eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Glycogen-Storage Disease Type 0

Author: Lynne Ierardi-Curto, MD, PhD, Medical Geneticist, Laboratory Corporation of America (LabCorp), Northeast Division, Genetics Services
Contributor Information and Disclosures

Updated: Aug 4, 2008

Introduction

Background

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, GSD-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 GSD-0 present with symptoms that range from asymptomatic hyperglycemia to recurrent hypoglycemic seizures.1

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 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 GSD-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. GSD-0 is a rare form, representing less than 1% of all cases. The identification of asymptomatic and oligosymptomatic siblings in several GSD-0 families has suggested that GSD-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

GSD-0 is most commonly diagnosed during infancy and early childhood.

Clinical

History

  • The most common clinical history 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.

Physical

  • Glycogen-storage disease type 0 (GSD-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.
  • 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

Causes

  • GSD-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.
  • A different gene (GYS1, 138570) encodes muscle glycogen synthetase, which has normal activity in patients with GSD-0.

More on Glycogen-Storage Disease Type 0

Overview: Glycogen-Storage Disease Type 0
Differential Diagnoses & Workup: Glycogen-Storage Disease Type 0
Treatment & Medication: Glycogen-Storage Disease Type 0
Follow-up: Glycogen-Storage Disease Type 0
References
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References

  1. Spiegel R, Mahamid J, Orho-Melander M, Miron D, Horovitz Y. The variable clinical phenotype of liver glycogen synthase deficiency. J Pediatr Endocrinol Metab. Dec 2007;20:1339-1342. [Medline].

  2. 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. Aug 1 1998;102(3):507-15. [Medline].

  3. Aynsley-Green A, Williamson DH, Gitzelmann R. Asymptomatic hepatic glycogen-synthetase deficiency. Lancet. Jan 21 1978;1(8056):147-8. [Medline].

  4. Aynsley-Green A, Williamson DH, Gitzelmann R. The dietary treatment of hepatic glycogen synthetase deficiency. Helv Paediatr Acta. Jun 1977;32(1):71-5. [Medline].

  5. Aynsley-Green A, Williamson DH, Gitzelmann R, et al. Hepatic glycogen synthetase deficiency. Definition of syndrome from metabolic and enzyme studies on a 9-year-old girl. Arch Dis Child. Jul 1977;52(7):573-9. [Medline].

  6. 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. Jun 2002;140(6):781-3. [Medline].

  7. Blumel P, Mullis PE. Effect of growth hormone treatment on hypoglycemia in a patient with both hepatic glycogen synthase and isolated growth hormone deficiencies. J Pediatr Endocrinol Metab. Sep-Oct 2001;14(8):1151-5. [Medline].

  8. Byrne BM, Gillmer MD, Turner RC, et al. Glucose homeostasis in adulthood and in pregnancy in a patient with hepatic glycogen synthetase deficiency. Br J Obstet Gynaecol. Nov 1995;102(11):931-3. [Medline].

  9. Chen YT, Burchell A. Glycogen storage diseases. In: The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York, NY: McGraw Hill; 1995:935-65.

  10. Gitzelmann R, Spycher MA, Feil G, et al. Liver glycogen synthase deficiency: a rarely diagnosed entity. Eur J Pediatr. Jul 1996;155(7):561-7. [Medline].

  11. Laberge AM, Mitchell GA, van de Werve G. Long-term follow-up of a new case of liver glycogen synthase deficiency. Am J Med Genet A. 2003;120(1):19-22. [Medline].

  12. Laberge AM, Mitchell GA, van de Werve G, Lambert M. Long-term follow-up of a new case of liver glycogen synthase deficiency. Am J Med Genet A. Jul 1 2003;120(1):19-22. [Medline].

  13. Lewis GM, Spencer-Peet J, Stewart KM. Infantile hypoglycaemia due to inherited deficiency of glycogen synthetase in liver. Arch Dis Child. 1963;38:40-8.

  14. Rutledge SL, Atchison J, Bosshard NU, Steinmann B. Case report: liver glycogen synthase deficiency--a cause of ketotic hypoglycemia. Pediatrics. Aug 2001;108(2):495-7. [Medline].

  15. Weinstein DA, Corneia CE, Saunders AC, Wolfsdorf JI. Hepatic glycogen synthase deficiency: an infrequently recognized cause of ketotic hypoglycemia. Mol Genet Metab. 2006;87(4):284-288. [Medline].

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Further Reading

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Keywords

glycogen-storage disease type 0, GSD-0, glycogen synthetase deficiency, aglycogenosis, hypoglycemia with deficiency of liver glycogen synthetase, liver glycogen synthetase deficiency, GYS2, hyperglycemia, hyperlacticacidemia, growth delay, osteopenia, hepatomegaly, lactic acidosis, hyperketosis, hypoketosis, cirrhosis, metabolic acidosis

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Contributor Information and Disclosures

Author

Lynne Ierardi-Curto, MD, PhD, Medical Geneticist, Laboratory Corporation of America (LabCorp), Northeast Division, Genetics Services
Disclosure: Nothing to disclose.

Medical Editor

Edward Kaye, MD, Vice President of Clinical Research, Genzyme Corporation
Edward Kaye, MD is a member of the following medical societies: American Academy of Neurology, American Society of Gene Therapy, American Society of Human Genetics, Child Neurology Society, and Society for Inherited Metabolic Disorders
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Hagop Youssoufian, MD, MSc, Vice President of Clinical Research, ImClone Systems Incorporated
Hagop Youssoufian, MD, MSc is a member of the following medical societies: American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, and American Society of Human Genetics
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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