AUTHOR INFORMATION

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Authored by Lynne Ierardi-Curto, MD, PhD, Former Clinical Assistant Professor of Pediatrics, University of Medicine and Dentistry of New Jersey; Former Chief, Division of Clinical Genetics, Robert Wood Johnson University Hospital

Lynne Ierardi-Curto, MD, PhD, is a member of the following medical societies: American Society of Human Genetics

Edited by Edward Kaye, MD, Vice President of Clinical Research, Genzyme Corporation; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Hagop Youssoufian, MSc, MD, Medical Director, Adjunct Associate Professor, Clinical Discovery Department, Bristol-Myers Squibb; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Lynne Ierardi-Curto, MD, PhD
Editor's Email:	Edward Kaye, MD

eMedicine Journal, April 21 2006, VOLUME 7, Number 4

INTRODUCTION

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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.

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 increased blood lactate levels, because glycogen synthesis is limited, and excess glucose is preferentially converted to lactate by means of the glycolytic pathway.

Frequency:

• Internationally: The overall frequency of glycogen-storage disease is approximately 1 case in 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 both severity and frequency.

• Major long-term concerns include growth delay and neurologic damage resulting in developmental delay, intellectual deficits, and personality changes.

Sex: No sexual predilection occurs 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

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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 gastrointestinal 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 affects only the liver.



• Growth delay may be evident with height and weight percentiles below average.



• Findings on abdominal examination 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 coding for liver glycogen synthetase (GYS2), which is located on chromosome band 12p12.2.



• 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.

DIFFERENTIALS

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Fructose 1-Phosphate Aldolase Deficiency (Fructose Intolerance)
Glycogen-Storage Disease Type I
Hypoglycemia

Other Problems to be Considered:

Important clinical criteria to consider in the evaluation of a child with hypoglycemia and suspected GSD-0 include (1) the presence or absence of hepatomegaly; (2) the characteristic schedule of hypoglycemia, including unpredictable, postprandial, short fast, long fast, or precipitating factors; (3) the presence or absence of lactic acidosis; (4) any associated hyperketosis or hypoketosis; and (5) any associated liver failure or cirrhosis.

The differential diagnosis also includes ketotic hypoglycemia. Patients with ketotic hypoglycemia have a normal response to glucagon in the fed state. Patients with GSD-0 have normal to increased response to glucagon in the fed state, with hyperglycemia and lactic acidemia.

WORKUP

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Lab Studies:

• 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 GSD-0 have an anion gap in the reference range and no acidosis.



• Serum lipids (including triglyceride and total cholesterol) may be measured. In patients with GSD-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 GSD-0, urine ketones are positive, and urine-reducing substances are negative. However, urine-reducing substances are positive (fructosuria) in those with fructose 1-phosphate aldolase deficiency (fructose intolerance).



• Serum lactate is in reference ranges in fasting patients with GSD-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 during a fast.

Other Tests:

• Evaluation of a patient with suspected GSD-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.

Procedures:

• Liver biopsy for microscopic analysis and enzyme assay is required for definitive diagnosis.



• Diagnosis may include linkage analysis in families with affected members and sequencing of the entire coding region of the GSY2 gene for mutations.

TREATMENT

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Medical Care:

• 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 GSD-0.



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

Consultations:

• Refer the patient to a dietitian experienced with GSD-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 GSD-0. Inheritance is autosomal recessive, and parents have a 25% risk of producing an affected offspring with each pregnancy.



• 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.

Diet:

• 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.



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

Activity: Activity restrictions are not indicated.

FOLLOW-UP

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Further Outpatient Care:

• 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.

Deterrence/Prevention:

• 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.

Prognosis:

• 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.

Patient Education:

• 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.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to provide adequate calories and protein for normal growth



• Failure to educate the patient and family about the importance of dietary intervention to avoid episodes of fasting hypoglycemia and to prevent long-term growth delay and neurologic sequelae



• Failure to educate the parents about the necessity of adequate oral intake during an acute illness or the administration of intravenous glucose infusion within a few hours of inadequate oral intake



• Failure to instruct the primary pediatrician about the need for administration of intravenous glucose solution during the early hours of an acute illness with poor oral intake



• Failure to evaluate siblings for mild manifestations of this disorder

TEST QUESTIONS

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CME Question 1: A patient with glycogen-storage disease type 0 (GSD-0, or glycogen synthetase deficiency) presents after 8 hours of vomiting and diarrhea. What finding is not expected for this patient?

A: Decreased blood glucose concentration
B: Increased urine ketone levels
C: Plasma lactate value in the reference range
D: Increased anion gap
E: Increased serum acetoacetate level

The correct answer is D: During starvation, patients with GSD-0 have hypoglycemia and ketosis with increased serum and urine ketone (acetoacetate and b-hydroxybutyrate) levels. Plasma lactate levels are characteristically within the reference ranges or slightly low. Acidosis is usually not observed; therefore, the anion gap should be normal.

CME Question 2: What is the appropriate long-term treatment for a 2-year-old boy with recently diagnosed glycogen-storage disease type 0?

A: Liver transplantation
B: High-fat diet
C: Frequent high-protein meals and overnight cornstarch feeds
D: Frequent high-carbohydrate meals and overnight cornstarch feeds
E: No treatment

The correct answer is C: Studies show that frequent high-protein meals eaten throughout the day and overnight feedings of uncooked cornstarch help maintain normoglycemia, prevent episodes of hypoglycemia, and normalize growth parameters.

Pearl Question 1 (T/F): Glycogen-storage disease type 0 affects skeletal muscle.

The correct answer is False: Glycogen-storage disease type 0 affects only the liver and is characterized by moderately decreased glycogen stores in the liver.

Pearl Question 2 (T/F): Long-term sequelae of untreated glycogen-storage disease type 0 are limited to short stature.

The correct answer is False: Long-term sequelae may include delayed growth parameters (height and weight) and impaired neurologic development.

Pearl Question 3 (T/F): Definitive diagnosis of glycogen-storage disease type 0 involves liver biopsy.

The correct answer is True: Liver biopsy is performed to determine glycogen content and liver glycogen synthetase activity.

Pearl Question 4 (T/F): Characteristic biochemical features of a patient with glycogen-storage disease type 0 after the ingestion of a meal include hyperglycemia and blood lactate levels in the reference range.

The correct answer is False: Postprandial hyperglycemia and increased blood levels of lactate occur in patients with glycogen-storage disease type 0.

BIBLIOGRAPHY

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• 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 1977 Jul; 52(7): 573-9[Medline].
• Aynsley-Green A, Williamson DH, Gitzelmann R: Asymptomatic hepatic glycogen-synthetase deficiency. Lancet 1978 Jan 21; 1(8056): 147-8[Medline].
• Aynsley-Green A, Williamson DH, Gitzelmann R: The dietary treatment of hepatic glycogen synthetase deficiency. Helv Paediatr Acta 1977 Jun; 32(1): 71-5[Medline].
• 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 Jun; 140(6): 781-3[Medline].
• 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 2001 Sep-Oct; 14(8): 1151-5[Medline].
• 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 1995 Nov; 102(11): 931-3[Medline].
• Chen YT, Burchell A: Glycogen storage diseases. In: The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York, NY: McGraw-Hill Professional; 1995: 935-65.
• Gitzelmann R, Spycher MA, Feil G, et al: Liver glycogen synthase deficiency: a rarely diagnosed entity. Eur J Pediatr 1996 Jul; 155(7): 561-7[Medline].
• 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 2003 Jul 1; 120(1): 19-22[Medline].
• 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].
• 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.
• 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 Aug 1; 102(3): 507-15[Medline].
• Rutledge SL, Atchison J, Bosshard NU, Steinmann B: Case report: liver glycogen synthase deficiency--a cause of ketotic hypoglycemia. Pediatrics 2001 Aug; 108(2): 495-7[Medline].
• 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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