The Genetic Roots of Pompe Disease


When two parents each pass on a mutated copy of a particular gene to their baby, that child can get Pompe disease. Because this rare condition doesn’t affect you if you carry just one faulty gene, parents usually don’t realize they could pass it to their children.

“Most of our families come to us without any knowledge of the disorder,” says Damara Ortiz, MD, director of the Lysosomal Storage Disorders Program at UPMC Children’s Hospital of Pittsburgh.

The gene linked to Pompe disease is known as the GAA gene. In healthy people, it produces the GAA enzyme. This enzyme breaks down a sugar called glycogen into glucose. Your body then uses the glucose for energy. The process takes place inside your cells, in structures known as lysosomes.

When someone has Pompe disease, their body doesn’t produce enough of the GAA enzyme. Glycogen then builds up within the lysosomes. This causes cell damage, especially within muscles. This may include the muscles that control your breathing and your heart.

The GAA gene is on what’s known as chromosome 17.

“We have two chromosome 17s — one we get from the father, one that comes from the mother,” says Jaya Ganesh, MD, an associate professor of genetics and pediatrics at Icahn School of Medicine at Mount Sinai in New York City. “Consequently, we have two copies of the Pompe gene.”

When someone is a carrier for Pompe disease, they have one GAA gene that works the right way and one that doesn’t. The working gene is dominant. So their bodies produce the enzyme needed to convert glycogen into glucose, and they don’t get Pompe disease.

Even when both parents have the mutated gene, all their children won’t necessarily get Pompe disease, or be carriers for it. When both parents are Pompe disease carriers, babies inherit two working GAA genes 25% of the time. They inherit two nonworking GAA genes — which leads to Pompe disease — 25% of the time. The rest of the time, they get one of each.

“[When] a healthy parent has a working copy and nonworking copy … they have [a] 50% chance of their child being a carrier,” says Ortiz, who is also medical director of medical genetics residency at the children’s hospital.

“You can get all of your children affected or none of your children affected, because each pregnancy is a separate, random event,” she says.

If one parent has Pompe disease and the second is a carrier, each of their children would have a 50-50 chance of inheriting the disease and a 50-50 chance of being a carrier. If both parents have Pompe disease, every child would inherit it.

Researchers have found hundreds of GAA gene mutations that can cause Pompe disease.

“There are now about 700 or more mutations, or variants, known in the GAA gene,” says Deeksha Bali, PhD, a professor of pediatrics at Duke University School of Medicine in Durham, NC.

Different GAA gene variants may affect how much working GAA enzyme your body produces. People who have 1% or 2% of normal enzyme activity usually get Pompe disease as infants. Those with 30% or 40% may not have symptoms until later in childhood or as adults.

Pompe disease affects all races and ethnic groups equally. Some groups may seem to have higher rates but are simply affected earlier in life.

“The African-American and the Taiwanese populations … have common infantile-onset Pompe disease variants,” Ortiz says. “Here, we see more commonly the late-onset variants, because our population happens to be more Caucasian.”

Couples who want to start families sometimes visit genetic counselors to learn if they’re at risk of passing genetic disorders to their children.

“Prenatal carrier screening has become very common,” Bali says. “In a lot of patients, carriers get picked up during prenatal carrier screening.”

When couples learn that they’re both carriers, they may decide to get pregnant naturally, then test the fetus to learn whether the baby has Pompe disease. Other couples do in-vitro fertilization, then test embryos.

“[They] then choose to implant the embryos that are either carriers or completely unaffected, so their children don’t have the same decision burden that they do,” Ortiz says.

Sometimes, prenatal genetic testing reveals that an adult has Pompe disease, although they don’t have symptoms — at least not yet.

“We are … picking up patients who we are screening for carrier status, but actually, they’re turning out to have mutations associated with later-onset disease and actually are diagnosed with Pompe disease,” Ganesh says.

In 2015, the U.S. Department of Health and Human Services added Pompe disease to the list of disorders that it recommends newborn babies be screened for. Now, many states screen all newborns for the condition.

“I’m actually very pleasantly surprised that in the past 5, 6 years since it started, about 27 states are already doing newborn screening for it,” Bali says.

When newborns are diagnosed with Pompe disease, they’re able to get treatment early. Enzyme replacement therapy extends the lives of people with the disorder.

“It is saving lives,” Bali says. “Kids who need treatment are getting treatments, and there is more awareness.”



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