Type Ia Glycogen Storage Disease

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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.[1]

The diagram below illustrates metabolic pathways of carbohydrates.



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Metabolic pathways of carbohydrates

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 [G-6-P] 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, also is 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 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, physical examination, muscle biopsy, electromyelography, ischemic forearm test, and creatine kinase levels. Biochemical assay for enzyme activity is the method of definitive diagnosis.

G-6-P deficiency is the specific enzyme deficiency in von Gierke disease. GSD type Ib is a similar condition with the defect in the G-6-P transporter protein. A newly described form, GSD type Ic, does not appear to be related to mutations within the transporter protein.

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. As noted above, G-6-P, which is found in the liver and kidney, is the specific enzyme that is deficient in von Gierke disease. Glucose-6-phosphate is an intermediate in the glycogen pathway.

Von Gierke disease is an autosomal-recessive condition. Von Gierke disease may be explained by mutations of the phosphohydrolase catalytic unit gene of the G-6-P complex, unlike GSD type Ib and GSD type Ic.

Deficiency of G-6-P blocks the final steps of glycogenolysis and gluconeogenesis.[2] This results in severe hypoglycemia. Glucose production increases with age, making hypoglycemia less of an issue.

Because glucose cannot leave the hepatocyte phosphorylated, an increase in glycolytic pathway metabolites occurs. These intermediates are metabolized into lactate. Lactate may provide the brain with a ready-to-use energy source. By competing with uric acid, lactate decreases renal clearance, resulting in hyperuricemia. Glucose also is shunted into making more triglycerides, causing an increase in low-density and very low-density lipoproteins.[3]

Epidemiology

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.

Mortality/Morbidity

Immediate morbidity arises from hypoglycemic seizures. Serious long-term complications resulting in morbidity and mortality include nephropathy and hepatic adenoma.[4]

Sex

GSDs are autosomal-recessive conditions, with an equal number of males and females being affected.

Age

In general, GSDs present in childhood. Later onset correlates with a less severe form.

History

See the list below:

Physical

See the list below:

Laboratory Studies

See the list below:

Imaging Studies

See the list below:

Other Tests

See the list below:

Histologic Findings

Biopsy of the kidney reveals focal glomerulosclerosis.

Medical Care

See the list below:

Surgical Care

Liver transplantation may be indicated for patients with hepatic malignancy. Whether transplantation prevents further complications remains unclear, although a study by Matern and colleagues demonstrated correction of metabolic abnormalities after transplantation.[13]

Consultations

See the list below:

Diet

See the list below:

Deterrence/Prevention

Early diet therapy may help prevent hepatic disease, including hepatocellular carcinoma.

Complications

See the list below:

Prognosis

See the list below:

Patient Education

See the list below:

Author

Wayne E Anderson, DO, FAHS, FAAN, Assistant Professor of Internal Medicine/Neurology, College of Osteopathic Medicine of the Pacific Western University of Health Sciences; Clinical Faculty in Family Medicine, Touro University College of Osteopathic Medicine; Clinical Instructor, Departments of Neurology and Pain Management, California Pacific Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Kent Wehmeier, MD, Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, St Louis University School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor Emeritus of Medicine, St Louis University School of Medicine

Disclosure: Nothing to disclose.

References

  1. Araoka T, Takeoka H, Abe H, Kishi S, Araki M, Nishioka K, et al. Early diagnosis and treatment may prevent the development of complications in an adult patient with glycogen storage disease type Ia. Intern Med. 2010. 49(16):1787-92. [View Abstract]
  2. Jones JG, Garcia P, Barosa C, et al. Hepatic anaplerotic outflow fluxes are redirected from gluconeogenesis to lactate synthesis in patients with Type 1a glycogen storage disease. Metab Eng. 2009 May. 11(3):155-62. [View Abstract]
  3. Bandsma RH, Prinsen BH, van Der Velden Mde S, et al. Increased de novo lipogenesis and delayed conversion of large VLDL into intermediate density lipoprotein particles contribute to hyperlipidemia in glycogen storage disease type 1a. Pediatr Res. 2008 Jun. 63(6):702-7. [View Abstract]
  4. Wang DQ, Fiske LM, Carreras CT, Weinstein DA. Natural history of hepatocellular adenoma formation in glycogen storage disease type I. J Pediatr. 2011 Sep. 159(3):442-6. [View Abstract]
  5. Schwahn B, Rauch F, Wendel U, Schönau E. Low bone mass in glycogen storage disease type 1 is associated with reduced muscle force and poor metabolic control. J Pediatr. 2002 Sep. 141(3):350-6. [View Abstract]
  6. Melis D, Rossi A, Pivonello R, Salerno M, Balivo F, Spadarella S, et al. Glycogen storage disease type Ia (GSDIa) but not Glycogen storage disease type Ib (GSDIb) is associated to an increased risk of metabolic syndrome: possible role of microsomal glucose 6-phosphate accumulation. Orphanet J Rare Dis. 2015 Jul 29. 10:91. [View Abstract]
  7. Kalkan Ucar S, Coker M, et al. A monocentric pilot study of an antioxidative defense and hsCRP in pediatric patients with glycogen storage disease type IA and III. Nutr Metab Cardiovasc Dis. 2009 Jul. 19(6):383-90. [View Abstract]
  8. Kishnani PS, Boney A, Chen YT. Nutritional deficiencies in a patient with glycogen storage disease type Ib. J Inherit Metab Dis. 1999 Oct. 22(7):795-801. [View Abstract]
  9. Nguyen AT, Bressenot A, Manole S, et al. Contrast-enhanced ultrasonography in patients with glycogen storage disease type Ia and adenomas. J Ultrasound Med. 2009 Apr. 28(4):497-505. [View Abstract]
  10. Seydewitz HH, Matern D. Molecular genetic analysis of 40 patients with glycogen storage disease type Ia: 100% mutation detection rate and 5 novel mutations. Hum Mutat (Online). 2000 Jan. 15(1):115-6. [View Abstract]
  11. Zingone A, Hiraiwa H, Pan CJ. Correction of glycogen storage disease type 1a in a mouse model by gene therapy. J Biol Chem. 2000 Jan 14. 275(2):828-32. [View Abstract]
  12. Bijvoet AG, Van Hirtum H, Vermey M. Pathological features of glycogen storage disease type II highlighted in the knockout mouse model. J Pathol. 1999 Nov. 189(3):416-24. [View Abstract]
  13. Matern D, Starzl TE, Arnaout W. Liver transplantation for glycogen storage disease types I, III, and IV. Eur J Pediatr. 1999 Dec. 158 Suppl 2:S43-8. [View Abstract]
  14. Amato AA. Acid maltase deficiency and related myopathies. Neurol Clin. 2000 Feb. 18(1):151-65. [View Abstract]
  15. Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics. 2000 Jan. 105(1):e10. [View Abstract]
  16. Chen Y. Glycogen Storage Diseases. 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.
  17. Fernandes J, Smit G. The Glycogen Storage Diseases. Fernandes J, Saudubray JM, Van Den Berghe G, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 3rd ed. New York, NY: Springer-Verlag; 2000. 87-101.
  18. Geberhiwot T, Alger S, McKiernan P, Packard C, Caslake M, Elias E. Serum lipid and lipoprotein profile of patients with glycogen storage disease types I, III and IX. J Inherit Metab Dis. 2007 Jun. 30(3):406. [View Abstract]
  19. Goldberg T, Slonim AE. Nutrition therapy for hepatic glycogen storage diseases. J Am Diet Assoc. 1993 Dec. 93(12):1423-30. [View Abstract]
  20. Hou DC, Kure S, Suzuki Y. Glycogen storage disease type Ib: structural and mutational analysis of the microsomal glucose-6-phosphate transporter gene. Am J Med Genet. 1999 Sep 17. 86(3):253-7. [View Abstract]
  21. Lin B, Hiraiwa H, Pan CJ. Type-1c glycogen storage disease is not caused by mutations in the glucose-6-phosphate transporter gene. Hum Genet. 1999 Nov. 105(5):515-7. [View Abstract]
  22. Moses SW. Historical highlights and unsolved problems in glycogen storage disease type 1. Eur J Pediatr. 2002 Oct. 161 Suppl 1:S2-9. [View Abstract]
  23. 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. 1998 Aug 1. 102(3):507-15. [View Abstract]
  24. Pears JS, Jung RT, Hopwood D. Glycogen storage disease diagnosed in adults. Q J Med. 1992 Mar. 82(299):207-22. [View Abstract]
  25. Reitsma-Bierens WC. Renal complications in glycogen storage disease type I. Eur J Pediatr. 1993. 152 Suppl 1:S60-2. [View Abstract]
  26. Salapata Y, Laskaris G, Drogari E. Oral manifestations in glycogen storage disease type 1b. J Oral Pathol Med. 1995 Mar. 24(3):136-9. [View Abstract]
  27. 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. [View Abstract]
  28. Stevens AN, Iles RA, Morris PG. Detection of glycogen in a glycogen storage disease by 13C nuclear magnetic resonance. FEBS Lett. 1982 Dec 27. 150(2):489-93. [View Abstract]
  29. Veiga-da-Cunha M, Gerin I, Chen YT. The putative glucose 6-phosphate translocase gene is mutated in essentially all cases of glycogen storage disease type I non-a. Eur J Hum Genet. 1999 Sep. 7(6):717-23. [View Abstract]
  30. Wolfsdorf JI, Holm IA, Weinstein DA. Glycogen storage diseases. Phenotypic, genetic, and biochemical characteristics, and therapy. Endocrinol Metab Clin North Am. 1999 Dec. 28(4):801-23. [View Abstract]
  31. Yang Chou J, Mansfield BC. Molecular Genetics of Type 1 Glycogen Storage Diseases. Trends Endocrinol Metab. 1999 Apr. 10(3):104-113. [View Abstract]

Metabolic pathways of carbohydrates

Metabolic pathways of carbohydrates