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Glycogen storage disease due to hepatic glycogen synthase deficiency
A rare genetically inherited anomaly of glycogen metabolism, considered a form of glycogen storage disease (GSD, or glycogenosis), characterized by post-meal hyperglycemia and fasting hypoglycemia. This is not a glycogenosis, strictly speaking, as there is no storage of glycogen, the enzyme deficiency preventing hepatic glycogen synthesis.
ORPHA:2089
Classification level: Disorder
- GSD due to hepatic glycogen synthase deficiency
- GSD type 0a
- Glycogen storage disease due to liver glycogen synthase deficiency
- Glycogen storage disease type 0a
- Glycogenosis type 0a
Prevalence: <1 / 1 000 000
Inheritance: Autosomal recessive
Age of onset: Childhood
It is an extremely rare disease; about 20 cases have been reported in the literature so far.
It commonly appears in infancy or early childhood. Patients present with morning fatigue and fasting hypoglycemia (without hepatomegaly) associated with hyperketonemia but without hyperalaninemia or hyperlactacidemia. After meals, major hyperglycemia, lactate and alanine increase and hyperlipidemia are observed.
Glycogen synthetase deficiency is caused by mutations in the GYS2 gene (12p12.2).
Glycemia measures during 24 hours, showing post meal hyperglycemia, and fasting hypoglycemia strongly suggest the diagnosis. Molecular analysis allows the confirmation of the diagnosis, with the identification of both mutant alleles within the GYS2 gene. Should the diagnosis remain likely despite a negative molecular study, a liver biopsy will be performed and show a slightly decreased glycogen concentration and evidence of the enzyme deficiency (it is not expressed in muscles, erythrocytes, leukocytes, or fibroblasts).
Differential diagnoses include hereditary fructose intolerance, glycogen storage disease due to glucose-6-phosphatase deficiency (GSD type I), and hypoglycemia.
Antenatal diagnosis is technically possible when pathogenic variants have previously been identified in the proband, but is usually not performed.
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
The condition is treated with a specific diet that includes frequent meals with high protein intake during the day and addition of uncooked starch in the evening.
Prognosis is favorable when the disease is correctly managed.
Last update: August 2024 - Expert reviewer(s): Dr Roseline FROISSART - Pr Philippe LABRUNE | MetabERN*
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