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Liver glycogen synthase deficiency (glycogen storage disease 0)

Liver glycogen synthase deficiency (glycogen storage disease 0)
Literature review current through: Jan 2024.
This topic last updated: Aug 01, 2022.

INTRODUCTION — Glycogen is the stored form of glucose and serves as a buffer for glucose needs. It is composed of long polymers of a 1-4 linked glucose, interrupted by a 1-6 linked branch point every 4 to 10 residues. Glycogen is formed in periods of dietary carbohydrate loading and broken down when glucose demand is high or dietary availability is low (figure 1).

There are a number of inborn errors of glycogen metabolism that result from pathogenic variants in genes for virtually all of the proteins involved in glycogen synthesis, degradation, or regulation. Those disorders that result in abnormal storage of glycogen are known as glycogen storage diseases (GSDs). They have largely been categorized by number according to the chronology of recognition of the responsible enzyme defect (table 1). The age of onset varies from in utero to adulthood.

Glycogen is most abundant in liver and muscle, which are most affected by these disorders. The physiologic importance of a given enzyme in liver and muscle determines the clinical manifestations of the disease.

The main role of glycogen in the liver is to store glucose for release to tissues that are unable to synthesize significant amounts during fasting. The major manifestations of disorders of glycogen metabolism affecting the liver are hypoglycemia and hepatomegaly. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".)

Glycogen is the primary source of energy for high-intensity muscle activity by providing substrates for the generation of adenosine triphosphate (ATP). The major manifestations of disorders of glycogen metabolism affecting muscle are muscle cramps, exercise intolerance and easy fatigability, and progressive weakness.

This topic will review liver glycogen synthase deficiency (GSD 0). An overview of GSD is presented separately. (See "Overview of inherited disorders of glucose and glycogen metabolism".)

PATHOGENESIS — Two isoforms of glycogen synthase have been described. Glycogen synthase 1 (GYS1) is expressed predominantly in skeletal and cardiac muscle, and glycogen synthase 2 (GYS2) is expressed in the liver. Glycogen storage disease type 0 (GSD 0; MIM #240600) is caused by a defect in the gene that encodes for liver glycogen synthase (GYS2). Liver glycogen synthase deficiency affects the rate-limiting step in glycogen synthesis. A defect in the GYS1 gene is associated with cardiomyopathy and exercise intolerance [1].

A defect in glycogenin-1 (GYG1), a self-glycosylating protein that serves to initiate glycogen synthesis, causes a disorder with a paucity of glycogen in muscle tissues and clinical features similar to GYS1 deficiency [2]. A defect in the liver isoform GYG2 due to a microdeletion of the X chromosome in males does not appear to result in any clinical symptoms [3].

GENETICS — Liver glycogen synthase deficiency is an autosomal-recessive trait with reduced penetrance. Pathogenic variants in the GYS2 gene located at 12p12.2 have been reported in familial cases [4-7].

CLINICAL FEATURES — The clinical features of liver glycogen synthase deficiency are fasting hypoglycemia, hypoalaninemia, ketosis, and postprandial hyperglycemia and lactic acidemia. Affected children present with morning fatigue and exhibit ketotic hypoglycemia during fasting that responds to a meal [8]. Rare patients may be identified by incidentally observed hyperglycemia [6]. Mildly affected or asymptomatic individuals have been identified following diagnosis of a clinically affected family member [9], while other children are symptomatic in infancy [10]. There is often improvement in tolerance to fasting with age, but, in poorly controlled patients, long-term complications may include short stature and osteopenia.

DIAGNOSIS — Liver glycogen synthase deficiency is likely underdiagnosed [11]. It should be suspected in children with ketotic hypoglycemia after other entities are excluded. In an affected child, typical biochemical findings following a fast are preprandial ketotic hypoglycemia and hypoalaninemia and postprandial hyperglycemia and lactic acidemia. There may be modest elevations in transaminases and hyperlipidemia. (See "Approach to hypoglycemia in infants and children".)

The diagnosis is confirmed by liver biopsy. Alternatively, mutation analysis of the GYS2 gene can be performed on leukocyte deoxyribonucleic acid (DNA), avoiding the need for liver biopsy [12].

Other biochemical findings include:

Glycogen content in liver is low, although not absent.

Glycogen synthase activity in liver tissue is low or not measurable [11].

Enzyme activity is normal in fibroblasts, which have a different tissue-specific isoform [13].

TREATMENT — Treatment of liver glycogen synthase deficiency consists of frequent protein-rich meals and avoidance of fasting. Glucose levels can be maintained during sleep in the absence of glycogen degradation by the administration of uncooked cornstarch. Cornstarch is a complex glucose polymer that is slowly digested over a two- to six-hour period [14]. Cornstarch may only be required at nighttime. A dose of 1 to 1.5 g/kg can be used [5].

SUMMARY

Liver glycogen synthase deficiency (glycogen storage disease type 0 [GSD 0]; MIM #240600) affects the rate-limiting step in glycogen synthesis. (See 'Pathogenesis' above.)

Liver glycogen synthase deficiency is an autosomal-recessive trait with reduced penetrance. (See 'Genetics' above.)

Affected children may present with morning fatigue. Laboratory features include fasting hypoglycemia, postprandial lactic acidemia, hyperglycemia, hypoalaninemia, and fasting ketosis. Long-term complications may include short stature and osteopenia. (See 'Clinical features' above.)

Liver glycogen synthase deficiency should be suspected in children with ketotic hypoglycemia after other entities are excluded. The diagnosis is confirmed by liver biopsy or mutation analysis for the glycogen synthase 2 (GYS2) gene in leukocyte DNA. (See 'Diagnosis' above.)

Treatment consists of frequent protein-rich meals and avoidance of fasting. Glucose levels can be maintained during sleep by the administration of uncooked cornstarch. (See 'Treatment' above.)

  1. Kollberg G, Tulinius M, Gilljam T, et al. Cardiomyopathy and exercise intolerance in muscle glycogen storage disease 0. N Engl J Med 2007; 357:1507.
  2. Moslemi AR, Lindberg C, Nilsson J, et al. Glycogenin-1 deficiency and inactivated priming of glycogen synthesis. N Engl J Med 2010; 362:1203.
  3. Irgens HU, Fjeld K, Johansson BB, et al. Glycogenin-2 is dispensable for liver glycogen synthesis and glucagon-stimulated glucose release. J Clin Endocrinol Metab 2015; 100:E767.
  4. Orho M, Bosshard NU, Buist NR, et al. Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0. J Clin Invest 1998; 102:507.
  5. Weinstein DA, Correia CE, Saunders AC, Wolfsdorf JI. Hepatic glycogen synthase deficiency: an infrequently recognized cause of ketotic hypoglycemia. Mol Genet Metab 2006; 87:284.
  6. Spiegel R, Mahamid J, Orho-Melander M, et al. The variable clinical phenotype of liver glycogen synthase deficiency. J Pediatr Endocrinol Metab 2007; 20:1339.
  7. Kasapkara ÇS, Aycan Z, Açoğlu E, et al. The variable clinical phenotype of three patients with hepatic glycogen synthase deficiency. J Pediatr Endocrinol Metab 2017; 30:459.
  8. Aynsley-Green A, Williamson DH, Gitzelmann R. Hepatic glycogen synthetase deficiency. Definition of syndrome from metabolic and enzyme studies on a 9-year-old girl. Arch Dis Child 1977; 52:573.
  9. Aynsley-Green A, Williamson DH, Gitzelmann R. Asymptomatic hepatic glycogen synthetase deficiency (Letter). Lancet 1978; I:147.
  10. Kamenets EA, Gusarova EA, Milovanova NV, et al. Hepatic glycogen synthase (GYS2) deficiency: seven novel patients and seven novel variants. JIMD Rep 2020; 53:39.
  11. Gitzelmann R, Spycher MA, Feil G, et al. Liver glycogen synthase deficiency: a rarely diagnosed entity. Eur J Pediatr 1996; 155:561.
  12. Bachrach BE, Weinstein DA, Orho-Melander M, et al. Glycogen synthase deficiency (glycogen storage disease type 0) presenting with hyperglycemia and glucosuria: report of three new mutations. J Pediatr 2002; 140:781.
  13. Gitzelmann R, Steinmann B, Aynsley-Green A. Hepatic glycogen synthetase deficiency not expressed in cultured skin fibroblasts. Clin Chim Acta 1983; 130:111.
  14. Chen YT, Cornblath M, Sidbury JB. Cornstarch therapy in type I glycogen-storage disease. N Engl J Med 1984; 310:171.
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