The cause of Pompe disease, which is characterized by widespread muscle weakness, is a mutation of the GAA gene.

Who gets Pompe disease?

Parents pass Pompe disease to their children. The gene responsible for the disease is located on chromosome 17. Everyone has two copies of a chromosome and therefore of each gene on a chromosome.

Pompe disease is inherited in an autosomal recessive manner, which means that a person develops the disease only if they inherit two defective copies of the GAA gene. This means that both parents of a person with Pompe must carry at least one copy of the faulty gene. Carrying only one defective gene makes a person a carrier, but does not result in the person developing Pompe disease.

When a couple with one defective GAA gene each decides to have a child, there is a 25 percent risk of the child developing Pompe disease, a 50 percent risk of the child being a carrier, and a 25 percent chance of the child being neither a carrier nor having Pompe disease.

Genetic defects and their consequences

The GAA gene is responsible for producing the acid alpha-glucosidase enzyme. In Pompe, a faulty gene causes the body to make less of this enzyme.

Scientists have found more than 200 mutations of the GAA gene that can cause Pompe disease. The mutations affect working levels of the acid alpha-glucosidase enzyme, which in turn affects the severity of the disease.

In general, the lower the amount of working enzyme, the earlier a person will develop the disease. Those who have between 2 and 40 percent of a working enzyme usually develop symptoms in childhood or early adulthood. Infants who develop Pompe a few months after birth usually have less than 1 percent working enzyme.

The acid alpha-glucosidase enzyme is crucial for breaking down glycogen, a complex sugar. Excess glycogen is particularly toxic to muscles, damaging both limb and heart muscle. This leads to muscle weakness whose symptoms include difficulty walking, moving and breathing, depending on the muscles that are affected. Weak heart muscles reduce the heart’s ability to pump blood through the body, and can cause heart failure.

Genetic testing and counseling

Genetic testing is available to detect mutations of the GAA gene, which can help doctors confirm Pompe disease. It is also the only way to know if a person has a defective copy of the GAA gene and is thus a carrier of Pompe. Doctors have found that testing for levels of the acid alpha-glucosidase enzyme is an unreliable way to know if a person is a carrier.

Doctors often suggest carrier testing for relatives of Pompe disease patients and for couples who may be at risk of being carriers and want to start a family. In addition, embryos of couples who are using vitro fertilization to have a baby can be tested for mutations of the GAA gene before being transferred to the mother’s womb. Those considering genetic testing can have genetic counseling before doing so.

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