Pompe disease is caused by a genetic problem that leads to a deficiency or absence of an important enzyme called acid alpha-glucosidase (GAA). This enzyme’s normal job is to break down glycogen, a stored form of sugar, inside the lysosomes of cells. Lysosomes are like the cell’s recycling centers, where various substances are broken down and reused. When GAA is missing or not working properly, glycogen cannot be broken down and starts to build up inside the lysosomes, especially in muscle cells. This accumulation causes damage to the muscles and other tissues, leading to the symptoms of Pompe disease.
The root cause of Pompe disease lies in mutations in the GAA gene, which provides instructions for making the acid alpha-glucosidase enzyme. These mutations are inherited in an autosomal recessive pattern, meaning a person must inherit two defective copies of the gene—one from each parent—to develop the disease. If someone has only one defective copy, they are a carrier but usually do not show symptoms.
There are many different mutations that can affect the GAA gene, and these mutations vary in how much they reduce the enzyme’s activity. Some mutations cause a complete absence of the enzyme, leading to the most severe form of Pompe disease, called infantile-onset Pompe disease. This form appears early in life and progresses rapidly, often causing serious heart and muscle problems. Other mutations allow for some residual enzyme activity, resulting in late-onset Pompe disease, which can begin anytime from infancy to adulthood and usually progresses more slowly.
Because the enzyme is deficient, glycogen accumulates primarily in skeletal muscles, heart muscle, and respiratory muscles. Over time, this buildup disrupts normal cell function and causes muscle weakness, respiratory difficulties, and in severe cases, heart enlargement and failure. The damage is progressive, meaning it worsens over time if untreated.
The genetic mutations that cause Pompe disease affect the production, folding, or function of the GAA enzyme. Some mutations change the enzyme’s structure so it cannot work properly, while others affect how much enzyme is made or how it is processed inside the cell. For example, a common mutation known as c.-32-13T>G affects the splicing of the GAA gene’s RNA, reducing the amount of functional enzyme produced. This particular mutation is frequently found in people with late-onset Pompe disease.
Because Pompe disease is inherited, it is present from birth, but symptoms may not appear immediately. The severity and age of onset depend on the specific mutations and how much enzyme activity remains. Early diagnosis is important because treatments that replace the missing enzyme can prevent or reduce muscle damage if started before severe symptoms develop.
In summary, Pompe disease is caused by inherited mutations in the GAA gene that reduce or eliminate the activity of the acid alpha-glucosidase enzyme. This enzyme deficiency leads to the harmful buildup of glycogen inside lysosomes, especially in muscle cells, causing progressive muscle weakness and other complications. The exact symptoms and severity depend on the type of genetic mutations and the resulting level of enzyme activity.
