Causes of Pompe Disease

Pompe disease, a rare disorder affecting the heart and skeletal muscles in particular, is caused by mutations in the GAA gene, which provides instructions for making an enzyme called acid alpha-glucosidase. This enzyme is responsible for breaking down the complex sugar molecule glycogen into a simple sugar molecule called glucose, which cells can use to produce energy.

The disease is also known as acid alpha-glucosidase deficiency, acid maltase deficiency, or glycogen storage disease type 2.

How mutations cause Pompe disease

More than 550 different mutations in the GAA gene have been identified in people with Pompe disease. Some of these mutations lead to the complete absence of the acid alpha-glucosidase enzyme, while others may cause a reduction in the activity of the enzyme.

In either case, the lack of functional enzyme causes glycogen to build up over time to toxic levels inside cellular compartments called lysosomes, leading to damage in organs, tissues, and particularly muscles. Lysosomes are cellular compartments that act like the “recycling plants” of cells, where specialized lysosomal enzymes help to break complex molecules down into simple components.

Muscle cells — which use glycogen breakdown to help provide the energy for muscle movement — are most affected in Pompe disease.

Accumulated glycogen displaces or distorts myofibrils, tiny fibers inside muscle cells that are necessary for the cells to contract. Excessive glycogen also leads lysosomes to become enlarged and eventually rupture, which releases lysosomal enzymes that further damage tissues.

How Pompe disease is inherited

Every person inherits two copies of the GAA gene. Pompe disease is inherited in an autosomal recessive pattern. This means that to have the disease, a person must inherit two mutated copies of the GAA gene, one from each biological parent. So, each parent must either have the disease — meaning both their copies of GAA are mutated — or be carriers of the disease, meaning that they have one mutated copy of GAA and one non-mutated copy.

If two people who are both carriers have biological children, there is a 25% chance that their child will develop Pompe disease, and a 50% chance that the child will be a carrier like their parents. Children of two carriers have a 25% chance of not inheriting any mutated copies of the gene.

If only one of the parents is a carrier, the offspring will have a 50% of being a carrier, and a 50% chance of not inheriting the mutated gene.

How symptoms and enzyme activity vary

The symptoms of Pompe disease may emerge at any age from birth to late adulthood, and this is associated with the specific mutation in the GAA gene. In general, mutations that lead to a greater loss of enzyme function are associated with more severe disease, though disease severity is also affected by non-genetic factors not completely understood.

In individuals with late-onset Pompe disease, enzyme activity is partially lost to usually less than 40% of normal. In babies with the early-onset form, enzyme activity typically is completely or almost completely absent.


Last updated: June 1, 2021


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