eMedicine Specialties > Endocrinology > Metabolic Disorders

Glycogen Storage Disease, Type IV

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

Branching enzyme defect results in an abnormal glycogen structure that is unique to Andersen disease (GSD type IV). Clinically, hepatosplenomegaly, cirrhosis of the liver, and hepatic failure are major concerns.

Pathophysiology

Transglucosidase, which is found in all tissues, is deficient. The condition is autosomal recessive. Due to abnormal glycogen, hepatic deposition may occur and result in severe cirrhosis, hepatic failure, or neuromuscular failure. It also can present as abnormal liver function tests in its mildest presentation.

Cardiac and skeletal muscle may show PAS+ eosinophilic cytoplasmic inclusions.

Bruno and colleagues and Janecke and colleagues have demonstrated at least 11 novel mutations of the branching enzyme gene resulting in GSD IV.1,2

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. GSD IV is very rare.

Mortality/Morbidity

Serious morbidities include hepatic failure, hepatosplenomegaly, and cardiomyopathy (less frequent).

Age

In general, GSDs present in childhood. Later onset correlates with a less severe form. Liver failure may occur in the first 5 years of life due to deposition of glycogen.

Clinical

History

  • History is not specific for Andersen disease. Patient complaints probably relate to end-organ injuries of Andersen disease, such as hepatic failure, cardiomyopathy, or muscular atrophy.
  • Sansone and colleagues report a distinct periodic paralysis of either hypokalemic or hyperkalemic type.3
  • Hypoglycemia is seen rarely.
  • Adults may present with central and peripheral nerve dysfunction.

Physical

Clinical findings of branching enzyme deficiency relate to liver disease and include hepatic failure, cirrhosis, hepatosplenomegaly, cardiomyopathy (less frequent), failure to thrive, and hypotonia (in some cases). Ventricular arrhythmia may occur.

More on Glycogen Storage Disease, Type IV

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

  1. Bruno C, van Diggelen OP, Cassandrini D, et al. Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV). Neurology. Sep 28 2004;63(6):1053-8. [Medline].

  2. Janecke AR, Dertinger S, Ketelsen UP, et al. Neonatal type IV glycogen storage disease associated with "null" mutations in glycogen branching enzyme 1. J Pediatr. Nov 2004;145(5):705-9. [Medline].

  3. Sansone V, Griggs RC, Meola G. Andersen''s syndrome: a distinct periodic paralysis. Ann Neurol. Sep 1997;42(3):305-12. [Medline].

  4. Shen J, Liu HM, McConkie-Rosell A. Prenatal diagnosis of glycogen storage disease type IV using PCR-based DNA mutation analysis. Prenat Diagn. Sep 1999;19(9):837-9. [Medline].

  5. Akman HO, Karadimas C, Gyftodimou Y, Grigoriadou M, Kokotas H, Konstantinidou A. Prenatal diagnosis of glycogen storage disease type IV. Prenat Diagn. Oct 2006;26(10):951-5. [Medline].

  6. 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].

  7. 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].

  8. Ewert R, Gulijew A, Wensel R. [Glycogenosis type IV as a seldom cause of cardiomyopathy - report about a successful heart transplantation]. Z Kardiol. Oct 1999;88(10):850-6. [Medline].

  9. 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].

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

  11. Aminoff MJ. Electromyography in Clinical Practice. 3rd ed. New York, NY: Churchill Livingstone; 1998.

  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. Bao Y, Kishnani P, Wu JY. Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene. J Clin Invest. Feb 15 1996;97(4):941-8. [Medline].

  14. Chan YJ, Lin SP, Chen BF. Glycogen storage disease type IV: a case report. Chung Hua I Hsueh Tsa Chih (Taipei). Oct 1999;62(10):743-7. [Medline].

  15. 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.

  16. Giuffre B, Parinii R, Rizzuti T, et al. Severe neonatal onset of glycogenosis type IV: clinical and laboratory findings leading to diagnosis in two siblings. J Inherit Metab Dis. 2004;27(5):609-19. [Medline].

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

  18. 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].

  19. Selby R, Starzl TE, Yunis E. Liver transplantation for type I and type IV glycogen storage disease. Eur J Pediatr. 1993;152 Suppl 1:S71-6. [Medline].

  20. Selby R, Starzl TE, Yunis E. Liver transplantation for type IV glycogen storage disease. N Engl J Med. Jan 3 1991;324(1):39-42. [Medline].

  21. 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].

  22. 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].

  23. Takahashi T, Tandai S, Toki T, et al. KCNJ2 mutation in intractable ventricular arrhythmia with Andersen's syndrome. Pediatr Int. Apr 2005;47(2):220-3. [Medline].

  24. 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

Andersen disease, glycogen storage disease type IV, GSD type IV, branching enzyme deficiency, amylopectinosis, Pompe disease, GSD type II, acid maltase deficiency, Cori disease, GSD type III, debranching enzyme deficiency, McArdle disease, GSD type V, myophosphorylase deficiency, Tarui disease, GSD type VII, phosphofructokinase deficiency, glycogen synthase deficiency

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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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