Genetics of Glycogen-Storage Disease Type III Workup

  • Author: David H Tegay, DO, FACMG; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Mar 13, 2012
 

Laboratory Studies

Initial laboratory workup should include serial measurements of blood glucose levels, correlated with the time of the last feeding. Because the entire pathway of gluconeogenesis is intact in patients with glycogen-storage disease (GSD) type III (GSD III), they can usually maintain their blood glucose concentrations at acceptable values for several hours after a meal. Even a moderately prolonged fasting study is inadvisable because blood glucose values may fall precipitously and without warning.

A complete panel of liver function studies, including prothrombin levels, is essential. Transaminases levels, which are routinely higher in infants and children, usually fall during pubescence and often return to reference range values. Alterations in prothrombin levels occur only in patients with significant fibrosis and/or cirrhosis.

Obtain a lipid profile. Modest elevations in very low-density lipoprotein cholesterol and triglyceride levels sometimes occur.[19]

Evaluate blood and urine for ketones, especially after a brief fast. Fasting ketosis is prominent.[20]

Obtain blood lactate levels after a brief fast. These levels are occasionally elevated, although rarely to more than a moderate extent.

Blood uric acid levels should also be obtained after a brief fast. These levels, too, are occasionally elevated, although rarely to more than a moderate extent.

Always obtain serum creatine kinase levels, even in infants and children, but remember that patients with GSD IIIb have no muscle involvement so their creatine kinase levels are within reference ranges. Because significant muscle involvement does not usually begin until the second or third decade of life, even in patients with GSD IIIa, reference range creatine kinase levels do not exclude debrancher activity deficiency in muscles. However, most patients with GSD IIIa have significantly elevated creatine kinase levels. No correlation is noted between the levels of serum creatine kinase and the extent of the myopathy.

To confirm GSD III, laboratory test results must demonstrate abnormal glycogen (ie, short outer branches) and a debrancher enzyme activity deficiency in liver and muscle tissues. Normal debrancher activity in muscle precludes a diagnosis of GSD IIIa or IIId.

An alternative method measures debrancher activity—and even the absolute quantity of enzyme protein—in skin fibroblasts or lymphocytes. This method, however, has not been as reliable as measuring debrancher activity in liver and muscle tissues.

Molecular analysis of the AGL gene using DNA isolated from peripheral blood is now clinically available in numerous laboratories and is diagnostic when mutations are detected. Direct genotype-phenotype correlations are still typically lacking.[21, 22]

Next

Imaging Studies

Abdominal ultrasonographic examinations can provide reliable estimates of the liver's size, an important assessment because patients' livers usually become smaller with aging. Abdominal ultrasonography also helps monitor the liver to detect adenomas and hepatocellular carcinomas.[23]

Perform a pelvic ultrasonographic examination of female patients to detect polycystic ovaries. These are common in all forms of GSD III, yet, remarkably, they do not seem to interfere with patients' fertility.

Perform abdominal CT scanning of patients who develop cirrhosis because scans may provide early detection of hepatocellular carcinoma.

Previous
Next

Other Tests

Electromyography is essential for early detection of myopathic changes. The technique also permits monitoring the rate of progression of myopathy. Nerve conduction studies also help evaluate patients for possible myopathic changes.

Glucagon administration 2 hours after a meal rich in carbohydrates usually induces a normal rise of blood glucose levels. Administering the same glucagon dose after a 6-hour to 8-hour fast rarely affects blood glucose levels. Administration of glucagon to patients with GSD III is entirely safe because the hormone does not induce the occasionally dangerous rises in blood lactate that may occur when patients with GSD I receive the drug.

Oral administration of galactose or fructose (1.75 g/kg) usually induces a normal rise in blood glucose levels. No elevation in blood lactate levels occurs as a result of these carbohydrate challenges in patients with GSD III, while levels almost invariably rise in patients with GSD I.

Although GSD I and GSD III may be almost indistinguishable during infancy and childhood, challenge tests involving glucagon, galactose, or fructose administration are not recommended to differentiate between these conditions because these tests may cause sudden, marked, and potentially dangerous lactic acid elevations.

Previous
Next

Histologic Findings

Accumulated glycogen in the livers of patients with GSD III causes extensive distention of hepatocytes. Fat rarely accumulates in their livers, a finding that distinguishes the histologic appearance of the liver in GSD III from the appearance in GSD I.

In addition, fibrous septa usually form in the livers of patients with GSD III but not in the livers of patients with GSD I. The extent of fibrosis ranges from minimal periportal fibrosis, to bridging fibrosis, to micronodular cirrhosis.[24] This fibrosis is not progressive in most patients, although it occasionally progresses to severe cirrhosis, a condition apparently most common in Japanese patients.

Hepatic adenomas are frequent, with a possible prevalence as high as 25% in French patients. While malignant transformation of the adenomas is unreported, 2 patients with end-stage cirrhosis developed hepatocellular carcinomas.

No extensive descriptions of histopathologic findings in skeletal and cardiac muscle are available, probably because myopathy or cardiomyopathy diagnoses are usually based on findings from electromyography, nerve conduction studies, electrocardiography, and echocardiography rather than histologic studies. The histopathologic findings consist of vacuoles within the myocytes. Vacuolization extent varies and does not correlate with myopathy extent. The vacuoles are periodic acid-Schiff positive, consistent with the limit dextrin produced by the action of phosphorylase on glycogen in the absence of debrancher.

Previous
Proceed to Treatment & Management
 
 
Contributor Information and Disclosures
Author

David H Tegay, DO, FACMG  Associate Professor of Medicine and Medical Genetics, New York College of Osteopathic Medicine at the New York Institute of Technology; Assistant Professor of Pediatrics, Stony Brook University Medical Center

David H Tegay, DO, FACMG is a member of the following medical societies: American College of Medical Genetics, American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Osteopathic Association, American Society of Human Genetics, and Federation of American Societies for Experimental Biology

Disclosure: Nothing to disclose.

Coauthor(s)

Riya Jose  Medicine Department Academic Fellow, New York College of Osteopathic Medicine of the New York Institute of Technology

Disclosure: Nothing to disclose.

Specialty Editor Board

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, American Society of Gene Therapy, American Society of Human Genetics, Child Neurology Society, and Society for Inherited Metabolic Disorders

Disclosure: Genzyme Corporation Salary Management position

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.

Hagop Youssoufian, MD, MSc  Vice President of Clinical Research, ImClone Systems Incorporated

Hagop Youssoufian, MD, MSc is a member of the following medical societies: American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, and American Society of Human Genetics

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Howard R Sloan, MD, PhD to the development and writing of this article.

References

  1. Chen YT. A novel point mutation in an acceptor splice site of intron 32 (IVS32 A-12®G) but no exon 3 mutations in the glycogen debranching enzyme gene in a homozygous patient with glycogen storage disease type IIIb. Hum Genet. Jan 1999;104(1):111-2. [Medline].

  2. Chen YT. The Metabolic and Molecular Bases of Inherited Disease. Vol 1. New York, NY: McGraw Hill; 2001:1521-51.

  3. Forbes G. Glycogen Storage Disease. Report of a case with abnormal glycogen structure in liver and skeletal muscle. J Pediatr. 1953;42:645-52.

  4. Illingworth B, Cori G. Structure of glycogens and amylopectins, III. Normal and abnormal human glycogen. J Biol Chem. 1952;199:653-9.

  5. Illingworth B, Cori G, Cori C. Amylo-1,6-glucosidase in muscle tissue in generalized glycogen storage disease. J Biol Chem. 1956;218:123-30.

  6. Snappes I, Van Creveld S. Un cas d'hypoglycemie avec acetonemie chez un enfant. Bull Mem Soc Med Hop (Paris). 1928;52:1315-7.

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

  8. Coleman RA, Winter HS, Wolf B, Chen YT. Glycogen debranching enzyme deficiency: long-term study of serum enzyme activities and clinical features. J Inherit Metab Dis. 1992;15(6):869-81. [Medline].

  9. Labrune P, Trioche P, Duvaltier I, et al. Hepatocellular adenomas in glycogen storage disease type I and III: a series of 43 patients and review of the literature. J Pediatr Gastroenterol Nutr. Mar 1997;24(3):276-9. [Medline].

  10. Shen J, Bao Y, Liu HM, et al. Mutations in exon 3 of the glycogen debranching enzyme gene are associated with glycogen storage disease type III that is differentially expressed in liver and muscle. J Clin Invest. Jul 15 1996;98(2):352-7. [Medline].

  11. Shin YS. Glycogen storage disease: clinical, biochemical, and molecular heterogeneity. Semin Pediatr Neurol. Jun 2006;13(2):115-20. [Medline].

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

  13. Santer R, Kinner M, Steuerwald U, et al. Molecular genetic basis and prevalence of glycogen storage disease type IIIA in the Faroe Islands. Eur J Hum Genet. May 2001;9(5):388-91. [Medline].

  14. Parvari R, Moses S, Shen J, Hershkovitz E, Lerner A, Chen YT. A single-base deletion in the 3'-coding region of glycogen-debranching enzyme is prevalent in glycogen storage disease type IIIA in a population of North African Jewish patients. Eur J Hum Genet. Sep-Oct 1997;5(5):266-70. [Medline].

  15. Lee PJ, Deanfield JE, Burch M, et al. Comparison of the functional significance of left ventricular hypertrophy in hypertrophic cardiomyopathy and glycogenosis type III. Am J Cardiol. Mar 15 1997;79(6):834-8. [Medline].

  16. Cleary MA, Walter JH, Kerr BA, Wraith JE. Facial appearance in glycogen storage disease type III. Clin Dysmorphol. Apr 2002;11(2):117-20. [Medline].

  17. Hadjigeorgiou GM, Comi GP, Bordoni A, et al. Novel donor splice site mutations of AGL gene in glycogen storage disease type IIIa. J Inherit Metab Dis. Aug 1999;22(6):762-3. [Medline].

  18. DiMauro S, Hartwig GB, Hays A, et al. Debrancher deficiency: neuromuscular disorder in 5 adults. Ann Neurol. May 1979;5(5):422-36. [Medline].

  19. Bernier AV, Sentner CP, Correia CE, et al. Hyperlipidemia in glycogen storage disease type III: effect of age and metabolic control. J Inherit Metab Dis. Dec 2008;31(6):729-32. [Medline].

  20. Manwaring V, Prunty H, Bainbridge K, Burke D, Finnegan N, Franses R, et al. Urine analysis of glucose tetrasaccharide by HPLC; a useful marker for the investigation of patients with Pompe and other glycogen storage diseases. J Inherit Metab Dis. Mar 2012;35(2):311-6. [Medline].

  21. Lucchiari S, Pagliarani S, Salani S, et al. Hepatic and neuromuscular forms of glycogenosis type III: nine mutations in AGL. Hum Mutat. Jun 2006;27(6):600-1. [Medline].

  22. Schüller A, Wenninger S, Strigl-Pill N, Schoser B. Toward deconstructing the phenotype of late-onset Pompe disease. Am J Med Genet C Semin Med Genet. Feb 15 2012;160(1):80-8. [Medline].

  23. Lee P, Mather S, Owens C, et al. Hepatic ultrasound findings in the glycogen storage diseases. Br J Radiol. Nov 1994;67(803):1062-6. [Medline].

  24. Markowitz AJ, Chen YT, Muenzer J, et al. A man with type III glycogenosis associated with cirrhosis and portal hypertension. Gastroenterology. Dec 1993;105(6):1882-5. [Medline].

  25. 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].

  26. Haagsma EB, Smit GP, Niezen-Koning KE, et al. Type IIIb glycogen storage disease associated with end-stage cirrhosis and hepatocellular carcinoma. The Liver Transplant Group. Hepatology. Mar 1997;25(3):537-40. [Medline].

  27. Iyer SG, Chen CL, Wang CC, et al. Long-term results of living donor liver transplantation for glycogen storage disorders in children. Liver Transpl. Jun 2007;13(6):848-52. [Medline].

  28. Matern D, Starzl TE, Arnaout W, et al. Liver transplantation for glycogen storage disease types I, III, and IV. Eur J Pediatr. Dec 1999;158 Suppl 2:S43-8. [Medline].

  29. Shen J, Liu HM, McConkie-Rosell A, Chen YT. Prenatal diagnosis and carrier detection for glycogen storage disease type III using polymorphic DNA markers. Prenat Diagn. Jan 1998;18(1):61-4. [Medline].

  30. Yang BZ, Ding JH, Brown BI, Chen YT. Definitive prenatal diagnosis for type III glycogen storage disease. Am J Hum Genet. Oct 1990;47(4):735-9. [Medline].

  31. Bhuiyan J, Al Odaib AN, Ozand PT. A simple, rapid test for the differential diagnosis of glycogen storage disease type 3. Clin Chim Acta. Sep 2003;335(1-2):21-6. [Medline].

  32. Okuda S, Kanda F, Takahashi K, et al. Fatal liver cirrhosis and esophageal variceal hemorrhage in a patient with type IIIa glycogen storage disease. Intern Med. Dec 1998;37(12):1055-7. [Medline].

  33. 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. Jan 2000;69(1):16-23. [Medline].

  34. Shen JJ, Chen YT. Molecular characterization of glycogen storage disease type III. Curr Mol Med. Mar 2002;2(2):167-75. [Medline].

  35. Siciliano M, De Candia E, Ballarin S, et al. Hepatocellular carcinoma complicating liver cirrhosis in type IIIa glycogen storage disease. J Clin Gastroenterol. Jul 2000;31(1):80-2. [Medline].

  36. Van Creveld S. Chronische hepatogene Hypoglykamie im Kindesalter. Z Kindern. 1932;52:299.

  37. Van Creveld S, Huijing F. Differential diagnosis of the type of glycogen disease in two adult patients with long history of glycogenosis. Metabolism. 1964;13:191-8.

  38. Wolfsdorf JI, Crigler JF Jr. Effect of continuous glucose therapy begun in infancy on the long-term clinical course of patients with type I glycogen storage disease. J Pediatr Gastroenterol Nutr. Aug 1999;29(2):136-43. [Medline].

 
Previous
Next
 
Schematic illustration of the degradation of glycogen by the concerted action of the enzymes phosphorylase and debranching enzyme. First, phosphorylase removes glucose moieties (linked to their neighbors via alpha1,4 glucosidic bonds and depicted as the 7 black circles) from the unbranched outer portions of the glycogen molecule until only 4 glucosyl units (depicted as the 3 green circles and the 1 red circle) remain before an alpha1,6 branch point. The transferase component of debranching enzyme then transfers the 3 (green) glucose residues from the short branch to the end of an adjacent branch of the glycogen molecule. The glucosidase component of debranching enzyme then removes the glucose moiety (depicted as the red circle) remaining at the alpha1,6 branch point. In the process, the branch point formed by the alpha1,6 glucosidic bond is removed, hence the name debrancher.Unlike phosphorylase, which removes glucose moieties from glycogen in the form of glucose-1-phosphate, debrancher releases 1 free glucose moiety from each branch point. After the cleavage of the branch site, phosphorylase attacks unbranched portions of the glycogen molecule until the enzyme is stymied by the appearance of another branch point, at which point debranching enzyme once again is called into play. Eventually, large portions of the glycogen molecule are degraded to free glucose by the action of the amylo-alpha1,6-glucosidase activity of debranching enzyme and to glucose-1-phosphate by the action of phosphorylase.
Schematic representation of a portion of a molecule of glycogen. Open circles represent the glucose moieties connected to each other via alpha1,4 linkages. Solid circles represent the glucose moieties connected to their neighbors via alpha1,6 linkages. Thus, each solid circle represents a branch point in the molecule.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.