How is Pompe disease inherited?
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Pompe disease is a genetic disorder caused by mutations inherited at conception from an individual’s biological parents.
Specifically, Pompe is caused by mutations in the GAA gene, which provides instructions for making the enzyme acid alpha-glucosidase. Pompe-causing mutations lead to little to no function of this enzyme, which results in a toxic buildup of the sugar molecule glycogen in the body’s cells, especially muscle cells.
The accumulation of glycogen damages cells, ultimately leading to symptoms including muscle weakness.
Inheritance pattern
Everyone inherits two copies of the GAA gene, one from each biological parent. The Pompe disease inheritance pattern is known as autosomal recessive, which means that the rare disorder will only develop in individuals who have mutations in both copies of the GAA gene.
People with one mutated copy of the GAA gene, and a second healthy copy, are known as carriers. Pompe carriers will not develop overt symptoms of the disorder, but they can pass on the disease-causing mutation to their biological children.
If two people who are both Pompe carriers have biological children, there is a:
- 25% (1 in 4) chance that the child will have Pompe disease
- 50% (1 in 2) chance that the child will be a Pompe carrier
- 25% (1 in 4) chance that the child will not have Pompe disease or be a carrier.
If people who have Pompe disease have biological children, they are guaranteed to pass one mutated copy of the GAA gene to any offspring. If someone with Pompe disease has children with someone who is not a carrier, all of their offspring will be carriers because they will inherit one mutated copy of the gene from the parent with Pompe disease, and one healthy copy from the noncarrier parent.
If someone who has Pompe has a biological child with someone who is a Pompe disease carrier, then there is a:
- 50% (1 in 2) chance that the child will have Pompe disease
- 50% (1 in 2) chance that the child will be a carrier for Pompe disease.
If two people with Pompe disease choose to have biological children with each other, they are each guaranteed to pass on a mutated copy of the GAA gene. That means their children also will have Pompe disease — though notably, children of Pompe parents may have different forms of the disease than either parent, with differences in age at onset and symptom manifestations.
Can people who aren’t carriers have children with Pompe disease?
In virtually all cases, if a child has Pompe disease, it means both parents carry a mutated copy of the GAA gene. Exceptions are extremely rare, but possible: in these rare cases, mutations develop de novo, meaning the mutation is only found in a child but not in either biological parent.
Age of onset
Based on the age at which symptoms first develop, there are three types of Pompe disease:
- In classic infantile-onset disease, symptoms such as heart disease, called cardiomyopathy, are present in the first year of life.
- In nonclassic infantile-onset disease, signs of the disorder appear in the first year of life, but generally without cardiomyopathy.
- In late-onset disease, symptoms develop after the first year of life, during childhood or in adulthood.
The age of onset of symptoms is partially dependent on the type of GAA mutation that a person carries.
In particular, babies with the most severe classic infantile-onset form of Pompe disease almost always carry mutations that lead to total or near-total absence of functional acid alpha-glucosidase enzyme. By contrast, patients with late-onset Pompe disease usually have mutations that allow more functional enzyme to be produced.
As a general rule, if a particular set of two mutations causes classic infantile-onset Pompe disease in one child, then every child carrying the same set of mutations also will develop this most severe form of Pompe disease.
The situation is more complicated, however, when it comes to mutations that are associated with the milder nonclassic infantile Pompe disease, or with the late-onset form.
In these cases, two people who carry an identical set of mutations may have substantially different manifestations, and the age at which Pompe disease symptoms appear can vary by decades. Consequently, it’s not possible to make detailed predictions about the age at onset and clinical course for people with mutations that are associated with milder forms of Pompe disease based on genetic data alone.
It’s also important to note that if someone with Pompe disease chooses to have biological children, and a child also is diagnosed with Pompe disease, the parent and child will only share one mutated copy of the GAA gene. As such, the type of Pompe disease and age of onset may vary between parents and children, depending on the mutation that is inherited from the other parent.
GAA gene mutations
More than 550 Pompe-causing mutations in the GAA gene have been documented so far, occurring in people of all backgrounds. Most of these mutations have only been found in a few people or families.
A notable exception is a mutation called c.-32-13T>G — up to 90% of people with late-onset forms of Pompe disease have been reported to carry at least one copy of the GAA gene with this mutation.
Genetic testing
Genetic testing to detect mutations in the GAA gene is usually used to help confirm a diagnosis of Pompe disease. Genetic testing also may be used to identify carriers of the disease and help inform decisions about family planning.
If the parents both are known carriers for Pompe disease, it is possible to perform genetic testing during pregnancy while a fetus is still developing. Pre-implementation genetic testing — where an embryo is fertilized in a lab and tested for Pompe disease before being implanted into the womb to initiate pregnancy — also may be available for known carriers.
Newborn screening
Newborn screening involves routinely testing all babies for Pompe disease within the first few days of life. This is usually done by pricking the baby’s heel to collect a small drop of blood, which is then used to check for low activity of the GAA enzyme.
If the screen is positive, the baby can then be referred for additional testing to confirm the results and establish a diagnosis. Getting an early diagnosis can help patients and their families make proactive plans about disease management, and allows treatment that can slow disease progression to be given at the earliest possible opportunity.
Pompe Disease News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
FAQs about Pompe inheritance
Pompe disease is a genetic disorder caused by mutations inherited from a person’s biological parents. People with a history of Pompe in their biological families are most likely to carry a disease-causing mutation that they can pass on to their offspring if they choose to have biological children. Genetic testing and counseling can identify Pompe disease carriers and inform individuals about their risk of passing disease-causing mutations to their children.
Although the mutations that cause Pompe disease are present at birth, some people with late-onset forms of Pompe will not start to experience any symptoms of the disease until adulthood.
A person will only develop overt symptoms of Pompe disease if they carry two mutated copies of the GAA gene. Someone who is a Pompe disease carrier has one mutated copy of the GAA gene, and a second healthy copy of the gene. By definition, carriers do not show overt symptoms of Pompe disease, but they may pass the mutated gene on to their biological children.
If people with Pompe disease choose to have children, they are guaranteed to pass on one mutated copy of the GAA gene to each child. But any children will only develop Pompe disease if they also inherit a second mutated copy of the GAA gene from their other biological parent. If the child inherits a healthy copy of the gene from the other parent, the child would be a carrier for Pompe disease, but would not develop the disease itself.
Newborn screening programs for Pompe disease have been implemented in more than half of states in the U.S., but at present, some U.S. states do not have a Pompe newborn screening program.
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