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Glycogen Storage Disease, Type IV: Differential Diagnoses & Workup

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

Differential Diagnoses

Glucagonoma
Glycogen Storage Disease, Type V
Glucose Intolerance
Glycogen Storage Disease, Type VI
Glucose-6-Phosphatase Deficiency
Glycogen Storage Disease, Type VII
Glucose-6-Phosphate Dehydrogenase Deficiency
Hepatic Carcinoma, Primary
Glycogen Storage Disease, Type Ia
Hepatic Failure
Glycogen Storage Disease, Type Ib
Hypoglycemia
Glycogen Storage Disease, Type II
Glycogen Storage Disease, Type III

Workup

Laboratory Studies

  • Obtain a creatine kinase level in all cases of suspected glycogen storage diseases (GSDs).
  • Because hypoglycemia may be found in some types of GSD, fasting glucose testing is indicated.
  • Urine studies are indicated because myoglobinuria may occur in some GSDs.
  • Hepatic failure occurs in some GSDs. Liver function studies are indicated and may reveal evidence of hepatic injury.
  • Biochemical assay of enzyme activity is necessary for definitive diagnosis. Glycogen structure is altered, with fewer branching points and longer peripheral chains. This abnormal glycogen structure is absent in other GSDs.
  • Shen and colleagues demonstrated that DNA mutation analysis by polymerase chain reaction is effective for prenatal diagnosis.4
  • Akman and colleagues demonstrated that prenatal diagnosis of GSD IV by DNA analysis is accurate in the genetically confirmed cases.5

Imaging Studies

  • Imaging may reveal hepatosplenomegaly.
  • Imaging also may reveal cardiomyopathy and heart failure.

Other Tests

  • Ischemic forearm test
    • The ischemic forearm test is an important tool for the 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.
    • A positive ischemic forearm test may occur in Cori disease, McArdle disease, and Tarui disease.
  • Electromyelography
    • Electromyelography patterns are diverse and vary from patient to patient.
    • Myopathic polyphasic responses are found, but amplitude and duration may be either decreased, as expected, or increased.
    • Spontaneous abnormal activity (fibrillation potential and positive sharp waves) may be found.
    • Myotonic discharges occur in some cases.
  • Electrocardiogram: A prolonged QT interval may be present.

Procedures

  • Liver biopsy may be needed to determine the cause of progressive liver dysfunction. Histologic findings are characteristic in the liver, with diffuse interstitial fibrosis, wide fibrous septa, and enlarged hepatocytes with periodic acid-Schiff positive inclusions. Electron microscopy shows alpha and beta glycogen particles.

Histologic Findings

Diffuse deposition of amylopectinlike materials in the heart, liver, muscle, spinal cord, and peripheral nerves may be present.

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.

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  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].

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  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].

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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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