AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

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

INTRODUCTION

Section 2 of 9  

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

Background

A glycogen storage disease (GSD) is the result of an enzyme defect. These enzymes normally catalyze reactions that ultimately convert glycogen compounds to glucose. Enzyme deficiency results in glycogen accumulation in tissues. In many cases, the defect has systemic consequences, but in some cases, the defect is limited to specific tissues. Most patients experience muscle symptoms, such as weakness and cramps, although certain GSDs manifest as specific syndromes, such as hypoglycemic seizures or cardiomegaly.

The following list contains a quick reference for 8 of the GSD types:

• 0 - Glycogen synthase deficiency
• Ia - Glucose-6-phosphatase deficiency (von Gierke disease)
• II - Acid maltase deficiency (Pompe disease)
• III - Debranching enzyme deficiency (Forbes-Cori disease)
• IV - Transglucosidase deficiency (Andersen disease, amylopectinosis)
• V - Myophosphorylase deficiency (McArdle disease)
• VI - Phosphorylase deficiency (Hers disease)
• VII - Phosphofructokinase deficiency (Tauri disease)

Although at least 14 unique GSDs are discussed in the literature, the 4 that cause clinically significant muscle weakness are Pompe disease (GSD type II, acid maltase deficiency), Cori disease (GSD type III, debranching enzyme deficiency), McArdle disease (GSD type V, myophosphorylase deficiency), and Tarui disease (GSD type VII, phosphofructokinase deficiency). One form, von Gierke disease (GSD type Ia, glucose-6-phosphatase deficiency), causes clinically significant end-organ disease with significant morbidity. The remaining GSDs are not necessarily benign but are less clinically significant; therefore, the physician should consider the aforementioned GSDs when initially entertaining the diagnosis of a GSD. Interestingly, GSD type 0 also is described, which is due to defective glycogen synthase.

These inherited enzyme defects usually present in childhood, although some, such as McArdle disease and Pompe disease (also known as acid maltase deficiency), have separate adult-onset forms. In general, GSDs are inherited as autosomal recessive conditions. Several different mutations recently have been reported for each disorder.

Unfortunately, no specific treatment or cure exists, although diet therapy may be highly effective at reducing clinical manifestations. In some cases, liver transplantation may abolish biochemical abnormalities. Active research continues.

Diagnosis depends on findings from patient history and physical examination, muscle biopsy, electromyography, ischemic forearm testing, and creatine kinase testing. Biochemical assay for enzyme activity is the method of definitive diagnosis.

In patients with Hers disease, defective liver phosphorylase results in hepatomegaly and hypoglycemia. The liver phosphorylase enzyme is found within the liver and red blood cells.

Pathophysiology

With an enzyme defect, carbohydrate metabolic pathways are blocked and excess glycogen accumulates in affected tissues. Each GSD represents a specific enzyme defect, and each enzyme is in specific, or most, body tissues. Liver phosphorylase, which is found in the liver and red blood cells, is deficient, which results in glycogen accumulation in the liver and subsequent hypoglycemia.

Several mutations of the liver glycogen phosphorylase gene are reported.

Frequency

International

Herling and colleagues studied the incidence and frequency of inherited metabolic conditions in British Columbia. GSDs are found in 2.3 children per 100,000 births per year.

Mortality/Morbidity

Morbidity results from consequences of hepatomegaly.

Age

In general, GSDs present in childhood. Later onset correlates with a less severe form. Consider Pompe disease if onset is in infancy.

CLINICAL

Section 3 of 9  

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

History

• Symptoms result from mild hypoglycemia.
• No specific symptoms are associated with Hers disease (glycogen storage disease, type VI).

Physical

• Hepatomegaly may be present; however, because many causes of hepatic injury exist, suspicion must be high.
• Growth retardation is possible.

Causes

• The liver isoform of phosphorylase is deficient.
• A mutation has been mapped to chromosome 14. A splicing site mutation has been identified.

DIFFERENTIALS

Section 4 of 9  

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

WORKUP

Section 5 of 9  

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

Lab Studies

• Obtain a creatine kinase level in all cases of suspected glycogen storage disease (GSD).
• Because hypoglycemia may be found in some types of GSD, fasting glucose testing is indicated. In Hers disease, hypoglycemia is a primary concern.
• Urine studies are indicated because myoglobinuria may occur in some patients with GSDs.
• Hepatic failure occurs in some patients with GSDs, although rarely in those with Hers disease. Liver function studies are indicated and may reveal evidence of hepatic injury.
• Biochemical assay of enzyme activity is necessary for definitive diagnosis.

Imaging Studies

Findings from imaging studies may reveal hepatomegaly.

Other Tests

• Ischemic forearm test
• • In the case of Hers disease, which is not associated with significant muscle involvement, the forearm ischemic test is most useful to help rule out other GSDs, most specifically Cori disease, McArdle disease, and Tarui disease. Test findings are expected to be negative in patients with Hers disease.
  • The ischemic forearm test is an important tool for diagnosis of muscle disorders. The basic premise is an analysis of the normal chemical reactions and products of muscle activity. Obtain consent before the test.
  • Instruct the patient to rest. Position a loosened blood pressure cuff on the arm, and place a venous line for blood samples in the antecubital vein.
  • Obtain blood samples for the following tests: creatine kinase, ammonia, and lactate. Repeat in 5-10 minutes.
  • Obtain a urine sample for myoglobin analysis.
  • Immediately inflate the blood pressure cuff above systolic blood pressure and have the patient repetitively grasp an object, such as a dynamometer. Instruct the patient to grasp the object firmly, once or twice per second. Encourage the patient for 2-3 minutes, at which time the patient may no longer be able to participate. Immediately release and remove the blood pressure cuff.
  • Obtain blood samples for creatine kinase, ammonia, and lactate immediately and at 5, 10, and 20 minutes.
  • Collect a final urine sample for myoglobin analysis.
• Interpretation of ischemic forearm test results
• • With exercise, carbohydrate metabolic pathways yield lactate from pyruvate. Lack of lactate production during exercise is evidence of a pathway disturbance, and an enzyme deficiency is suggested. In such cases, muscle biopsy with biochemical assay is indicated.
  • Healthy patients demonstrate an increase in lactate of at least 5-10 mg/dL and ammonia of at least 100 mcg/dL. Levels will return to baseline.
  • If neither level increases, the exercise was not strenuous enough and the test is not valid.
  • Increased lactate at rest (before exercise) is evidence of mitochondrial myopathy.
  • Failure of lactate to increase with ammonia is evidence of a GSD resulting in a block in carbohydrate metabolic pathways. Not all patients with GSDs have positive ischemic test results.
  • Failure of ammonia to increase with lactate is evidence of myoadenylate deaminase deficiency.
  • Positive ischemic forearm test results may occur in patients with Cori disease, McArdle disease, and Tarui disease.
  • In patients with Hers disease, ischemic test results are negative.

Procedures

Liver biopsy may be required to diagnose the cause of hepatomegaly.

TREATMENT

Section 6 of 9  

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

Medical Care

• In general, no specific treatment exists for glycogen storage diseases (GSDs).
• In some cases, diet therapy is helpful. Meticulous adherence to a dietary regimen may reduce liver size, prevent hypoglycemia, reduce symptoms, and allow for growth and development.
• Zingone and colleagues demonstrated the abolition of the murine clinical manifestations of von Gierke disease with a recombinant adenoviral vector.¹ These findings suggest that corrective gene therapy for GSDs may be possible in humans.
• An encouraging study by Bijvoet and colleagues provides evidence of successful enzyme replacement for the mouse model of GSD type II, which may lead to therapies for other enzyme deficiencies.²
• A study by Asami and colleagues suggests that clonidine might be a treatment modality for Hers disease.³

Diet

• Growing evidence indicates that a high-protein diet may provide increased muscle function in patients with weakness or exercise intolerance. Evidence also exists that a high-protein diet may slow or arrest progression of the disease.
• High-carbohydrate diet is effective in preventing hypoglycemia.
• Most patients require little specific dietary intervention.

FOLLOW-UP

Section 7 of 9  

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

Complications

Complications are related to hypoglycemia.

Prognosis

Hers disease is not curable. Hypoglycemia is preventable.

Patient Education

As with all genetic diseases, genetic counseling is appropriate.

MULTIMEDIA

Section 8 of 9  

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

Media file 1:  Metabolic pathways of carbohydrates.
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REFERENCES

Section 9 of 9

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

1. Zingone A, Hiraiwa H, Pan CJ. Correction of glycogen storage disease type 1a in a mouse model by gene therapy. J Biol Chem. Jan 14 2000;275(2):828-32. [Medline].
2. Bijvoet AG, Van Hirtum H, Vermey M. Pathological features of glycogen storage disease type II highlighted in the knockout mouse model. J Pathol. Nov 1999;189(3):416-24. [Medline].
3. Asami T, Kikuchi T, Asami K. Effect of clonidine on the height of a child with glycogen storage disease type VI: a 13 year follow-up study. Acta Paediatr Jpn. Oct 1996;38(5):524-8. [Medline].
4. Amato AA. Acid maltase deficiency and related myopathies. Neurol Clin. Feb 2000;18(1):151-65. [Medline].
5. Aminoff MJ, ed. Electromyography in Clinical Practice. 3^rd ed. New York, NY: Churchill Livingstone; 1998.
6. Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics. Jan 2000;105(1):e10. [Medline].
7. 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].
8. Chen Y. Glycogen Storage Diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 1. 8^th ed. New York, NY: McGraw-Hill; 2000:1537-8.
9. DiMauro S, Bruno C. Glycogen storage diseases of muscle. Curr Opin Neurol. Oct 1998;11(5):477-84. [Medline].
10. Goldberg T, Slonim AE. Nutrition therapy for hepatic glycogen storage diseases. J Am Diet Assoc. Dec 1993;93(12):1423-30. [Medline].
11. Orho M, Bosshard NU, Buist NR. 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].
12. Smit GP, Fernandes J, Leonard JV. The long-term outcome of patients with glycogen storage diseases. J Inherit Metab Dis. 1990;13(4):411-8. [Medline].
13. Stevens AN, Iles RA, Morris PG. Detection of glycogen in a glycogen storage disease by 13C nuclear magnetic resonance. FEBS Lett. Dec 27 1982;150(2):489-93. [Medline].
14. 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].
15. Wolfsdorf JI, Holm IA, Weinstein DA. Glycogen storage diseases. Phenotypic, genetic, and biochemical characteristics, and therapy. Endocrinol Metab Clin North Am. Dec 1999;28(4):801-23. [Medline].

Article Last Updated: Sep 21, 2007