eMedicine Specialties > Endocrinology > Metabolic Disorders

Glycogen Storage Disease, Type Ia

Author: Wayne E Anderson, DO, Assistant Professor of Internal Medicine/Neurology, Western University of Health Sciences; Assistant Professor of Family Medicine, Touro University College of Osteopathic Medicine; Consulting Staff in Pain Management, Department of Neurology, California Pacific Medical Center; Consulting Staff in Neurology, Department of Neurology, California Pacific Medical Center
Contributor Information and Disclosures

Updated: Nov 5, 2009

Introduction

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. (See image below and Image 1.)

Metabolic pathways of carbohydrates

Metabolic pathways of carbohydrates

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Metabolic pathways of carbohydrates

Metabolic pathways of carbohydrates


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 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.1 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.2

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

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.3
  • 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.

More on Glycogen Storage Disease, Type Ia

Overview: Glycogen Storage Disease, Type Ia
Differential Diagnoses & Workup: Glycogen Storage Disease, Type Ia
Treatment & Medication: Glycogen Storage Disease, Type Ia
Follow-up: Glycogen Storage Disease, Type Ia
Multimedia: Glycogen Storage Disease, Type Ia
References
Further Reading
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References

  1. Jones JG, Garcia P, Barosa C, et al. Hepatic anaplerotic outflow fluxes are redirected from gluconeogenesis to lactate synthesis in patients with Type 1a glycogen storage disease. Metab Eng. May 2009;11(3):155-62. [Medline].

  2. Bandsma RH, Prinsen BH, van Der Velden Mde S, et al. Increased de novo lipogenesis and delayed conversion of large VLDL into intermediate density lipoprotein particles contribute to hyperlipidemia in glycogen storage disease type 1a. Pediatr Res. Jun 2008;63(6):702-7. [Medline].

  3. 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].

  4. Kalkan Ucar S, Coker M, et al. A monocentric pilot study of an antioxidative defense and hsCRP in pediatric patients with glycogen storage disease type IA and III. Nutr Metab Cardiovasc Dis. Jul 2009;19(6):383-90. [Medline].

  5. 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].

  6. Nguyen AT, Bressenot A, Manole S, et al. Contrast-enhanced ultrasonography in patients with glycogen storage disease type Ia and adenomas. J Ultrasound Med. Apr 2009;28(4):497-505. [Medline].

  7. 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].

  8. 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].

  9. 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].

  10. 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].

  11. Amato AA. Acid maltase deficiency and related myopathies. Neurol Clin. Feb 2000;18(1):151-65. [Medline].

  12. Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics. Jan 2000;105(1):e10. [Medline].

  13. Chen Y. Glycogen Storage Diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001:1521-51.

  14. Fernandes J, Smit G. The Glycogen Storage Diseases. In: Fernandes J, Saudubray JM, Van Den Berghe G, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 3rd ed. New York, NY: Springer-Verlag; 2000:87-101.

  15. 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].

  16. Goldberg T, Slonim AE. Nutrition therapy for hepatic glycogen storage diseases. J Am Diet Assoc. Dec 1993;93(12):1423-30. [Medline].

  17. 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].

  18. 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].

  19. Moses SW. Historical highlights and unsolved problems in glycogen storage disease type 1. Eur J Pediatr. Oct 2002;161 Suppl 1:S2-9. [Medline].

  20. 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].

  21. Pears JS, Jung RT, Hopwood D. Glycogen storage disease diagnosed in adults. Q J Med. Mar 1992;82(299):207-22. [Medline].

  22. Reitsma-Bierens WC. Renal complications in glycogen storage disease type I. Eur J Pediatr. 1993;152 Suppl 1:S60-2. [Medline].

  23. 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].

  24. 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].

  25. 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].

  26. 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].

  27. 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].

  28. Yang Chou J, Mansfield BC. Molecular Genetics of Type 1 Glycogen Storage Diseases. Trends Endocrinol Metab. Apr 1999;10(3):104-113. [Medline].

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Further Reading

Clinical guidelines:
 AASLD practice guidelines: evaluation of the patient for liver transplantation. American Association for the Study of Liver Diseases - Private Nonprofit Research Organization. 2000 Jan (revised 2005 Jun). 26 pages. NGC:004333 :

Clinical trials:
Growth and Development Study of Myozyme

Pompe Disease Registry

Pompe Lactation Sub-Registry

Pompe Pregnancy Sub-Registry

Pompe Prevalence Study in Patients With Muscle Weakness Without Diagnosis (POPS)

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Keywords

glycogen storage disease, von Gierke's disease, gluconeogenesis, glucose 6 phosphatase, glucose 6 phosphatase deficiency, G6P, von Gierke disease, glycogen storage disease type Ia, GSD type Ia, hepatonephromegaly glycogenica

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Contributor Information and Disclosures

Author

Wayne E Anderson, DO, Assistant Professor of Internal Medicine/Neurology, Western University of Health Sciences; Assistant Professor of Family Medicine, Touro University College of Osteopathic Medicine; Consulting Staff in Pain Management, Department of Neurology, California Pacific Medical Center; Consulting Staff in Neurology, Department of Neurology, California Pacific Medical Center
Wayne E Anderson, DO is a member of the following medical societies: American Academy of Neurology, American Medical Association, American Society of Law Medicine and Ethics, California Medical Association, and San Francisco Medical Society
Disclosure: Cephalon Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching; King Honoraria Consulting

Medical Editor

Barry J Goldstein, MD, PhD, Director, Division of Endocrinology, Diabetes and Metabolic Diseases, Professor, Department of Internal Medicine, Thomas Jefferson University
Barry J Goldstein, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, and Endocrine Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Kent Wehmeier, MD, Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, St Louis University School of Medicine
Kent Wehmeier, MD is a member of the following medical societies: American Society of Hypertension, Endocrine Society, and International Society for Clinical Densitometry
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

 
 
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