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Genetics of Glycogen-Storage Disease Type IV Workup

  • Author: Lynne Ierardi-Curto, MD, PhD; Chief Editor: Maria Descartes, MD  more...
 
Updated: Jan 08, 2016
 

Laboratory Studies

In patients suspected to have the classic form of glycogen-storage disease type IV (GSD IV), perform laboratory evaluations to assess the degree of liver dysfunction. Patients may exhibit all, some, or none of the associated biochemical abnormalities, depending on the degree of liver dysfunction and counter-regulatory processes.

In general, prolonged prothrombin time (PT) and decreased plasma albumin levels correlate with the degree of hepatic cirrhosis. Increased plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase (GGT) correlate with the degree of hepatocellular insufficiency. Patients with primary muscle, nervous system, or cardiac involvement and minimal or no liver dysfunction may demonstrate laboratory values within reference ranges.

CBC count: Normochromic anemia or normocytic anemia usually results from chronic blood loss due to coagulopathy, folate deficiency, and hemolysis. Morphologically abnormal erythrocytes on peripheral blood smear findings result from decreased splenic function. Thrombocytopenia and leukopenia result from splenic sequestration.

PT, activated partial thromboplastin time, and fibrinogen: Liver disease causes decreased synthesis of vitamin K–dependent coagulation factors and fibrinogen, inadequate absorption of vitamin K, and thrombocytopenia; therefore, progressive liver failure leads to prolonged PT and prolonged activated partial thromboplastin time (aPTT), decreased fibrinogen levels with progressive coagulopathy, and risk of disseminated intravascular coagulation.

ALT and AST: Measurement of liver enzyme levels usually reveals progressive elevation consistent with hepatocellular damage and release of enzymes into the blood.

Total and indirect (conjugated) bilirubin: In the early stages of liver dysfunction, conjugated bilirubin levels rise because the liver can conjugate this fluid but cannot adequately excrete it. In patients with progressive liver failure, both conjugated and unconjugated bilirubin levels rise.

Serum alkaline phosphatase, GGT, and 5' nucleotidase: Levels of these hepatocellular enzymes may be normal or slightly elevated and may vary with the degree of hepatic bile secretory function.

Serum albumin: Hypoalbuminemia is a result of decreased hepatic synthetic function but also depends on dietary protein intake and on fluid and electrolyte dynamics.

Electrolytes: Associated renal dysfunction causes electrolyte imbalance with hyponatremia, hypokalemia, and decreased serum calcium and magnesium levels.

BUN: BUN levels are abnormally low despite associated renal dysfunction, secondary to impaired hepatic synthetic function.

Creatinine: Creatinine levels are usually within the reference range.

Serum creatine kinase: Serum creatine kinase levels are within the reference ranges, even in patients with severe hypotonia.

Blood glucose: Hypoglycemia may result from severe hepatocellular damage and from glycogenolysis and gluconeogenesis that are inadequate to maintain serum glucose.

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Imaging Studies

Abdominal Doppler ultrasonography may reveal the presence of portal hypertension, esophageal varices, and liver echogenicity. Ultrasonography may also reveal portal vein diameter and blood flow directionality.

Abdominal MRI or CT scanning may reveal evidence of cirrhotic changes in liver parenchyma and the vascular system. Liver and spleen volume quantitation may be performed.

Characteristic features on liver-spleen scintigraphy using technetium-99m sulfur colloid include decreased uptake in the liver with an irregular pattern and increased uptake in the spleen and bone marrow.

MRI of the head may reveal leukoencephaly and cortical atrophy in patients with adult polyglucosan body disease (APBD) and CNS involvement. MRI typically demonstrates medullary and spinal atrophy, mild thinning of corpus callosum, and symmetric periventricular white matter changes with occipital predominance.[5]

Proton MR spectroscopy of the head may reveal changes consistent with white matter degeneration.[8]

Echocardiography may reveal evidence of dilated cardiomyopathy and impaired myocardial function.

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Other Tests

Definitive biochemical diagnosis of glycogen-storage disease type IV relies on demonstration of deficient glycogen-branching enzyme activity in the liver or in the muscle tissue.

Because glycogen-storage disease type IV is a multisystem disorder, evidence of abnormal glycogen content can be demonstrated in many tissues and cells, including the liver, leukocytes, erythrocytes, and cultured skin fibroblasts. The sole exception is APBD in Ashkenazi Jewish patients whose deficient glycogen-branching enzyme activity may be demonstrated only in leukocytes and nerve cells.

Patients demonstrate approximately 1-10% of the glycogen-branching enzyme activity found in persons without glycogen-storage disease. Heterozygotes may be identified based on an intermediate reduction in glycogen-branching enzyme activity.

The demonstration of homozygous or compound heterozygous mutations in the GBE1 gene by sequence analysis is considered definitive molecular diagnosis of glycogen-storage disease type IV. Targeted mutation analysis may be considered in Ashkenazi Jewish patients with suspected APBD and when a familial mutation has been previously identified.

Prenatal testing is based on the levels of glycogen-branching enzyme activity in cultured amniocytes and chorionic villi. Histological evaluation of placental biopsy samples for the presence of polyglucosan bodies may provide another method of prenatal diagnosis.[9] Molecular diagnosis may be performed if the parental GBE1 mutations have been identified.

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Procedures

Definitive biochemical diagnosis of glycogen-storage disease type IV may require obtaining a biopsy of the liver or other affected organs (eg, muscle, nerve, heart) for microscopic examination and enzyme assay.

Esophagogastroduodenoscopy is the definitive procedure to document the presence and position of esophageal varices.

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Histologic Findings

Characteristic microscopic findings in liver sections include a distorted architecture with diffuse interstitial fibrosis and wide fibrous septa surrounding micronodular areas of parenchyma. Hepatocytes are typically enlarged 2-fold to 3-fold, with faintly stained basophilic inclusions within their cytoplasm.

Liver section from a patient with glycogen-storage Liver section from a patient with glycogen-storage disease type IV (GSD IV) stained with hematoxylin and eosin. Characteristic findings include distorted hepatic architecture with diffuse interstitial fibrosis and wide fibrous septa surrounding micronodular areas of parenchyma. Hepatocytes are typically enlarged 2-fold to 3-fold, with faintly stained basophilic cytoplasmic inclusions.

Histological analysis of the liver and other affected tissues demonstrates periodic acid-Schiff (PAS)–positive, diastase-resistant, coarsely clumped material consistent with abnormal glycogen. Iodine staining forms a characteristic complex with a distinctive blue color. Electron microscopic examination of affected tissues reveals normal alpha- and beta-glycogen particles in addition to fibrillary aggregates typical of amylopectin. In many reports, the cytoplasm of affected cells contains many of these abnormal aggregates, termed polyglucosan bodies. Histological analysis of muscle fibers from affected patients demonstrates severe depletion of myofibrils.[1]

Liver section from a patient with glycogen-storage Liver section from a patient with glycogen-storage disease type IV (GSD IV) stained with periodic acid-Schiff (PAS) after diastase treatment. Coarsely clumped material cytoplasmic material representing the accumulated abnormal glycogen is resistant to diastase treatment and is readily stained with PAS.
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Contributor Information and Disclosures
Author

Lynne Ierardi-Curto, MD, PhD Attending Physician, Division of Metabolism, Children's Hospital of Philadelphia

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Edward Kaye, MD Vice President of Clinical Research, Genzyme Corporation

Edward Kaye, MD is a member of the following medical societies: American Academy of Neurology, Society for Inherited Metabolic Disorders, American Society of Gene and Cell Therapy, American Society of Human Genetics, Child Neurology Society

Disclosure: Received salary from Genzyme Corporation for management position.

References
  1. Nolte KW, Janecke AR, Vorgerd M, Weis J, Schroder JM. Congenital type IV glycogenosis: the spectrum of pleomorphic polyglucosan bodies in muscle, nerve, and spinal cord with two novel mutations in the GBE1 gene. Acta Neuropathol. 2008 Nov. 116(5):491-506. [Medline].

  2. Akman HO, Sampayo JN, Ross FA, et al. Fatal infantile cardiac glycogenosis with phosphorylase kinase deficiency and a mutation in the gamma2-subunit of AMP-activated protein kinase. Pediatr Res. 2007 Oct. 62(4):499-504. [Medline].

  3. Ravenscroft G, Thompson EM, Todd EJ, et al. Whole exome sequencing in foetal akinesia expands the genotype-phenotype spectrum of GBE1 glycogen storage disease mutations. Neuromuscul Disord. 2013 Feb. 23(2):165-9. [Medline].

  4. Raju GP, Li HC, Bali DS, et al. A case of congenital glycogen storage disease type IV with a novel GBE1 mutation. J Child Neurol. 2008 Mar. 23(3):349-52. [Medline].

  5. Mochel F, Schiffmann R, Steenweg ME, et al. Adult polyglucosan body disease: Natural History and Key Magnetic Resonance Imaging Findings. Ann Neurol. 2012 Sep. 72(3):433-41. [Medline].

  6. Magoulas PL, El-Hattab AW, Roy A, Bali DS, Finegold MJ, Craigen WJ. Diffuse reticuloendothelial system involvement in type IV glycogen storage disease with a novel GBE1 mutation: a case report and review. Hum Pathol. 2012 Jun. 43(6):943-51. [Medline].

  7. Li SC, Hwu WL, Lin JL, et al. Association of the congenital neuromuscular form of glycogen storage disease type IV with a large deletion and recurrent frameshift mutation. J Child Neurol. 2012 Feb. 27(2):204-8. [Medline].

  8. Escobar LF, Wagner S, Tucker M, Wareham J. Neonatal presentation of lethal neuromuscular glycogen storage disease type IV. J Perinatol. 2012 Oct. 32(10):810-3. [Medline].

  9. Konstantinidou AE, Anninos H, Dertinger S, et al. Placental involvement in glycogen storage disease type IV. Placenta. 2008 Apr. 29(4):378-81. [Medline].

  10. Sokal EM, Van Hoof F, Alberti D, de Ville de Goyet J, de Barsy T, Otte JB. Progressive cardiac failure following orthotopic liver transplantation for type IV glycogenosis. Eur J Pediatr. 1992 Mar. 151(3):200-3. [Medline].

  11. Starzl TE, Demetris AJ, Trucco M, et al. Chimerism after liver transplantation for type IV glycogen storage disease and type 1 Gaucher's disease. N Engl J Med. 1993 Mar 18. 328(11):745-9. [Medline]. [Full Text].

  12. Romano F, Stroppa P, Bravi M, et al. Favorable outcome of primary liver transplantation in children with cirrhosis and hepatocellular carcinoma. Pediatr Transplant. 2011 Sep. 15(6):573-9. [Medline].

  13. Murray KF, Carithers RL Jr. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology. 2005 Jun. 41(6):1407-32. [Medline].

  14. Escobar LF, Wagner S, Tucker M, Wareham J. Neonatal presentation of lethal neuromuscular glycogen storage disease type IV. J Perinatol. 2012 Oct. 32(10):810-3. [Medline].

  15. Akman HO, Karadimas C, Gyftodimou Y, et al. Prenatal diagnosis of glycogen storage disease type IV. Prenat Diagn. 2006 Oct. 26(10):951-5. [Medline].

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

  17. Brown BI, Brown DH. Branching enzyme activity of cultured amniocytes and chorionic villi: prenatal testing for type IV glycogen storage disease. Am J Hum Genet. 1989 Mar. 44(3):378-81. [Medline]. [Full Text].

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

  19. Burrow TA, Hopkin RJ, Bove KE, et al. Non-lethal congenital hypotonia due to glycogen storage disease type IV. Am J Med Genet A. 2006 Apr 15. 140(8):878-82. [Medline].

  20. Giuffre B, Parini 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].

  21. L'hermine-Coulomb A, Beuzen F, Bouvier R, et al. Fetal type IV glycogen storage disease: clinical, enzymatic, and genetic data of a pure muscular form with variable and early antenatal manifestations in the same family. Am J Med Genet A. 2005 Dec 1. 139A(2):118-22. [Medline].

  22. Lossos A, Meiner Z, Barash V, et al. Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329Ser mutation in the glycogen-branching enzyme gene. Ann Neurol. 1998 Dec. 44(6):867-72. [Medline].

  23. Massa R, Bruno C, Martorana A, de Stefano N, van Diggelen OP, Federico A. Adult polyglucosan body disease: proton magnetic resonance spectroscopy of the brain and novel mutation in the GBE1 gene. Muscle Nerve. 2008 Apr. 37(4):530-6. [Medline].

  24. McConkie-Rosell A, Wilson C, Piccoli DA, et al. Clinical and laboratory findings in four patients with the non-progressive hepatic form of type IV glycogen storage disease. J Inherit Metab Dis. 1996. 19(1):51-8. [Medline].

  25. Nambu M, Kawabe K, Fukuda T, et al. A neonatal form of glycogen storage disease type IV. Neurology. 2003 Aug 12. 61(3):392-4. [Medline].

  26. Nase S, Kunze KP, Sigmund M, Schroeder JM, Shin Y, Hanrath P. A new variant of type IV glycogenosis with primary cardiac manifestation and complete branching enzyme deficiency. In vivo detection by heart muscle biopsy. Eur Heart J. 1995 Nov. 16(11):1698-704. [Medline].

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

  28. Servidei S, Riepe RE, Langston C, et al. Severe cardiopathy in branching enzyme deficiency. J Pediatr. 1987 Jul. 111(1):51-6. [Medline].

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

 
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Liver section from a patient with glycogen-storage disease type IV (GSD IV) stained with hematoxylin and eosin. Characteristic findings include distorted hepatic architecture with diffuse interstitial fibrosis and wide fibrous septa surrounding micronodular areas of parenchyma. Hepatocytes are typically enlarged 2-fold to 3-fold, with faintly stained basophilic cytoplasmic inclusions.
Liver section from a patient with glycogen-storage disease type IV (GSD IV) stained with periodic acid-Schiff (PAS) after diastase treatment. Coarsely clumped material cytoplasmic material representing the accumulated abnormal glycogen is resistant to diastase treatment and is readily stained with PAS.
 
 
 
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