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


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

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


Infantile-onset forms (classic and non-classic) of Pompe disease

Affected infants typically present with muscle weakness, hypotonia, and motor delay within the first 6 months of life (20%-63% of patients).

Feeding difficulties and failure to thrive are described in 44%-97% of patients.

Early cardiac failure results from LV enlargement and outflow obstruction (50%-92% of patients), along with respiratory concerns (27%-78% of patients). ​Electrocardiography (ECG) findings show a shortened PR interval with a broad and wide QRS complex. In one infant described, the presenting sign was Wolff-Parkinson-White syndrome.[11]

Family histories are usually noncontributory. Families with a history of consanguinity should raise concern.

Late-onset form of Pompe disease

TThe history of childhood and juvenile-onset glycogen-storage disease type II (GSD II) is as follows:

  • Patients present with delayed motor milestones, muscle weakness, and hypotonia.
  • Intelligence is normal.

The history of adult-onset GSD II is as follows:

  • Patients present with physical challenges related to proximal muscle weakness, such as difficulty climbing stairs.
  • Respiratory symptoms are present in about 33% of cases.
  • Other symptoms may include exercise intolerance, orthopnea, somnolence, and headaches.
  • Cardiac involvement is not a significant component.


Infantile-onset form of GSD II

Abnormal glycogen storage (eg, macroglossia, hepatomegaly, normal or increased muscle bulk) is clinically evident.

Involvement of respiratory muscles manifests as respiratory distress (eg, tachypnea).

Cardiomegaly or cardiomyopathy leads to murmur and signs of cardiac failure, such as feeding difficulties.

Profound diffuse hypotonia and muscle weakness occurs.

Cognitive development is normal.

Late-onset form of GSD II

The juvenile form is characterized by the following:

  • Respiratory distress
  • Hypotonia (typically more proximal than distal)
  • Macroglossia and hepatomegaly (not common)
  • No associated cardiomegaly or cardiomyopathy

The adult form is characterized by the following:

  • Proximal muscle weakness
  • Decreased bulk of involved muscles
  • Diminished deep tendon reflexes


Pompe disease, or glycogen-storage disease type II (GSD II), is inherited in an autosomal-recessive manner. Clinical presentation requires two copies of pathogenic variants of the gene, GAA. GAA codes for the enzymatic activity of acid alpha-glucosidase and is the only human gene mutation known to cause GSD II. GAA has been localized in the human karyotype to the long arm of chromosome 17 at band q25.2 - q25.3. Heterozygotes, or carriers (persons with one normal copy and one pathogenic variant copy of the gene), are asymptomatic and hence have no clinical manifestations of the disease. Two copies of the mutated variant are needed to express the clinical disease, GSD II.

Allelic variants have been identified within GAA and include missense, nonsense, intragenic deletions/insertions, and splice-site mutations.[12, 13] The spectrum of mutations can result in the following:

  • No detectable messenger RNA (mRNA) and complete absence of enzymatic protein
  • A normal amount of enzyme with reduced activity (eg, reduced affinity for glycogen)
  • A reduced amount of enzyme with normal activity
  • No detectable enzyme activity in infantile form; varying amounts of residual enzyme activity in late-onset forms

Molecular genetic testing enables for the identification of the more common allelic variants within the GAA gene. Ethnicity and phenotype can help identify the more likely pathogenic variants, such as p.Arg854Ter, p.Asp645Glu, and c.336-13T>G.

  • p.Arg854Ter is present in 50%-60% of African Americans with infantile-onset GSD II. [3]
  • p.Asp645Glu is identified in 40%-80% of patients of Chinese ancestry with infantile-onset GSD II. [3]
  • The c.336-13T>G mutation is most commonly found in late-onset adult patients with GSD II. [14] This mutation is present is 50%-85% of affected persons. [3, 15] No individuals with this mutation have the classic infantile-onset form. Cardiac involvement is rare among patients with this genotype. [16]
Contributor Information and Disclosures

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.


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.

  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: Available at 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. Available at 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].

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.