosis, with lactate and alanine levels in the low or normal part of the reference range approximately 5-7 hours after fasting.

A glucagon challenge test may be needed if the fast fails to elicit the expected rise in plasma glucose. Lactate and alanine levels are in the reference range.

By contrast, a glucagon challenge test after a meal causes hyperglycemia, with increased levels of plasma lactate and alanine.

Oral loading of glucose, galactose, or fructose results in a marked rise in blood lactate levels.

Liver biopsy for microscopic analysis and enzyme assay confirms the diagnosis. Liver biopsy may show low but not absent glycogen content and low or absent glycogen synthase activity.[4] Diagnosis may include linkage analysis in families with affected members and sequencing of the entire coding region of the GSY2 gene for mutations. Genetic testing may help avoid the need for a liver biopsy.

Histologic analysis of liver tissue demonstrates moderately decreased amounts of periodic acid-Schiff (PAS)–positive, diastase-sensitive glycogen stores.

Evidence of increased fat accumulation in the liver may be observed, as in other glycogen-storage diseases.

Electron microscopic analysis of liver sections shows normal glycogen structure.

Muscle glycogen stores are normal.

Treat the patient with an acute episode of hypoglycemia according to the standard fasting protocol. An endocrinologist or metabolic or biochemical specialist is suggested to evaluate and manage the long-term care of a patient with suspected glycogen-storage disease type 0 (GSD-0).

Management includes the provision of an adequate diet and avoidance of fasting hypoglycemia.

Refer the patient to a dietitian experienced with glycogen-storage disease type 0 and the management of disorders that increase the risk of hypoglycemic episodes.

Refer the family of the affected child to a medical geneticist or genetic counselor to review the inheritance of glycogen-storage disease type 0. Inheritance is autosomal recessive, and parents have a 25% risk of producing an affected offspring with each pregnancy. Extended relatives may also be identified as carriers, with accompanying risks to future children.

Formally evaluate siblings of the affected patient (proband) for manifestations because intrafamily variability is observed, and a child with mild disease may be clinically asymptomatic.

Determine the degree of dietary intervention required for each patient and carefully follow up the patient to ensure that he or she is consuming a constant source of glucose to prevent fasting hypoglycemia and to provide adequate calories and protein for growth.

Dietary management includes frequent consumption of protein-rich meals and nighttime feedings of uncooked cornstarch (2g/kg), which acts as a slow-release form of glucose. This can also be administered during acute illness or times of inadequate oral intake.[5]

Recommend the avoidance of highly processed carbohydrates to prevent conversion of excess glucose to lactate.

Activity restrictions are not indicated.

Conduct a follow-up evaluation to assess for adequate physical growth, developmental maturation, and avoidance of hypoglycemic episodes, with adjustments in dietary management as needed.

Avoid prolonged fasting of greater than 5-7 hours. Some patients cannot tolerate even a shorter fasting period of less than 5 hours. During an acute illness with decreased oral intake, maintain normoglycemia with intravenous infusion of glucose-containing solution.

The prognosis is good for normal growth and intellectual development when the condition is diagnosed early and when episodes of hypoglycemia are prevented with good dietary management.

Educate the patient and parents about proper diet management and avoidance of fasting. Educate the parents and primary physician about the administration of intravenous glucose solutions during acute illness with decreased oral intake. Dietary teaching is suggested for children as soon as they are developmentally ready. Educate the patient and the family about the autosomal-recessive inheritance of this condition and recurrent risk within the same family, as well as extended relatives.