AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Glycogen-storage disease type VI (GSD VI) represents a heterogeneous group of hepatic glycogenoses with mild clinical manifestations and benign course. Patients typically exhibit prominent hepatomegaly, growth retardation, and variable but mild episodes of fasting hypoglycemia and hyperketosis during childhood. Hyperlacticacidemia and hyperuricemia are characteristically absent. In addition, patients may demonstrate elevated serum transaminases, hyperlipidemia, hypotonia, and muscle weakness. These clinical features and biochemical abnormalities generally resolve by puberty. Rare variants may have associated proximal renal tubule acidosis, myopathy, peripheral neuropathy, or fatal cardiomyopathy.

In general, GSD VI is caused by defects in the hepatic glycogen phosphorylase-activating system. The classic form of GSD VI results from a primary deficiency of liver phosphorylase. Other defects of the phosphorylase cascade system now included in this form of GSD include phosphorylase b kinase deficiency (formerly glycogen-storage disease type IX [GSD IX] and glycogen-storage disease type VIII [GSD VIII]) and adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase deficiency (formerly glycogen-storage disease type X [GSD X]).

Pathophysiology

Phosphorylase, the rate-limiting enzyme of glycogenolysis or glycogen breakdown, is activated by a cascade of enzymes, including adenyl cyclase, phosphorylase b kinase, and cAMP-dependent protein kinase. Enzyme deficiency anywhere along this pathway results in impaired cleavage of glucose units from the straight chains of the glycogen molecule. In most patients, the enzyme deficiency is incomplete, and gluconeogenesis remains intact. As a result, the ability of the liver to maintain normoglycemia during fasting may be partially impaired, resulting in an increased risk of mild fasting hypoglycemia and associated hyperketosis. Increased levels of urinary ketones and serum ketone bodies (eg, acetoacetate, beta-hydroxybutyrate) are proportional to the degree of fasting. Other biochemical derangements include mild-to-moderate hyperlipidemia, with elevation of serum cholesterol more than elevation of triglycerides and variably elevated serum transaminases with no other evidence of liver dysfunction.

Frequency

International

The overall frequency of GSD is 1 case per 20,000-25,000 persons, with approximately 30% of cases representing GSD VI, thus making GSD VI one of the most common forms of GSD. Approximately 75% of all cases of GSD VI result from the X-linked recessive forms of phosphorylase kinase deficiency.

Mortality/Morbidity

GSD VI has a rather benign course, with risk of growth retardation, mild fasting hypoglycemia, hypotonia, and delayed motor milestones in early childhood. These clinical features gradually normalize before or at puberty. Adult patients exhibit normal stature, motor function, and biochemical parameters. A subset of patients with the autosomal recessive form of GSD VI due to deficiency of phosphorylase kinase activity may be at increased risk for liver cirrhosis. Rare variants may cause muscle dysfunction, peripheral neuropathy, proximal renal tubule acidosis, or severe cardiomyopathy.

Race

GSD VI is most common among members of the Mennonite religious group.¹ A specific splice-site mutation in the liver phosphorylase gene (PYGL) occurs in the chromosomes of 3% of this religious group. GSD VI has an estimated frequency of 0.1% in the Mennonite population.

Sex

The X-linked recessive form of liver phosphorylase kinase deficiency is primarily expressed in affected males, although asymptomatic males and heterozygous (carrier) females with mild symptoms have been reported. All other forms of GSD VI are autosomal-recessive and equally affect both sexes.

Age

GSD VI usually manifests during early childhood.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The most common presentation is in children aged 1-5 years, with a history of protuberant abdomen, growth retardation, and slight delay in motor milestones. These children may also have histories of mild fasting hypoglycemia and hypotonia. Some patients remain asymptomatic, and routine physical examination reveals hepatomegaly.

Physical

Although children may have growth delay and short stature, adolescents and adults often have normal stature. The abdomen of a child with glycogen-storage disease type VI (GSD VI) usually protrudes, and abdominal examination reveals hepatomegaly and increased liver span. In some cases, hepatomegaly may be massive. However, splenomegaly is always absent. Adult patients may have mild or no hepatomegaly. Delay in motor milestones may be noted in a young child, and mild hypotonia and muscle weakness may be present. In an adolescent or adult, muscle strength and tone are usually normal. Some patients may have signs of peripheral neuropathy upon examination.

Causes

GSD VI results from a deficiency in the activity of one of several enzymes in the phosphorylase-activating cascade. Most cases result from defects of phosphorylase b kinase, an enzyme that activates phosphorylase by phosphorylation. Phosphorylase b kinase is a multimeric unit consisting of 4 different subunits, each coded by a unique gene located on different chromosomes. Mutations in 3 genes (PHKA2, PHKB, and PHKG2) have been demonstrated in patients with phosphorylase b kinase deficiency.²

In addition, several subtypes of phosphorylase kinase deficiency have been identified, based on the tissues affected and the mode of inheritance (autosomal recessive or X-linked recessive).³ The most common subgroup is the X-linked recessive form.

Classic GSD VI results from a primary deficiency of liver phosphorylase (PYGL). Patients with a defect of the cAMP-dependent protein kinase have been infrequently reported.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

The extent and severity of biochemical abnormalities vary in affected children.

• Blood glucose: After a short fast (3-5 h), mild hypoglycemia may develop in younger patients.
• Urine ketones, serum ketone bodies: Levels of urine ketones and serum ketone bodies (eg, acetoacetate, beta-hydroxybutyrate) may be elevated during a short fast and are proportional to the degree of fasting.
• Lipid profile: Mild hyperlipidemia may be present, with serum cholesterol elevations higher than serum triglycerides.
• Serum transaminases: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels may be mildly elevated. Other liver function test findings are usually normal, unless cirrhosis is present.
• Patients with proximal renal tubule acidosis may have increased urine pH levels with abnormal levels of calcium, phosphate, and amino acids and decreased blood pH levels with a normal anion gap.

Imaging Studies

• Liver volume quantitation may be performed using abdominal MRI or CT scanning.

Other Tests

• Evaluation of a patient with suspected glycogen-storage disease type VI (GSD VI) requires monitored assessment of fasting adaptation in an inpatient setting. After 3-5 hours of fasting, patients with GSD VI typically exhibit hypoglycemia with a normal serum lactic acid level. This same pattern also occurs in patients with glycogen-storage disease type 0 (GSD 0) and glycogen-storage disease type III (GSD III) and in patients with hereditary fructose intolerance (HFI). Patients with HFI can be identified by development of hypoglycemia and increased lactic acid after oral fructose loading.
• A fasted glucagon challenge may further narrow the field of diagnostic possibilities. Patients with GSD VI may have a normal hyperglycemic response without change in lactic acid after glucagon administration, although results may be inconclusive.
• Molecular diagnostic testing for a specific mutation in the PYGL gene may be used to identify carriers and affected children in the Mennonite population.

Procedures

• Definitive diagnosis of GSD VI requires a liver biopsy and enzyme assay. Histological examination and determination of glycogen content may also be performed.
• An enzyme assay can be performed in more easily obtainable cells, including RBCs and WBCs. However, due to the presence of isoenzymes, the presence of normal enzyme activity in these cells does not exclude the possibility of isolated hepatic involvement in an affected patient.

Histologic Findings

• Histological analysis of the liver typically reveals glycogen-distended hepatocytes.
• The accumulated glycogen (ie, alpha particles, rosette form) appears frayed or burst and is less compact than the glycogen present in glycogen-storage disease types I or III.
• Interlobular fibrous septa and low-grade inflammatory changes may be seen.
• Liver glycogen content may also be increased as much as 4-fold, although muscle glycogen remains normal in structure and quantity.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Consultations

• Refer the patient to a dietitian experienced with glycogen-storage diseases and the management of disorders associated with an increased risk of hypoglycemic episodes.
• Refer families to a medical geneticist or genetic counselor to review the specific inheritance of glycogen-storage disease type VI (GSD VI) present in the affected child. Inheritance may be autosomal recessive or X-linked recessive. Parents have a 25% risk of an affected offspring with each pregnancy or a 50% risk with each male offspring, respectively. An X-linked dominant inheritance is rarely reported.

Diet

• Dietary management is the only form of treatment necessary for this rather mild form of glycogen-storage disease.
• A high carbohydrate diet and frequent feedings are recommended only for those patients who exhibit fasting hypoglycemia.
• Although some patients have been given a high-protein diet or supplementation of unsaturated fats, most patients require no dietary intervention.

Activity

• Do not restrict the patient's activity unless significant hepatomegaly is present; recommend that patients with significant hepatomegaly avoid contact sports and activities.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug therapy is not currently a component of the standard of care for this disease.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Perform follow-up evaluation to assess physical growth and to prevent hypoglycemic episodes by adjusting diet, as needed.

Deterrence/Prevention

• Instruct patients who exhibit episodes of fasting hypoglycemia to avoid prolonged fasts exceeding 5-7 hours.
• During an acute illness with decreased oral intake, maintain normoglycemia with intravenous infusion of glucose-containing solution.

Prognosis

• Patients have an excellent prognosis for normal stature and development, even without dietary management during childhood.
• Most patients exhibit resolution of hepatomegaly, hypotonia, muscle weakness, risk of fasting hypoglycemia, and abnormal biochemical parameters before or at puberty.
• The overall prognosis of rare variants with associated muscle or cardiac involvement depends on the severity of organ dysfunction.

Patient Education

• Educate patients and parents about proper diet management and fasting avoidance techniques.
• Parents and primary physicians of an affected child with episodes of fasting hypoglycemia should know how to administer intravenous glucose solutions during periods of acute illness with decreased oral intake.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to educate the family about the effects of fasting and decreased oral intake during acute illness in those patients with episodes of fasting hypoglycemia

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Chang S, Rosenberg MJ, Morton H. Identification of a mutation in liver glycogen phosphorylase in glycogen storage disease type VI. Hum Mol Genet. May 1998;7(5):865-70. [Medline].
2. Burwinkel B, Rootwelt T, Kvittingen EA. Severe phenotype of phosphorylase kinase-deficient liver glycogenosis with mutations in the PHKG2 gene. Pediatr Res. 2003;54(6):834-839. [Medline].
3. Burwinkel B, Amat L, Gray RG. Variability of biochemical and clinical phenotype in X-linked liver glycogenosis with mutations in the phosphorylase kinase PHKA2 gene. Hum Genet. Apr 1998;102(4):423-9. [Medline].
4. Bashan N, Iancu TC, Lerner A. Glycogenosis due to liver and muscle phosphorylase kinase deficiency. Pediatr Res. Apr 1981;15(4 Pt 1):299-303. [Medline].
5. Beauchamp NJ, Taybert J, Champion MP et al. High frequency of missense mutations in glycogen storage disease type VI. J Inherit Metab Dis. Oct 2007;30:722-734. [Medline].
6. Burwinkel B, Bakker HD, Herschkovitz E. Mutations in the liver glycogen phosphorylase gene (PYGL) underlying glycogenosis type VI. Am J Hum Genet. Apr 1998;62(4):785-91. [Medline].
7. Burwinkel B, Bakker HD, Herschkovitz E, et al. Mutations in the liver glycogen phosphorylase gene (PYGL) underlying glycogenosis type VI. Am J Hum Genet. Apr 1998;62(4):785-91. [Medline].
8. Chen Y-T, Burchell A. Glycogen storage diseases. In: The Metabolic and Molecular Bases of Inherited Disease. Vol 1. 1995:935-65.
9. Goldberg T, Slonim AE. Nutrition therapy for hepatic glycogen storage diseases. J Am Diet Assoc. Dec 1993;93(12):1423-30. [Medline].
10. Hendrickx J, Bosshard NU, Willems P. Clinical, biochemical and molecular findings in a patient with X-linked liver glycogenosis followed for 40 years. Eur J Pediatr. Nov 1998;157(11):919-23. [Medline].
11. Hendrickx J, Lee P, Keating JP. Complete genomic structure and mutational spectrum of PHKA2 in patients with x-linked liver glycogenosis type I and II. Am J Hum Genet. Jun 1999;64(6):1541-9. [Medline].
12. Kotb MA, Abdallah HK, Kotb A. Liver glycogenoses: are they a possible cause of polyneuropathy? A cross-sectional study. J Trop Pediatr. Aug 2004;50(4):196-202. [Medline].
13. Newgard CB, Fletterick RJ, Anderson LA. The polymorphic locus for glycogen storage disease VI (liver glycogen phosphorylase) maps to chromosome 14. Am J Hum Genet. Apr 1987;40(4):351-64. [Medline].
14. Ozen H. Glycogen storage diseases: new perspectives. World J Gastroenterol. May 2007;13:2541-2553. [Medline].
15. Tang NL, Hui J, Young E, et al. A novel mutation (G233D) in the glycogen phosphorylase gene in a patient with hepatic glycogen storage disease and residual enzyme activity. Mol Genet Metab. Jun 2003;79(2):142-5. [Medline].
16. Willems PJ, Gerver WJ, Berger R. The natural history of liver glycogenosis due to phosphorylase kinase deficiency: a longitudinal study of 41 patients. Eur J Pediatr. Jan 1990;149(4):268-71. [Medline].

Article Last Updated: Aug 4, 2008