Cause of the Disease
The underlying cause of Pompe disease is always the same in all patients: the absence or marked deficiency of a specific enzyme, acid alpha-glucosidase (pronounced “AL-fa glue-CO-sih-days” and often abbreviated GAA). As explained below, this absence leads to excessive buildup of a substance called glycogen within muscle cells. This accumulated glycogen affects muscle structure and function and results in muscle weakness. Exactly which areas of the body are affected, and how severely, may vary from patient to patient.
Why Does Glycogen Build Up?
An Enzyme Deficiency
The human body produces various enzymes that help break down substances that play a role in the function of cells throughout the body. This breakdown process occurs in small compartments within the cells called lysosomes. One particular enzyme, acid alpha-glucosidase, is responsible for breaking down glycogen in the lysosome. Glycogen is a form of sugar that is used for energy storage and is often found in muscle cells.
In patients with Pompe disease, this enzyme is either missing, deficient or not functioning properly. As a result, glycogen is not adequately broken down and accumulates within cell lysosomes, causing damage that leads to muscle weakness.
A Genetic Basis
The GAA gene is responsible for the production of the enzyme acid alpha-glucosidase. When there is a mutation, or defect, in this gene, the enzyme is not be produced in sufficient amounts or does not function properly. Pompe disease occurs when a person inherits this gene defect from both parents.
Learn more about how Pompe disease is inherited
Enzyme & Gene Terminology
Throughout this website, and in other materials, the abbreviation GAA is used interchangeably to refer to both the gene and the enzyme involved in Pompe disease. Although GAA is an abbreviation for “glucosidase acid alpha,” the name of the gene, it is often used to describe the deficient enzyme, acid alpha-glucosidase. (The enzyme acid alpha-glucosidase is sometimes also notated as acid α-glucosidase, α-glu, or AGLU.)
How Are Muscles Affected?
As excess glycogen builds up, the cell’s lysosomes begin to swell beyond their normal size and can interfere with normal muscle function. In addition, lysosomes can rupture causing cellular damage. The following illustration provides a cross-section view of this process.
Muscle cell affected by Pompe disease
- In the healthy muscle cell, lysosomes are normal.
- With Pompe disease, accumulated glycogen causes lysosomes to expand, interfering with normal structure and function.
- In addition, glycogen and other contents may leak out of the lysosomes and further damage the cell and surrounding tissue.
Damage to individual muscle cells eventually results in weakness of larger muscle bundles, leading to patients’ symptoms. The symptoms typically get worse over time, as more glycogen accumulates and the destructive process continues.
How Do Symptoms Vary Among Patients?
Pompe disease is a genetic disorder that is always present at birth. However, symptoms may not always be apparent at birth and can present at any age from infancy through adulthood. Regardless of the age of onset, symptoms usually worsen over time. Typically, the earlier symptoms manifest, the more serious the disease course is likely to be.
Moreover, while all people with Pompe disease have lower-than-normal amounts of the GAA enzyme activity (and sometimes none at all), the amount of residual enzyme activity also often varies with the patient’s age:
- Affected infants under age 1 usually have less than 1% of normal enzyme levels
- In children and adult patients, enzyme levels usually range from 1% to 40% of normal
In infants, the almost complete absence of the enzyme seems to consistently result in very severe signs and symptoms, including extreme muscle weakness, breathing difficulties, and serious heart problems. These symptoms generally progress, or worsen, at a very rapid rate, and are often fatal., 
The variable enzyme levels seen in older patients are not necessarily associated with specific patterns of symptoms, which can vary widely and be difficult to predict. Unlike affected infants, older patients usually have little or no heart problems. Their muscle and breathing problems may start out milder and worsen gradually.
Learn more about Pompe disease progression
- 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. 3389-3420.
- 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.
- 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.
- 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.
- 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.