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

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.

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]

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). 

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 (due to the prolonged overnight fast) or after an inadvertent fast (usually longer than 3 hours). In affected infants, this event typically begins after they outgrow their nighttime feeds, although there have been rare cases with a neonatal onset of hypoglycemia reported.[4]  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.[1] 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. Splenomegaly is not an expected finding. 

Signs of acute hypoglycemia may be present, including the following[1] :

• Lethargy

• Apathy

• Jitteriness

• Diaphoresis

• Tachycardia

• Pallor

• Nausea and vomiting

• Headache

• Mental confusion

• Visual disturbances

• Hypotonia

• Seizures

• Coma

• Death

Glycogen storage disease type 0 is caused by genetic defects ("variants") in the gene that codes for liver glycogen synthetase (GYS2), which is located on chromosome band 12p12.2.[5]

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 created by the protein glycogenin. Its action is highly regulated by a mechanism of phosphorylation and dephosphorylation and modulated by hormones including insulin, epinephrine, and glucagon.

Pathogenic variants (previously known as "mutations") in both copies (alleles) of the gene for liver glycogen synthetase (GYS2, 138571) result in decreased or absent activity of liver glycogen synthetase and decreased amounts of structurally normal glycogen in the liver. Genetic studies of patients with glycogen-storage disease type 0 do not demonstrate correlations between genotype and phenotype, meaning that disease severity cannot be predicted based on the specific genetic results based on the current knowledge.[6] A different gene (GYS1, 138570) encodes muscle glycogen synthetase, which has normal activity in patients with glycogen storage disease type 0.

Diagnosis of glycogen storage disease type 0 (GSD 0) can be established by sequencing of the GYS2 gene. Negative sequencing in high suspicion cases should be followed by deletion/duplication analysis of GYS2 if the sequencing test is unable to detect copy number variants.[1]

Serum glucose levels are measured to document the degree of hypoglycemia with fasting. Patients may have post-prandial hyperglycemia. Serum electrolytes calculate the anion gap to determine presence of metabolic acidosis; typically, patients with GSD 0 have an anion gap within the reference range and no acidosis, though there may be a transient lactic acidosis in the post-prandial state. 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, different than in other types of glycogen storage disease such as GSD 1, which cause disproportionally high plasma triglyceride levels. 

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 may be elevated. Urine ketones are less sensitive than serum ketones, however, and the absence of ketonuria should not be used to rule out GSD 0.

Serum lactate is within 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. During fasting, alanine levels may decrease as this amino acid is used for gluconeogenesis. 

Liver studies provide evidence of mild hepatocellular damage in some patients with mild elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, although most patients will have levels within the reference ranges. 

Skeletal radiography and bone density studies 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 molecular diagnosis is not available or is inconclusive. This should be performed in a well-monitored (inpatient) environment, as the hypoglycemia in individuals with GSD 0 is refractory to glucagon administration. 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. This is not recommended as a diagnostic test due to the availability of better diagnostic options and the dangers associated with this testing modality.

Liver biopsy for microscopic analysis and enzyme assay confirms the diagnosis, but is only performed if genetic testing has been inconclusive (ie, one or more variant of uncertain significance in GYS2) in a patient with a compelling clinical picture and no alternative diagnostic explanation.[1] Liver biopsy may show low but not absent glycogen content and low or absent glycogen synthase activity.[7]  

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

Evidence of increased fat accumulation in the liver may be observed.

Electron microscopic analysis of liver sections shows normal glycogen structure.

Muscle glycogen stores are normal.

Treatment is focused on avoiding hypoglycemia while providing healthy, good quality nutrition. 

Treat the patient with an acute episode of hypoglycemia according to standard institutional protocols based on the resources available. 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. A dietary plan should be crafted in conjunction with a medical geneticist and a metabolic dietitian to provide adequate calories and nutrients to avoid hypoglycemia and promote healthy growth and development. 

Refer the patient to a medical geneticist experienced with glycogen storage diseases and the management of disorders that increase the risk of hypoglycemic episodes. The management of this disorder is multidisciplinary and mainly involves medical geneticists and metabolic dietitians.

A medical geneticist or a genetic counselor will also 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 if they are confirmed to be carriers (if one of the variants is de novo - that is, new in the proband), the recurrence risk will differ. Extended relatives may also be identified as carriers, with accompanying risks to future children. Carriers are not known to display any symptoms.

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 they are consuming a constant source of glucose to prevent fasting hypoglycemia and to provide adequate calories and protein for growth.

A diet plan should be made in conjunction with a metabolic dietitian, and may include frequent consumption of meals rich in protein and complex carbohydrates, as well as nighttime feedings of uncooked cornstarch (usually 1-2 g/kg/dose), which acts as a slow-release form of glucose, if nocturnal or early-morning hypoglycemia is present. This can also be administered during acute illness or times of inadequate oral intake.[8]

Recommend the avoidance of highly-processed, "simple" carbohydrates to prevent conversion of excess glucose to lactate.  

Activity restrictions are not indicated. If exercise-induced hypoglycemia is present, diet modifications (such as high-carbohydrate, high-protein snacks before and during practice) may be indicated.

The major complications of GSD 0 are the complications of untreated hypoglycemia. If hypoglycemia is severe enough and not promptly reversed by dextrose administration, it may lead to seizures and brain injury. 

Hepatic steatosis has been reported in approximately 73% of patients, but it is of uncertain clinical significance.[9]

Intermittent, mild hypoglycemia with over-comsumption of carbohydrates may lead to bone mineral disease, which may manifest as osteopenia in some patients. 

Couples that are known to be carriers of pathogenic variants in GYS2 will have a 25% risk per child to have more affected children. In vitro fertilization with pre-implantation genetic testing may be available to reduce the risk of having further affected children. After the diagnosis of an affected child, parents should be referred for genetic counseling to discuss recurrence risk and reproductive options.

Long-term monitoring is important and may include: 

• Blood glucose and ketone logs in association with dietary journals
• Pre- and post-prandial blood glucose, lactate, alanine, and ketones
• Monitoring of liver disease (e.g., serum liver transaminases, liver ultrasounds)
• Careful developmental evaluations to detect any developmental delays stemming from repeated hypoglycemia
• Bone mineral density assessments (e.g., dual-energy X-ray absorptiometry)

There are no published guidelines for glycogen storage disease type 0.

There are no specific medications indicated for the treatment of glycogen storage disease type 0.

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 in childhood, greater than 3-4 hours in infancy; fasting tolerance varies between patients and may be shorter or longer than that. During an acute illness with decreased oral intake, maintain euglycemia 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.