eMedicine Specialties > Endocrinology > Metabolic Disorders

Glycogen Storage Disease, Type III

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

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)

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.

Differential Diagnoses

Workup

Laboratory Studies

• Because hypoglycemia may be found in some types of GSD, fasting glucose is indicated. Hypoglycemia is concerning and may lead to hypoglycemic seizures.
• Urine studies are indicated because myoglobinuria may occur in some cases of GSD.
• Hepatic failure occurs in some cases of GSD. Liver function studies are indicated.
• The presence of dextrin is unique to Cori disease.
• With a biochemical assay, debrancher enzyme activity is reduced or absent.
• Hyperlipidemia is a common finding.
• Fasting ketonemia is noted with the rapid metabolism of fatty acids.

Imaging Studies

• Imaging may reveal hepatomegaly.
• Cardiomegaly may be present, but heart failure is not typical of GSD II.

Other Tests

• Ischemic forearm test
  • The ischemic forearm test is an important tool for 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 in 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 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 µg/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 GSDs have a positive result on ischemic test.
  • Failure of ammonia to increase with lactate is evidence of myoadenylate deaminase deficiency.
  • In Cori disease, the ischemic forearm test result is positive.
• Electromyography
  • Electromyography patterns are diverse and vary from patient to patient.
  • The myopathic finding of polyphasic responses is found, but amplitude and duration may be either decreased, as expected, or increased in some cases.
  • Spontaneous abnormal activity (fibrillation potential and positive sharp waves) may be found.
  • Myotonic discharges are observed in some cases.

Histologic Findings

Muscle biopsy is periodic acid-Schiff positive with basophilic deposits in all tissues, including the CNS.

Treatment

Medical Care

• In general, no specific treatment exists for GSDs.
• In some cases, diet therapy is helpful. Meticulous adherence to a dietary regimen may reduce liver size, prevent hypoglycemia, allow for reduction in symptoms, and allow for growth and development.
• Zingone and colleagues demonstrated the abolition of the murine clinical manifestations of Von Gierke disease with a recombinant adenoviral vector.⁶ These findings suggest that corrective gene therapy for GSDs may be possible in humans.
• An encouraging study by Bijvoet and colleagues provides evidence of successful enzyme replacement for the mouse model of Pompe disease, which may lead to therapies for other enzyme deficiencies.⁷

Surgical Care

Liver transplantation may be indicated for patients with hepatic malignancy. Whether transplantation prevents further complications is not clear, although a study by Matern and colleagues demonstrated posttransplantation correction of metabolic abnormalities.⁸

Consultations

• Consultation with a neurologist with special training in muscle physiology may help in establishing the diagnosis.
• A consultation with a hepatologist-liver specialist may be helpful in the evaluation of liver abnormalities.

Diet

Cornstarch therapy may be beneficial in reducing hypoglycemia.

Follow-up

Complications

• Hepatocellular carcinoma
• Hepatic failure

Prognosis

• Unfortunately, severe hepatic failure with possible malignant transformation may be fatal. Matern and colleagues (1999) present evidence that hepatic transplant may be effective at arresting this condition.⁸

Miscellaneous

Medicolegal Pitfalls

• Because of the risk of hepatocellular carcinoma, lesions of the liver must be diagnosed and followed aggressively.
• Adequate treatment of hypoglycemia is essential. Diet may be supplemented with protein to serve as an alternative for the production of glucose.

Multimedia

Media file 1: Metabolic pathways of carbohydrates.

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].

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

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

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Barry J Goldstein, MD, PhD, Director, Division of Endocrinology, Diabetes and Metabolic Diseases, Professor, Department of Internal Medicine, Thomas Jefferson University
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