Acid Maltase Deficiency Myopathy 

  • Author: Michael Weinik, DO; Chief Editor: Denise I Campagnolo, MD, MS   more...
 
Updated: Jan 18, 2012
 

Background

Acid maltase deficiency (AMD) is an autosomal recessive disease characterized by an excessive accumulation of glycogen within lysosome-derived vacuoles in nearly all types of cells. Excessive quantities of free extralysosomal glycogen also have been described. AMD first was described by JC Pompe in Amsterdam in 1932; Pompe reported the case of a 7-month-old girl who became fatally ill from what appeared to be pneumonia. An autopsy revealed an unusually enlarged heart with normal valves. Pompe called this condition cardiomegalia glycogenica diffusa and considered it a disease analogous to von Gierke syndrome. The first article by Pompe was followed by similar reports by 2 independent authors, who described children with severe muscle weakness and cardiomegaly who died in early infancy. Their disease was attributed to an excessive deposition of glycogen in various tissues. This entity was named Pompe disease, and in 1957, GT Cori classified it as type II glycogenosis. See the image below.

Glycogen molecule; by cleaving glycogen's 1,4 and Glycogen molecule; by cleaving glycogen's 1,4 and 1,6 alpha-glycosidic linkages, the enzyme acid maltase gives rise to free glucose molecules.

The following clinical phenotypes of AMD have been identified:

  • Infantile (Pompe disease)
  • Late infantile
  • Juvenile
  • Adult

Infantile acid maltase deficiency (Pompe disease) is the classic example of a metabolic myopathy and motor neuron disease that causes infantile hypotonia. This form of the disorder is the most severe and carries the worst prognosis, with death ensuing between ages 6 months and 2 years. The other forms are somewhat milder and vary in clinical presentation.[1, 2, 3]

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Pathophysiology

Acid alpha-1,4 glucosidase (acid maltase), like other lysosomal enzymes, is synthesized as a precursor form (molecular weight 105,000) in the endoplasmic reticulum. The precursor molecule then is modified by the addition of a mannose-6-phosphate recognition signal that allows its transport to the lysosomes. Then, the acid maltase is partially degraded into a mature form with a molecular weight of 76,001. The gene for acid alpha-glucosidase is on chromosome band 17q23.

Acid maltase cleaves glycogen 1,4 and 1,6 alpha-glycosidic linkages. Its action gives rise to free glucose molecules (see History).[4, 5] See the images below.

Glycogen molecule; by cleaving glycogen's 1,4 and Glycogen molecule; by cleaving glycogen's 1,4 and 1,6 alpha-glycosidic linkages, the enzyme acid maltase gives rise to free glucose molecules. Metabolic pathways of carbohydrates. Metabolic pathways of carbohydrates.

Nearly 35 distinct mutations have been identified in the q23-28 locus of chromosome 17, which encodes acid maltase. Establishing the genotype-phenotype correlation is difficult; however, the severity of mutation usually correlates with the severity of the disease. Deletions or missense mutations (mutations in which the base replacement changes the codon for one amino acid to that for another) usually are associated with the infantile variant (Pompe disease), whereas "leaky" (partial) mutations are associated with the childhood and adult forms of acid maltase deficiency.

The absence of acid maltase leads to an excessive accumulation of glycogen in lysosome-derived vacuoles. The presence of abnormal quantities of glycogen disrupts the normal architecture and function of the affected cells. The excess glycogen is expected to be, at least initially, in the vacuolar system. This has been found to be true in the liver and in other tissues; in muscle, however, most of the polysaccharide appears to be extravacuolar, possibly reflecting the fact that the glycogen is packed so densely in skeletal muscle that the surrounding membrane is difficult to see. Another possibility is that the intense pressure exerted on the vacuoles during muscular contracture causes them to rupture, allowing the contents to spill over into the cytosol.

Abnormal storage of glycogen occurs in many organs, including the central nervous system (CNS), heart, liver, and skeletal muscles,[1] thus leading to hypotonia; weak, bulky muscles; macroglossia; cardiomegaly; and congestive heart failure. The intramuscular storage of glycogen is more severe in Pompe disease than in any other glycogenosis.

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Epidemiology

Frequency

United States

Pompe disease, or infantile acid maltase deficiency, occurs in 1 out of 50,000 live births.

Mortality/Morbidity

Pompe disease is inherited as an autosomal recessive disease. In the infantile form, death usually occurs between ages 6 months and 2 years; however, a less severe infantile form, with a better prognosis and improved survival, has been identified. Patients with the late infantile form may survive for several years. Patients with either the juvenile or adult form of acid maltase deficiency (each of which is also known as late-onset AMD) have been known to survive into the sixth or seventh decade of life. The clinical presentation may vary considerably, and some cases may go undetected; hence, the life expectancy for these groups is not exactly known.

Race

No ethnic predilection exists in connection with acid maltase deficiency.

Sex

Acid maltase deficiency occurs with equal frequency in males and females.

Age

The correlation of acid maltase deficiency with age depends on the form of the disease.

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Contributor Information and Disclosures
Author

Michael Weinik, DO  Associate Chairman, Associate Professor, Physical Medicine and Rehabilitation, Temple University Hospital

Michael Weinik, DO is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation

Disclosure: Nothing to disclose.

Coauthor(s)

Frank J King, MD  Clinical Instructor, Department of Physical Medicine and Rehabilitation, Georgia Pain Physicians/Emory School of Medicine

Frank J King, MD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, American Medical Association, and Association of Academic Physiatrists

Disclosure: Nothing to disclose.

Specialty Editor Board

Elizabeth A Moberg-Wolff, MD  Medical Director, Pediatric Rehabilitation Medicine Associates

Elizabeth A Moberg-Wolff, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine and American Academy of Physical Medicine and Rehabilitation

Disclosure: Medtronic Neurological None Speaking and teaching

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

Disclosure: Medscape Salary Employment

Kat Kolaski, MD  Assistant Professor, Departments of Orthopedic Surgery and Pediatrics, Wake Forest University School of Medicine

Kat Kolaski, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine and American Academy of Physical Medicine and Rehabilitation

Disclosure: Nothing to disclose.

Kelly L Allen, MD  Medical Director, Medevals

Disclosure: Nothing to disclose.

Chief Editor

Denise I Campagnolo, MD, MS  Director of Multiple Sclerosis Clinical Research and Staff Physiatrist, Barrow Neurology Clinics, St Joseph's Hospital and Medical Center; Investigator for Barrow Neurology Clinics; Director, NARCOMS Project for Consortium of MS Centers

Denise I Campagnolo, MD, MS is a member of the following medical societies: Alpha Omega Alpha, American Association of Neuromuscular and Electrodiagnostic Medicine, American Paraplegia Society, Association of Academic Physiatrists, and Consortium of Multiple Sclerosis Centers

Disclosure: Teva Neuroscience Honoraria Speaking and teaching; Serono-Pfizer Honoraria Speaking and teaching; Genzyme Corporation Grant/research funds investigator; Biogen Idec Grant/research funds investigator; Genentech, Inc Grant/research funds investigator; Eli Lilly & Company Grant/research funds investigator; Novartis investigator; MSDx LLC Grant/research funds investigator; BioMS Technology Corp Grant/research funds investigator; Avanir Pharmaceuticals Grant/research funds investigator

Additional Contributors

The editors would like to thank Daniel A Lee, MD, for his previous association with this article.

References

  1. Fukuda T, Roberts A, Plotz PH, et al. Acid alpha-glucosidase deficiency (Pompe disease). Curr Neurol Neurosci Rep. Jan 2007;7(1):71-7. [Medline].

  2. van der Ploeg AT, Reuser AJ. Pompe's disease. Lancet. Oct 11 2008;372(9646):1342-53. [Medline].

  3. Bembi B, Cerini E, Danesino C, et al. Management and treatment of glycogenosis type II. Neurology. Dec 2 2008;71(23 Suppl 2):S12-36. [Medline].

  4. Richard E, Douillard-Guilloux G, Caillaud C. New insights into therapeutic options for Pompe disease. IUBMB Life. Nov 2011;63(11):979-86. [Medline].

  5. Byrne BJ, Falk DJ, Pacak CA, Nayak S, Herzog RW, Elder ME, et al. Pompe disease gene therapy. Hum Mol Genet. Apr 15 2011;20:R61-8. [Medline]. [Full Text].

  6. Hagemans ML, Winkel LP, Van Doorn PA, et al. Clinical manifestation and natural course of late-onset Pompe's disease in 54 Dutch patients. Brain. Mar 2005;128(Pt 3):671-7. [Medline]. [Full Text].

  7. Hagemans ML, Winkel LP, Hop WC, et al. Disease severity in children and adults with Pompe disease related to age and disease duration. Neurology. Jun 28 2005;64(12):2139-41. [Medline].

  8. Hagemans ML, Hop WJ, Van Doorn PA, et al. Course of disability and respiratory function in untreated late-onset Pompe disease. Neurology. Feb 28 2006;66(4):581-3. [Medline].

  9. Muller-Felber W, Horvath R, Gempel K, et al. Late onset Pompe disease: clinical and neurophysiological spectrum of 38 patients including long-term follow-up in 18 patients. Neuromuscul Disord. Oct 2007;17(9-10):698-706. [Medline].

  10. 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. Feb 2009;19(2):113-7. [Medline].

  11. Papadimas GK, Spengos K, Papadopoulos C, Manta P. Late Onset Glycogen Storage Disease Type II: Pitfalls in the Diagnosis. Eur Neurol. Dec 15 2011;67(2):65-68. [Medline].

  12. Bembi B, Cerini E, Danesino C, et al. Diagnosis of glycogenosis type II. Neurology. Dec 2 2008;71(23 Suppl 2):S4-11. [Medline].

  13. Parenti G, Andria G. Pompe disease: from new views on pathophysiology to innovative therapeutic strategies. Curr Pharm Biotechnol. Jun 2011;12(6):902-15. [Medline].

  14. Van den Hout H, Reuser AJ, Vulto AG, et al. Recombinant human alpha-glucosidase from rabbit milk in Pompe patients. Lancet. Jul 29 2000;356(9227):397-8. [Medline].

  15. Rossi M, Parenti G, Della Casa R, et al. Long-term enzyme replacement therapy for Pompe disease with recombinant human alpha-glucosidase derived from Chinese hamster ovary cells. J Child Neurol. May 2007;22(5):565-73. [Medline].

  16. 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. Mar 2009;11(3):210-219. [Medline].

  17. Schoser B, Hill V, Raben N. Therapeutic approaches in glycogen storage disease type II/Pompe Disease. Neurotherapeutics. Oct 2008;5(4):569-78. [Medline].

  18. Amato AA. Acid maltase deficiency and related myopathies. Neurol Clin. Feb 2000;18(1):151-65. [Medline].

  19. Behrman RE. Nelson Textbook of Pediatrics. 16th ed. Philadelphia, Pa: WB Saunders; 2000:. 411-13.

  20. Bijvoet AG, Van Hirtum H, Kroos MA, et al. Human acid alpha-glucosidase from rabbit milk has therapeutic effect in mice with glycogen storage disease type II. Hum Mol Genet. Nov 1999;8(12):2145-53. [Medline].

  21. Bodamer OA, Halliday D, Leonard JV. The effects of l-alanine supplementation in late-onset glycogen storage disease type II. Neurology. Sep 12 2000;55(5):710-2. [Medline].

  22. Bradley WG. Neurology in Clinical Practice: The Neurological Disorders. 2nd ed. Boston, Mass: Butterworth-Heinemann; 1995:. 1537-38.

  23. Braunwald E. Heart Disease: A Textbook of Cardiovascular Medicine. 4th ed. Philadelphia, Pa: WB Saunders; 1992:. 995-6.

  24. Caliskan M, Yilmaz Y, Serdaroglu P, et al. Late infantile acid maltase deficiency: a case report. Turk J Pediatr. Jan-Mar 1999;41(1):121-5. [Medline].

  25. Chen YT, Amalfitano A. Towards a molecular therapy for glycogen storage disease type II (Pompe disease). Mol Med Today. Jun 2000;6(6):245-51. [Medline].

  26. Damjanov I, Linder J. Anderson's Pathology. 10th ed. St. Louis, Mo: Mosby; 1996:. 2699-2700.

  27. Goetz CG, Pappert EJ. Textbook of Clinical Neurology. Philadelphia, Pa: WB Saunders; 1999:. 571-3.

  28. McKusick VA. Mendelian Inheritance in Man. 10th ed. Baltimore, Md: Johns Hopkins University Press; 1992.

  29. McMillan JA. Oski's Pediatrics: Principles and Practice. 3rd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999:. 1961, 1977-8.

  30. Mellies U, Ragette R, Schwake C, et al. Sleep-disordered breathing and respiratory failure in acid maltase deficiency. Neurology. Oct 9 2001;57(7):1290-5. [Medline].

  31. Melvin JJ. Pompe's disease. Arch Neurol. Jan 2000;57(1):134-5. [Medline].

  32. Poenaru L. Approach to gene therapy of glycogenosis type II (Pompe disease). Mol Genet Metab. Jul 2000;70(3):163-9. [Medline].

  33. Rowland LP. Merritt's Textbook of Neurology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1995:. 506.

  34. Scriver CR. The Metabolic Basis of Inherited Disease. 6th ed. New York, NY: McGraw-Hill; 1989:. 437-440.

  35. Selak MA, de Chadarevian JP, Melvin JJ, et al. Mitochondrial activity in Pompe's disease. Pediatr Neurol. Jul 2000;23(1):54-7. [Medline].

  36. Slonim AE, Bulone L, Ritz S, et al. Identification of two subtypes of infantile acid maltase deficiency. J Pediatr. Aug 2000;137(2):283-5. [Medline].

  37. Stryer L. Biochemistry. 3rd ed. New York, NY: WH Freeman & Co; 1988.

  38. Umapathysivam K, Whittle AM, Ranieri E, et al. Determination of acid alpha-glucosidase protein: evaluation as a screening marker for Pompe disease and other lysosomal storage disorders. Clin Chem. Sep 2000;46(9):1318-25. [Medline].

  39. van der Ploeg AT. Monitoring of pulmonary function in Pompe disease: a muscle disease with new therapeutic perspectives. Eur Respir J. Dec 2005;26(6):984-5.

  40. Vorgerd M, Burwinkel B, Reichmann H, et al. Adult-onset glycogen storage disease type II: phenotypic and allelic heterogeneity in German patients. Neurogenetics. Mar 1998;1(3):205-11. [Medline].

  41. Winkel LP, Kamphoven JH, van den Hout HJ, et al. Morphological changes in muscle tissue of patients with infantile Pompe's disease receiving enzyme replacement therapy. Muscle Nerve. Jun 2003;27(6):743-51. [Medline].

  42. Winkel LP, Van den Hout JM, Kamphoven JH, et al. Enzyme replacement therapy in late-onset Pompe's disease: a three-year follow-up. Ann Neurol. Apr 2004;55(4):495-502.

 
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Glycogen molecule; by cleaving glycogen's 1,4 and 1,6 alpha-glycosidic linkages, the enzyme acid maltase gives rise to free glucose molecules.
Metabolic pathways of carbohydrates.
 
 
 
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