AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

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

INTRODUCTION

Section 2 of 10  

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

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 [G-6-P] deficiency), causes clinically significant end-organ disease with significant morbidity. The remaining GSDs are not 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, which is due to defective glycogen synthase, also is recognized.

These inherited enzyme defects usually present in childhood, although some, such as McArdle disease and Pompe disease, 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 patient history, physical examination, muscle biopsy, electromyelography, ischemic forearm test, and creatine kinase levels. Biochemical assay for enzyme activity is the method of definitive diagnosis.

G-6-P deficiency is the specific enzyme deficiency in von Gierke disease. GSD type Ib is a similar condition with the defect in the G-6-P transporter protein. A newly described form, GSD type Ic, does not appear to be related to mutations within the transporter protein.

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. As noted above, G-6-P, which is found in the liver and kidney, is the specific enzyme that is deficient in von Gierke disease. Glucose-6-phosphate is an intermediate in the glycogen pathway.

Von Gierke disease is an autosomal-recessive condition. Von Gierke disease may be explained by mutations of the phosphohydrolase catalytic unit gene of the G-6-P complex, unlike GSD type Ib and GSD type Ic.

Deficiency of G-6-P blocks the final steps of glycogenolysis and gluconeogenesis. This results in severe hypoglycemia. Glucose production increases with age, making hypoglycemia less of an issue.

Because glucose cannot leave the hepatocyte phosphorylated, an increase in glycolytic pathway metabolites occurs. These intermediates are metabolized into lactate. Lactate may provide the brain with a ready-to-use energy source. By competing with uric acid, lactate decreases renal clearance, resulting in hyperuricemia. Glucose also is shunted into making more triglycerides, causing an increase in low-density and very low-density lipoproteins.

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

Immediate morbidity arises from hypoglycemic seizures. Serious long-term complications resulting in morbidity and mortality include nephropathy and hepatic adenoma.

Sex

GSDs are autosomal-recessive conditions, with an equal number of males and females being affected.

Age

In general, GSDs present in childhood. Later onset correlates with a less severe form.

CLINICAL

Section 3 of 10  

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

History

• Initial presentation may be active seizures, specifically hypoglycemic seizures.
• Global muscle weakness is not a uniform feature of von Gierke disease. Schwahn and colleagues found height, weight, bone mass and grip force decreased in one group of GSD 1a patients.¹
• Patients may give a history of kidney stones or gout.
• Patients may have had pancreatitis.

Physical

• Physical examination may reveal hepatomegaly. Because many causes of hepatic injury exist, suspicion of glycogen storage disease (GSD) must be high.
• Hypotonia is found in infants.
• Hypoglycemia is concerning and may lead to hypoglycemic seizures.
• Xanthomas may be present on the buttocks or extensor surfaces.
• Acute manifestations of gout may be observed.
• Hypertension or other manifestations of renal failure may be present.
• Short stature may be seen in the untreated patient.

DIFFERENTIALS

Section 4 of 10  

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

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• 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. Hypoglycemia is concerning and may lead to hypoglycemic seizures.
• Urine studies are indicated because myoglobinuria may occur in some GSDs.
• Hepatic failure occurs in some GSDs. Liver function studies are indicated.
• Hyperlipidemia is found in GSD Ia although there is no clear evidence of increased atherosclerosis.
• Laboratory abnormalities also include hyperuricemia, hyperlactacidemia, hyperlipidemia, hypercalciuria, and azotemia.
• Normochromic anemia has been documented.
• Measuring lipase and amylase may be justified in suspected cases of pancreatitis.
• Renal function studies may reveal renal failure. Nephropathy is a serious long-term complication of von Gierke disease.
• Obtaining a 24-hour urine collection to measure protein and creatinine clearance may be useful.
• Nutritional status
  
  
  • Kishnani and colleagues reported on 1 patient with von Gierke disease who was compliant with a high-protein diet but who developed emesis, weight loss, weakness, ataxia, agraphia, and oral ulcers. He was found to be deficient in vitamin B-12, folate, and iron. Correction of deficiencies allowed for symptomatic recovery.²
  • Other authors note that oral ulcers are secondary to impaired neutrophil migration, one feature of this disorder.

Imaging Studies

• Imaging may reveal hepatic adenoma, which may become malignant.
• Bone densitometry in older individuals may show low bone mass.
• Renal ultrasound may show enlarged kidneys.

Other Tests

• Ischemic forearm test
• • 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 from 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 a positive ischemic test.
  • Failure of ammonia to increase with lactate is evidence of myoadenylate deaminase deficiency.
  • In von Gierke disease, the ischemic forearm test is negative.
• Molecular genetic analysis
• • Seydewitz and Matern report a study of 40 patients with von Gierke disease. Mutations were found on all 80 alleles, which is evidence that molecular genetic analysis is a reliable diagnostic modality in addition to enzyme assay.³
  • Biochemical assay of enzyme activity is required for definitive diagnosis.

Histologic Findings

Biopsy of the kidney reveals focal glomerulosclerosis.

TREATMENT

Section 6 of 10  

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

Medical Care

• In general, no specific treatment exists to cure glycogen storage diseases (GSDs).
• In some cases, diet therapy is helpful. Meticulous adherence to a dietary regimen may reduce liver size, prevent hypoglycemia, allow for reduction in 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.⁴ These findings suggest that corrective gene therapy of GSDs may be possible for humans.
• An encouraging study by Bijvoet and colleagues provides evidence of successful enzyme replacement for the mouse model of Pompe disease, which may lead to therapies for other enzyme deficiencies.⁵

Surgical Care

Liver transplantation may be indicated for patients with hepatic malignancy. Whether transplantation prevents further complications remains unclear, although a study by Matern and colleagues demonstrated correction of metabolic abnormalities after transplantation.⁶

Consultations

• Due to the progressive kidney dysfunction, referral to a nephrologist may be appropriate.
• Consultation with a hepatologist may be necessary for management of liver dysfunction.

Diet

• Growing evidence indicates that a high-protein diet may provide increased muscle function in cases of weakness or exercise intolerance. Evidence also exists that indicates a high-protein diet may slow or arrest disease progression.
• Prevention of hypoglycemia in affected infants can be challenging. Nasogastric drip-feeding has allowed continuous feeding during the night. Uncooked starch may be used in older children.

FOLLOW-UP

Section 7 of 10  

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

Deterrence/Prevention

Early diet therapy may help prevent hepatic disease, including hepatocellular carcinoma.

Complications

• Hypoglycemic seizures
• Nephropathy with renal failure
• Hepatic adenoma with potential malignant transformation

Prognosis

• Von Gierke disease is not curable.

Patient Education

• Educate patients in the recognition of hypoglycemia and its appropriate treatment.

MISCELLANEOUS

Section 8 of 10  

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

Medical/Legal Pitfalls

• Parents must understand the consequences of hypoglycemia, including death if prolonged.
• Due to the possibility of hepatic adenomas and carcinomas, close follow-up is indicated.

MULTIMEDIA

Section 9 of 10  

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

Media file 1:  Metabolic pathways of carbohydrates
	View Full Size Image
Media type:  Image

REFERENCES

Section 10 of 10

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

1. Schwahn B, Rauch F, Wendel U, Schönau E. Low bone mass in glycogen storage disease type 1 is associated with reduced muscle force and poor metabolic control. J Pediatr. Sep 2002;141(3):350-6. [Medline].
2. Kishnani PS, Boney A, Chen YT. Nutritional deficiencies in a patient with glycogen storage disease type Ib. J Inherit Metab Dis. Oct 1999;22(7):795-801. [Medline].
3. Seydewitz HH, Matern D. Molecular genetic analysis of 40 patients with glycogen storage disease type Ia: 100% mutation detection rate and 5 novel mutations. Hum Mutat (Online). Jan 2000;15(1):115-6. [Medline].
4. 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].
5. 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].
6. Matern D, Starzl TE, Arnaout W. Liver transplantation for glycogen storage disease types I, III, and IV. Eur J Pediatr. Dec 1999;158 Suppl 2:S43-8. [Medline].
7. Amato AA. Acid maltase deficiency and related myopathies. Neurol Clin. Feb 2000;18(1):151-65. [Medline].
8. Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics. Jan 2000;105(1):e10. [Medline].
9. Chen Y. Glycogen Storage Diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease. 8^th ed. New York, NY: McGraw-Hill; 2001:1521-51.
10. Fernandes J, Smit G. The Glycogen Storage Diseases. In: Fernandes J, Saudubray JM, Van Den Berghe G, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 3^rd ed. New York, NY: Springer-Verlag; 2000:87-101.
11. Geberhiwot T, Alger S, McKiernan P, Packard C, Caslake M, Elias E. Serum lipid and lipoprotein profile of patients with glycogen storage disease types I, III and IX. J Inherit Metab Dis. Jun 2007;30(3):406. [Medline].
12. Goldberg T, Slonim AE. Nutrition therapy for hepatic glycogen storage diseases. J Am Diet Assoc. Dec 1993;93(12):1423-30. [Medline].
13. Hou DC, Kure S, Suzuki Y. Glycogen storage disease type Ib: structural and mutational analysis of the microsomal glucose-6-phosphate transporter gene. Am J Med Genet. Sep 17 1999;86(3):253-7. [Medline].
14. Lin B, Hiraiwa H, Pan CJ. Type-1c glycogen storage disease is not caused by mutations in the glucose-6-phosphate transporter gene. Hum Genet. Nov 1999;105(5):515-7. [Medline].
15. Moses SW. Historical highlights and unsolved problems in glycogen storage disease type 1. Eur J Pediatr. Oct 2002;161 Suppl 1:S2-9. [Medline].
16. 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].
17. Pears JS, Jung RT, Hopwood D. Glycogen storage disease diagnosed in adults. Q J Med. Mar 1992;82(299):207-22. [Medline].
18. Reitsma-Bierens WC. Renal complications in glycogen storage disease type I. Eur J Pediatr. 1993;152 Suppl 1:S60-2. [Medline].
19. Salapata Y, Laskaris G, Drogari E. Oral manifestations in glycogen storage disease type 1b. J Oral Pathol Med. Mar 1995;24(3):136-9. [Medline].
20. 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].
21. 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].
22. Veiga-da-Cunha M, Gerin I, Chen YT. The putative glucose 6-phosphate translocase gene is mutated in essentially all cases of glycogen storage disease type I non-a. Eur J Hum Genet. Sep 1999;7(6):717-23. [Medline].
23. 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].
24. Yang Chou J, Mansfield BC. Molecular Genetics of Type 1 Glycogen Storage Diseases. Trends Endocrinol Metab. Apr 1999;10(3):104-113. [Medline].

Article Last Updated: Sep 20, 2007