eMedicine Specialties > Endocrinology > Metabolic Disorders

Glycogen Storage Disease, Type III

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
Contributor Information and Disclosures

Updated: Sep 20, 2007

Introduction

Background

A glycogen storage disease (GSD) results from the absence of enzymes 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 (Tarui 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 IIIa, 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 benign but are less clinically significant; therefore, the physician should consider the aforementioned GSDs when initially entertaining the diagnosis of a GSD. Interestingly, a GSD type 0 also exists, which is due to defective glycogen synthase.

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 and physical examination, muscle biopsy, electromyelography, ischemic forearm test, and creatine kinase levels. Biochemical assay for enzyme activity is the method of definitive diagnosis.

The debranching enzyme converts glycogen to glucose-1,6-phosphate. Deficiency leads to liver disease, with subsequent hypoglycemia and seizure. Progressive muscle weakness also occurs.

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.

The enzyme amylo-1,6-glucosidase is deficient, leading to an accumulation of dextrin. The site of glycogen accumulation is primarily cytoplasmic. Conversion generally is a one-way reaction from glycogen to glucose-1,6-phosphate. The enzyme is found in all tissues.

Disease results from a pan-deficiency of the enzyme (GSD IIIa) or muscle-specific retention of glycogen debranching enzyme (GSD IIIb). The condition is autosomal recessive. No common mutation has been described in Cori disease (types a and b), although 2 alleles have been reported for GSD IIIb and 1 allele has been found in North African Jewish people with GSD IIIa. The first report of a causative missense mutation was published in 1999 based on the work of Okubo and colleagues.1

GSD type IIIb is caused by mutation in exon 3 of the glycogen debranching enzyme. Lam and colleagues demonstrate different haplotypes for GSD type IIIa.2 GSD III can occur not only in humans, but also in other mammals.

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. In non-Ashkenazi Jewish people of North Africa, the frequency has been reported as 1 out of 5400 people. Zimakas and Rodd report the rare presence of GSD type III in Inuit children.3

Mortality/Morbidity

  • Immediate morbidity may arise from hypoglycemic seizures that occur in the first decade of life.
  • Long-term morbidity arises from hepatic disease and progressive muscle weakness.
  • Ingle and colleagues report sudden mortality by exsanguination related to hepatocellular failure.4
  • Demo and colleagues report two cases of hepatocellular carcinoma as a long-term complication of GSD III, possibly emerging because of increased overall survival with GSD III.5

Age

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

Clinical

History

  • Although the enzyme is found in all tissues, clinical manifestations generally are nonmyopathic.
  • History usually consists of infant seizures.
  • Other features include hepatomegaly and growth retardation.
  • Muscle weakness is very slow in progressing. Vigorous exercise is not associated with cramping, tenderness, or myoglobulinuria.
  • Cortical malformations are reported. Vincentiis and colleagues report one case of polymicrogyria.

Physical

  • Debrancher enzyme deficiency may manifest as progressive weakness.
  • Hepatomegaly and splenomegaly are present. Unlike GSD I, kidney enlargement is not observed.
  • Growth retardation may occur.
  • In adults, it may progress to liver cirrhosis or hepatic adenomas.
  • Muscle wasting of interossei may occur.

More on Glycogen Storage Disease, Type III

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

  1. Okubo M, Kanda F, Horinishi A, et al. Glycogen storage disease type IIIa: first report of a causative missense mutation (G1448R) of the glycogen debranching enzyme gene found in a homozygous patient. Hum Mutat (Online). 14(6):542-3. [Medline].

  2. Lam CW, Lee AT, Lam YY, et al. DNA-based subtyping of glycogen storage disease type III: mutation and haplotype analysis of the AGL gene in Chinese. Mol Genet Metab. Nov 2004;83(3):271-5. [Medline].

  3. Zimakas PJ, Rodd CJ. Glycogen storage disease type III in Inuit children. CMAJ. Feb 1 2005;172(3):355-8. [Medline].

  4. Ingle SA, Moulick ND, Ranadive NU, Khedekar K. Hepatocellular failure in glycogen storage disorder type 3. J Assoc Physicians India. Feb 2004;52:158-60. [Medline].

  5. Demo E, Frush D, Gottfried M, Koepke J, Boney A, Bali D. Glycogen storage disease type III-hepatocellular carcinoma a long-term complication?. J Hepatol. Mar 2007;46(3):492-8. [Medline].

  6. Zingone A, Hiraiwa H, Pan CJ, et al. Correction of glycogen storage disease type 1a in a mouse model by gene therapy. J Biol Chem. 275(2):828-32. [Medline].

  7. Bijvoet AG, Van Hirtum H, Vermey M, et al. Pathological features of glycogen storage disease type II highlighted in the knockout mouse model. J Pathol. 189(3):416-24. [Medline].

  8. Matern D, Starzl TE, Arnaout W, et al. Liver transplantation for glycogen storage disease types I, III, and IV. Eur J Pediatr. 158 Suppl 2:S43-8. [Medline].

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

  10. Aminoff MJ. Electromyography in Clinical Practice. New York, NY: Churchill Livingstone; 1998.

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

  12. Chen Y. The Metabolic and Molecular Bases of Inherited Disease. In: Scriver CR, Beaudet AL, Sly WS, et al. Glycogen Storage Diseases. New York, NY: McGraw-Hill; 2001:1521-51.

  13. Coleman RA, Winter HS, Wolf B, et al. Glycogen storage disease type III (glycogen debranching enzyme deficiency): correlation of biochemical defects with myopathy and cardiomyopathy. Ann Intern Med. 116(11):896-900. [Medline].

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

  15. Gregory BL, Shelton GD, Bali DS, Chen YT, Fyfe JC. Glycogen storage disease type IIIa in curly-coated retrievers. J Vet Intern Med. Jan-Feb 2007;21(1):40-6. [Medline].

  16. Gremse DA, Bucuvalas JC, Balistreri WF. Efficacy of cornstarch therapy in type III glycogen-storage disease. Am J Clin Nutr. Oct 1990;52(4):671-4. [Medline].

  17. Levin S, Moses SW, Chayoth R, et al. Glycogen storage disease in Israel. A clinical, biochemical and genetic study. Isr J Med Sci. May-Jun 1967;3(3):397-410. [Medline].

  18. 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. 102(3):507-15. [Medline].

  19. Shaiu WL, Kishnani PS, Shen J, et al. Genotype-phenotype correlation in two frequent mutations and mutation update in type III glycogen storage disease. Mol Genet Metab. 69(1):16-23. [Medline].

  20. Smit GP, Fernandes J, Leonard JV, et al. The long-term outcome of patients with glycogen storage diseases. J Inherit Metab Dis. 13(4):411-8. [Medline].

  21. Stevens AN, Iles RA, Morris PG, Griffiths JR. Detection of glycogen in a glycogen storage disease by 13C nuclear magnetic resonance. FEBS Lett. 150(2):489-93. [Medline].

  22. Vincentiis S, Valente KD, Valente M. Polymicrogyria in glycogenosis type III: an incidental finding?. Pediatr Neurol. Aug 2004;31(2):143-5. [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].

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Further Reading

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Keywords

Cori disease, GSD type III, Illingworth-Cori-Forbes disease, amylo-1,6-glucosidase debrancher deficiency, glycogenosis III, debranching enzyme deficiency, limit dextrinosis, GSD type 0, glycogen synthase deficiency, GSD type Ia, glucose-6-phosphatase deficiency, G-6-P deficiency, von Gierke disease, GSD type II, acid maltase deficiency, Pompe disease, Forbes-Cori disease, GSD type IV, transglucosidase deficiency, Andersen disease, amylopectinosis, GSD type V, myophosphorylase deficiency, McArdle disease, GSD type VI, phosphorylase deficiency, Hers disease, GSD type VII, phosphofructokinase deficiency, Tarui disease

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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
Wayne E Anderson, DO is a member of the following medical societies: American Academy of Neurology, American Academy of Pain Medicine, American Medical Association, American Society of Law Medicine and Ethics, California Medical Association, and San Francisco Medical Society
Disclosure: Cephalon Honoraria Speaking and teaching; Janssen Honoraria Speaking and teaching; Ligand Honoraria Consulting; Alpharma Honoraria Speaking and teaching

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: Nothing to disclose.

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, MD, Head, Vascular Division, Baker Medical Research Institute; Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, Director of General Internal Medicine, St Louis University
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, and Endocrine Society
Disclosure: Nothing to disclose.

 
 
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