Underlying Pathology of Pompe Disease

Although the clinical manifestations of Pompe disease can vary widely in terms of severity of signs and symptoms, rate of progression, and age of onset, the pathologic basis is always the same: intralysosomal accumulation of glycogen, predominantly in muscle tissue.


A Genetic Basis

A gene located on chromosome 17 (17q25.2-q25.3) encodes for the production of acid alpha-glucosidase (GAA), an enzyme responsible for the breakdown of glycogen to glucose inside lysosomes. Mutations in this gene cause marked deficiency or absence of GAA enzyme activity, resulting in intralysosomal accumulation of glycogen, primarily in muscle cells.[1]

Learn more about the genetic defect behind Pompe disease

Cellular and Tissue Damage

Continuous accumulation of glycogen causes lysosomes to swell and rupture resulting in cellular damage. This in turn leads to progressive degeneration of skeletal muscles, including respiratory, and, primarily in infants, cardiac muscles, eventually resulting in loss of function.[2]

This microscopy image is an example of glycogen accumulation and the resulting muscle pathology, which often occurs before any clinically detectable signs or symptoms.

 Affected Pompe cell

Electron micrograph of Pompe affected muscle cell
This electron micrograph of a human skeletal muscle cell is characteristic of patients with Pompe disease. As glycogen accumulates, it causes the lysosomes to enlarge and to abnormally invade cellular space (see arrows). Although some healthy myofibrils may still be present early in the course of the disease, the myofibrils are almost completely replaced by glycogen in advanced Pompe disease, eventually impairing muscle function.

Note that the glycogen buildup in Pompe disease typically does NOT cause abnormalities of glucose metabolism such as hypoglycemia, because glycogen stored in lysosomes is not part of the gluconeogenic pathway.[1]

Single Pathology, Variable Disease Progression

Enzyme Level Variability

While Pompe disease is always described by below-normal levels of GAA enzyme activity, the residual enzyme activity levels vary among patients and patient populations:

  • Infants with Pompe disease usually have less than 1% of normal GAA levels.[1]
  • Children and adults with Pompe disease may show enzyme levels ranging anywhere from 1% to 40% of normal enzyme activity.[3]

In general, however, there is poor correlation between residual GAA activity and clinical manifestations.

Disease Course

Infants with Pompe disease usually show an almost complete absence of GAA, marked cardiomegaly, as well as rapid glycogen accumulation in skeletal muscle that may be more than 10 times normal.[1] In this patient population disease progresses very rapidly and is usually fatal within the first year of life.

In children and adults the disease generally progresses at a slower rate than in infants, with little or no cardiac involvement, but is always relentlessly progressive and associated with significant morbidity and/or premature mortality, as an abrupt and rapid decline can happen at any time.[4-8]

Learn more about the progression and varied spectrum of Pompe disease


  1. Hirschhorn, Rochelle and Arnold J. J. Reuser. Glycogen Storage Disease Type II: Acid Alpha-glucosidase (Acid Maltase) Deficiency. In: Scriver C, Beaudet A, Sly W, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. 8th Edition. New York: McGraw-Hill, 2001. 5568.
  2. Hesselink RP, Wagenmakers AJ, Drost MR, Van der Vusse GJ. Lysosomal dysfunction in muscle with special reference to glycogen storage disease type II. Biochim Biophys Acta. 2003;1637(2):164-170.
  3. Chen YT, Amalfitano A. Towards a molecular therapy for glycogen storage disease type II (Pompe disease). Mol Med Today 2000 Jun; 6(6): 245-51.
  4. Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline. Genet Med 2006; 8:267-88.
  5. Kishnani PS, Hwu W-L, Mandel H, Nicolino M, Yong F, Corzo D. A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr 2006; 148:671-676.
  6. Van den Hout HMP. The natural course of infantile Pompe’s disease: 20 original cases compared with 133 cases from the literature. Pediatr 2003 Aug; 112 (2): 332-340.
  7. 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 2006; 128:671-7.
  8. Wokke J, Escolar D, Pestronk A, Jaffe K, Carter G, van den Berg L, et al. Clinical features of late-onset Pompe disease: A prospective cohort study. Muscle Nerve 2008;38:1236-45.

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