Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Genetics of Glycogen-Storage Disease Type II (Pompe Disease)

  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
 
Updated: Feb 29, 2016
 

Background

Glycogen-storage disease type II (GSD II), also known as Pompe disease, is part of a group of metabolic diseases called lysosomal storage disorders (LSDs). GSD II is an autosomal-recessive disorder that results from deficiency of acid alpha-glucosidase (also known as acid maltase), a lysosomal hydrolase. The cellular role of acid alpha-glucosidase is to convert glycogen into glucose within the lysosomes. The Danish pathologist Joannes Cassianus Pompe first described this disease in 1932 when he was presented with a 7-month-old girl who died after developing idiopathic hypertrophic cardiomyopathy. Pompe observed an abnormal accumulation of glycogen in all postmortem tissues examined and described the cardinal pathologic features of this lysosomal storage disorder.

Pompe disease (GSD II) has a broad clinical spectrum. Classification is based on age of onset, organ involvement, severity, and the rate of disease progression. Three major forms of GSD II are recognized: classic infantile-onset, non-classic variant of infantile-onset, and late-onset (includes childhood, juvenile, and adult-onset).

Classic infantile-onset Pompe disease may be apparent in utero, but more often presents within the first two months of life. In this form, cardiac, skeletal, and respiratory muscles are involved. Clinical hallmarks of classic infantile-onset Pompe disease include hypotonia, generalized muscle weakness, cardiomegaly, hypertrophic cardiomyopathy, feeding difficulties, failure to thrive, respiratory distress, and hearing loss. Classic infantile-onset GSD II is marked by a progressive and rapidly fatal course. Without enzyme replacement therapy (ERT), classic infantile-onset Pompe disease commonly results in death within the first year of life due to cardiac disease from progressive left ventricular (LV) outflow obstruction.

The non-classic variant of infantile-onset Pompe disease presents within the first year of life. Patients older than 6 months present with motor delays and/or slowly progressive muscle weakness. Death results from ventilatory failure in early childhood. In this form, cardiac disease is not found to be a major cause of morbidity; however, cardiomegaly may be seen.

Late-onset GSD II is characterized by proximal muscle weakness and respiratory compromise. Adults with late-onset GSD II typically present with proximal muscle weakness between the second and sixth decades of life. These individuals ultimately die of respiratory failure. Cardiac involvement is less likely among individuals with disease onset at an older age.[1, 2]

The photomicrographs below document liver findings in GSD II.

Glycogen-storage disease type II (Pompe disease). Glycogen-storage disease type II (Pompe disease). Photomicrograph of the liver. Note the intensively stained vacuoles in the hepatocytes (periodic acid-Schiff, original magnification X 27).
Glycogen-storage disease type II (Pompe disease). Glycogen-storage disease type II (Pompe disease). Photomicrograph of the liver. Note the regular reticular net and hepatocytes vacuolization (Gordon-Sweet stain, original magnification X 25).
Next

Pathophysiology

Acid alpha-glucosidase (also known as acid maltase) is a lysosomal hydrolase that is required for the degradation of a small percentage (1%-3%) of cellular glycogen. The main pathway for glycogen degradation is not deficient in GSD II; therefore, energy production is not impaired, and hypoglycemia does not occur. However, the deficiency of acid alpha-glucosidase activity does result in the accumulation of structurally normal glycogen in lysosomes and in the cytoplasm of affected individuals. Excessive glycogen storage within lysosomes interrupts normal functioning of other organelles and leads to cellular injury. In turn, this leads to enlargement and dysfunction of the entire organ involved (eg, cardiomyopathy).

In the classic infantile form of Pompe disease, clinically significant glycogen storage occurs in cardiac muscle. Over time, cardiomegaly with LV thickening occurs, eventually leading to outflow tract obstruction. Glycogen storage in skeletal muscle leads to hypotonia and weakness. The respiratory muscles are also affected, resulting in hypoventilation and progressive respiratory compromise. Central nervous system (CNS) involvement is primarily limited to the anterior horn cells of the spinal cord and brain stem nuclei. Despite CNS involvement, intellect remains normal. In non-classic variant infantile-onset Pompe disease, skeletal and respiratory involvement is common; the level of cardiac involvement varies. In cases of late-onset GSD II, significant cardiac involvement is not observed.

Previous
Next

Epidemiology

The combined incidence of all forms of Pompe disease (GSD II) varies depending on ethnicity and geographic region.

United States

The total incidence of Pompe disease (all variants of GSD II) is estimated at 1 per 40,000 population. This calculation is based on estimated gene frequencies in healthy individuals from various US ethnic groups. The highest incidence has been observed in the African American population, in which the combined incidence may be as high as 1 per 14,000 population.[3]

International

Among individuals of European descent, the incidence of infantile-onset Pompe disease is reported as 1 per 100,000 population and the incidence of late-onset Pompe disease is reported as 1 per 60,000 population.[4]

The combined incidence of Pompe disease in Taiwan and southern China is estimated at 1 per 50,000 population.[5]

The combined incidence of Pompe disease in the Netherlands is estimated at 1 per 40,000 population (1 per 138,000 population for infantile-onset, 1 per 57,000 population for late-onset [adult]).[6] A common GAA pathogenic variant among the Dutch people is c.525delT, which is found in 34% of cases.[7]

In Portugal, the combined incidence of Pompe disease is estimated at 1 per 600,000 population.[8]

In Australia, the combined incidence of Pompe disease is estimated at 1 per 145,000 population.[9]

Mortality/Morbidity

Classic infantile-onset GSD II is usually fatal during the first year of life. As weakness progresses, affected individuals develop feeding difficulties and respiratory insufficiency. Cardiac enlargement of the LV leads to outflow tract obstruction and ventricular failure. Death results from cardiopulmonary failure. Non-classic infantile-onset Pompe disease presents later, within the first year of life, with clinical findings of motor delays and progressive muscle weakness. Death due to ventilatory failure occurs in early childhood.

Late-onset Pompe disease (childhood and juvenile) progresses more slowly and is uniformly fatal. Affected individuals generally do not survive beyond the second or third decade of life. All affected individuals have involvement of pulmonary system, and most die of respiratory failure. Several patients with this form are reported to have died of basilar artery aneurysm;[10] all were found to have abnormal glycogen storage within the lysosomes of arterial smooth muscle fibers.

Patients with late-onset (adult) Pompe disease may survive for decades following diagnosis. Muscle weakness may interfere with normal daily activities, and respiratory insufficiency is often associated with sleep apnea. Death usually results from respiratory failure.

Race

Common mutations within the GAA gene associated with the infantile-onset forms of Pompe disease have been discovered in Taiwanese, Dutch, and African-American populations. A common mutation associated with the late-onset form has been found in whites.

Sex

GSD II has no sexual predilection.

GSD II is inherited as an autosomal recessive disorder with the gene locus at 17q25.3; hence, the inheritance of this disease is not related to the sex chromosomes.

Age

Age of onset helps distinguish the current three defined age-onset categories of GSD II. The classic and non-classic infantile-onset forms present from birth to two months of life and within the first year of life, respectively. The late-onset definition includes childhood, juvenile, and adult.

Previous
 
 
Contributor Information and Disclosures
Author

Germaine L Defendi, MD, MS, FAAP Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center

Germaine L Defendi, MD, MS, FAAP is a member of the following medical societies: American Academy of Pediatrics

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.

Lois J Starr, MD, FAAP Assistant Professor of Pediatrics, Clinical Geneticist, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center

Lois J Starr, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

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.

Margaret M McGovern, MD, PhD Professor and Chair of Pediatrics, Stony Brook University School of Medicine

Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Acknowledgements

Jennifer Ibrahim, MD Chief, Genetics Division, St Joseph's Children's Hospital

Jennifer Ibrahim, MD is a member of the following medical societies: American Society of Human Genetics

Disclosure: Nothing to disclose.

References
  1. Chien YH, Hwu WL, Lee NC. Pompe disease: early diagnosis and early treatment make a difference. Pediatr Neonatol. 2013 Aug. 54(4):219-27. [Medline].

  2. van der Beek NA, de Vries JM, Hagemans ML, Hop WC, Kroos MA, Wokke JH, et al. Clinical features and predictors for disease natural progression in adults with Pompe disease: a nationwide prospective observational study. Orphanet J Rare Dis. 2012 Nov 12. 7:88. [Medline]. [Full Text].

  3. Hirschhorn R, Reuser AJJ. Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency. In: Scriver CR, Beaudet AL,et, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. 2001. 3389-3420.

  4. Martiniuk F, Chen A, Mack A, Arvanitopoulos E, Chen Y, Rom WN, et al. Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease. Am J Med Genet. 1998 Aug 27. 79 (1):69-72. [Medline].

  5. Lin CY, Hwang B, Hsiao KJ, Jin YR. Pompe's disease in Chinese and prenatal diagnosis by determination of alpha-glucosidase activity. J Inherit Metab Dis. 1987. 10 (1):11-7. [Medline].

  6. Ausems MG, Verbiest J, Hermans MP, et al. Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet. 1999 Sep. 7(6):713-6. [Medline].

  7. Van der Kraan M, Kroos MA, Joosse M, Bijvoet AG, Verbeet MP, Kleijer WJ, et al. Deletion of exon 18 is a frequent mutation in glycogen storage disease type II. Biochem Biophys Res Commun. 1994 Sep 30. 203 (3):1535-41. [Medline].

  8. Pinto R, Caseiro C, Lemos M, Lopes L, Fontes A, Ribeiro H, et al. Prevalence of lysosomal storage diseases in Portugal. Eur J Hum Genet. 2004 Feb. 12 (2):87-92. [Medline].

  9. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999 Jan 20. 281 (3):249-54. [Medline].

  10. Miyamoto Y, Etoh Y, Joh R, et al. Adult-onset acid maltase deficiency in siblings. Acta Pathol Jpn. 1985 Nov. 35(6):1533-42. [Medline].

  11. Bulkley BH, Hutchins GM. Pompe's disease presenting as hypertrophic myocardiopathy with Wolff-Parkinson-White syndrome. Am Heart J. 1978 Aug. 96(2):246-52. [Medline].

  12. Galehdari H, Emami M, Mohammadian G, Khodadadi A, Azmoon S, Baradaran M. Detection of a novel mutation in the GAA gene in an Iranian child with glycogen storage disease type II. Arch Iran Med. 2013 Feb. 16(2):126-8. [Medline].

  13. Amiñoso C, Vallespin E, Fernández L, Arrabal LF, Desviat LR, Pérez B, et al. Identification of the first deletion-insertion involving the complete structure of GAA gene and part of CCDC40 gene mediated by an Alu element. Gene. 2013 Apr 25. 519(1):169-72. [Medline].

  14. Kroos MA, Pomponio RJ, Hagemans ML, et al. Broad spectrum of Pompe disease in patients with the same c.-32-13T->G haplotype. Neurology. 2007 Jan 9. 68(2):110-5. [Medline].

  15. Montalvo AL, Bembi B, Donnarumma M, Filocamo M, Parenti G, Rossi M, et al. Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II. Hum Mutat. 2006 Oct. 27 (10):999-1006. [Medline].

  16. van der Beek NA, Soliman OI, van Capelle CI, Geleijnse ML, Vletter WB, Kroos MA, et al. Cardiac evaluation in children and adults with Pompe disease sharing the common c.-32-13T>G genotype rarely reveals abnormalities. J Neurol Sci. 2008 Dec 15. 275(1-2):46-50. [Medline].

  17. Leslie N, Tinkle BT. Glycogen Storage Disease Type II (Pompe Disease). GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1261/. Available at http://www.ncbi.nlm.nih.gov/books/NBK1261/. May 9, 2013; Accessed: January 20, 2016.

  18. Young SP, Piraud M, Goldstein JL, Zhang H, Rehder C, Laforet P, et al. Assessing disease severity in Pompe disease: the roles of a urinary glucose tetrasaccharide biomarker and imaging techniques. Am J Med Genet C Semin Med Genet. 2012 Feb 15. 160C (1):50-8. [Medline].

  19. Laforêt P, Nicolino M, Eymard PB, Puech JP, Caillaud C, Poenaru L, et al. Juvenile and adult-onset acid maltase deficiency in France: genotype-phenotype correlation. Neurology. 2000 Oct 24. 55 (8):1122-8. [Medline].

  20. Winkel LP, Hagemans ML, van Doorn PA, Loonen MC, Hop WJ, Reuser AJ, et al. The natural course of non-classic Pompe's disease; a review of 225 published cases. J Neurol. 2005 Aug. 252 (8):875-84. [Medline].

  21. van den Hout HM, Hop W, van Diggelen OP, Smeitink JA, Smit GP, Poll-The BT, et al. The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature. Pediatrics. 2003 Aug. 112 (2):332-40. [Medline].

  22. Kishnani PS, Corzo D, Leslie ND, et al. Early treatment with alglucosidase alpha prolongs long-term survival of infants with Pompe disease. Pediatr Res. 2009 Sep. 66(3):329-35. [Medline].

  23. Nicolino M, Byrne B, Wraith JE, et al. Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease. Genet Med. 2009 Mar. 11(3):210-9. [Medline].

  24. Merk T, Wibmer T, Schumann C, Krüger S. Glycogen storage disease type II (Pompe disease)--influence of enzyme replacement therapy in adults. Eur J Neurol. 2009 Feb. 16(2):274-7. [Medline].

  25. Forsha D, Li JS, Smith PB, van der Ploeg AT, Kishnani P, Pasquali SK. Cardiovascular abnormalities in late-onset Pompe disease and response to enzyme replacement therapy. Genet Med. 2011 Jul. 13(7):625-631. [Medline]. [Full Text].

  26. [Guideline] Cunniff C. Prenatal screening and diagnosis for pediatricians. Pediatrics. 2004 Sep. 114(3):889-94. [Medline].

  27. Ausems MG, Lochman P, van Diggelen OP, et al. A diagnostic protocol for adult-onset glycogen storage disease type II. Neurology. 1999 Mar 10. 52(4):851-3. [Medline].

  28. Clinical Trials. A Study to Evaluate the Effects of Pharmacological Chaperones in Cells From Patients With Pompe Disease. clinicaltrials.gov. Available at http://clinicaltrials.gov/ct/show/NCT00515398?order=2. Accessed: 2007.

  29. Engel AG, Gomez MR, Seybold ME, Lambert EH. The spectrum and diagnosis of acid maltase deficiency. Neurology. 1973 Jan. 23(1):95-106. [Medline].

  30. Engel AG, Hirschhorn R. Acid maltase deficiency. Engel AG, Franzine-Armstrong C, eds. Myology: Basic and Clinical. New York, NY: McGraw-Hill; 1996. 1533-53.

  31. Hirschhorn R. Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency. Scriver CR, Beaudet AL, Sly W, Valle E, eds. The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill; 1995. 2443-64.

  32. Isaacs H, Savage N, Badenhorst M, Whistler T. Acid maltase deficiency: a case study and review of the pathophysiological changes and proposed therapeutic measures. J Neurol Neurosurg Psychiatry. 1986 Sep. 49(9):1011-8. [Medline].

  33. Umapathysivam K, Hopwood JJ, Meikle PJ. Determination of acid alpha-glucosidase activity in blood spots as a diagnostic test for Pompe disease. Clin Chem. 2001 Aug. 47(8):1378-83. [Medline].

  34. Van der Beek NA, Hagemans ML, Reuser AJ, et al. Rate of disease progression during long-term follow-up of patients with late-onset Pompe disease. Neuromuscul Disord. 2009 Feb. 19(2):113-7. [Medline].

  35. Pompe Disease Diagnostic Working Group, Winchester B, Bali D, Bodamer OA, Mengel E, Müller-Felber W, et al. Methods for a prompt and reliable laboratory diagnosis of Pompe disease: report from an international consensus meeting. Mol Genet Metab. 2008 Mar. 93 (3):275-81. [Medline].

 
Previous
Next
 
Glycogen-storage disease type II (Pompe disease). Photomicrograph of the liver. Note the intensively stained vacuoles in the hepatocytes (periodic acid-Schiff, original magnification X 27).
Glycogen-storage disease type II (Pompe disease). Photomicrograph of the liver. Note the regular reticular net and hepatocytes vacuolization (Gordon-Sweet stain, original magnification X 25).
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.