Pompe disease is a rare, inherited disorder, also known as Glycogen Storage Disease Type II, that affects the body’s ability to break down the complex sugar glycogen. The disease causes progressive muscle weakness and wasting throughout the body, including the muscles that control breathing and the heart. The root cause lies in genetic instructions that govern cellular function.
The Genetic Blueprint
The root cause of Pompe disease lies in mutations within the GAA gene, which provides the code for producing a specific digestive enzyme necessary for cellular metabolism. Mutations prevent the cell from producing a functional enzyme or significantly reduce its quantity. Over 560 different mutations have been identified, and the specific type inherited dictates how severely the enzyme’s function is impaired, directly influencing the disease’s presentation.
Enzyme Deficiency and Glycogen Storage
The protein encoded by the GAA gene is the enzyme acid alpha-glucosidase (acid maltase). This enzyme operates primarily inside the cell’s lysosomes, where its normal function is to break down glycogen, a complex sugar used for energy storage. Within the lysosome, the enzyme converts glycogen into glucose, which the cell uses for fuel.
When the GAA gene is mutated, the enzyme is either missing or unable to perform this breakdown effectively, leading to metabolic failure. Undigested glycogen begins to accumulate, causing the lysosomes to swell dramatically. This excessive buildup damages cells, especially in muscle tissue. The damage is most pronounced in the skeletal muscles and the cardiac muscle of the heart, resulting in the characteristic muscle weakness and organ dysfunction.
Autosomal Recessive Inheritance
Pompe disease follows an autosomal recessive pattern of inheritance, meaning a child must inherit two copies of the mutated GAA gene—one from each biological parent—to develop the condition. The parents are typically carriers, possessing one working copy and one mutated copy, but they do not exhibit symptoms themselves.
When two parents are carriers, there is a 25% chance with each pregnancy that the child will inherit both mutated copies and be affected by Pompe disease. There is a 50% chance the child will inherit one mutated copy and become a carrier, and a 25% chance the child will inherit two normal copies of the gene.
How Enzyme Activity Dictates Disease Severity
The clinical outcome of Pompe disease is directly correlated with the amount of functional acid alpha-glucosidase enzyme the body still produces. This residual enzyme activity is determined by the specific genetic mutations inherited. The disease is broadly classified into two main forms based on this relationship: Infantile-Onset and Late-Onset.
Infantile-Onset Pompe Disease
Infantile-Onset Pompe disease is the most severe form, occurring when there is a near-total or complete absence of the enzyme, defined as less than 1% of normal activity. This profound deficiency leads to rapid, widespread glycogen accumulation and severe symptoms, including hypertrophic cardiomyopathy and respiratory failure. Symptoms typically manifest within the first few months of life, and without treatment, infants rarely survive past their first year.
Late-Onset Pompe Disease
Conversely, Late-Onset Pompe disease results from some residual enzyme activity, often ranging from 2% to 40% of normal levels. This partial activity allows for some glycogen breakdown, which slows the rate of accumulation and disease progression. Symptoms, such as progressive muscle weakness and breathing difficulties, can appear anytime from late childhood to adulthood. The heart is often spared the severe damage seen in the infantile form.