Pathophysiology

Acid alpha-glucosidase (GAA) is a lysosomal hydrolase found in tissues -- including skeletal and cardiac muscle--that is responsible for the degradation of a small percentage (1-3%) of glycogen.¹ As a result, a deficiency of GAA enzyme activity results in the excessive storage of glycogen in lysosomes.

Eventually this accumulation can disrupt the architecture and function of affected cells, causing significant cardiomyopathy (in infantile-onset cases) and generalized muscle weakness. Unlike other glycogen storage diseases (GSDs), Pompe disease does not cause hypoglycemia or low energy production.

Take a Closer Look: Electron Micrograph of Pompe Affected Muscle Cells >

Clinical Presentation

The clinical presentation of Pompe disease is highly variable, depending on:

Age of onset
The range and rate of progression of organ involvement
Amount of residual GAA enzyme activity (phenotypes generally correlate with this factor)

In some patients with the infantile-onset form, there may be a complete or near complete absence of enzyme activity. In others, researchers believe that residual enzyme activity prevents cardiac involvement and delays the onset of muscle weakness.

As measured in skin fibroblasts:²

Most patients with the infantile-onset presentation generally demonstrate less than 1% of normal GAA enzyme activity
Patients with late-onset presentation display less than 40% of normal GAA enzyme activity

An Illustration of Enzyme Activity & Spectrum of Pompe

Most patients with infantile-onset disease have undetectable to minimal GAA activity, leading to massive glycogen accumulation and rapid and aggressive progression in skeletal muscle and in several organ systems (heart, liver). In contrast, late-onset patients tend to have limited, but detectable, residual GAA activity; in these cases, organ damage is less pronounced and disease progression is slower.

As a result, the severity of disease course ranges from death due to cardiorespiratory failure in infants to a varying degree of disability due to slowly progressive skeletal and respiratory weakness, and ultimately death, in adults.

Although the three predominant phenotypes--infantile, juvenile, and adult onset--have historically been regarded as disease "types" in the literature, these labels do not adequately reflect the type and severity of symptoms at any given point in time.³

The Spectrum of Pompe Disease

Therefore, the disease may be better characterized based on the rate of progression to death (rapid or gradual) and the presence of cardiomegaly (common or infrequent). This results in two major classifications of the disease--infantile-onset and late-onset, respectively--and a more continuous spectrum. Within the late-onset classification especially, patients may exhibit mild, moderate, or severe symptoms.

It is estimated that:

Approximately one third of those with Pompe disease have the rapidly fatal infantile-onset form⁴
The majority of patients present with the slowly progressive late-onset form

References

1. Ibrahim, Jennifer. Glycogen Storage Disease Type II. eMedicine Specialties. Available at: http://www.emedicine.com/ped/topic1866.htm. Accessed August 22, 2005. ((Ibrahim, pp. 1,2))

2. 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.

3. 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.

4. Martiniuk F, Chen A, Mack A, 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; 79: 69-72.