GAA gene and Pompe disease
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Pompe disease is caused by mutations in the GAA gene, which is responsible for providing instructions for the production of an enzyme called acid alpha-glucosidase, also known as the GAA enzyme.
Pompe disease has a broad spectrum of severity, ranging from the more severe classic and nonclassic infantile-onset types that are characterized by abnormally low levels of muscle tone and delayed motor development, to the late-onset type of the disease that has slower progression in muscle weakness and breathing difficulties.
What is the GAA gene?
The GAA gene encodes instructions for the production of the GAA enzyme, which is needed to break down a complex sugar molecule called glycogen into a simpler sugar called glucose when the body needs energy. Muscle cells use glycogen to help provide the energy needed to power muscle movements.
Mutations in the GAA gene associated with Pompe disease either lead to the production of a GAA enzyme that doesn’t work properly or stops the enzyme from being made at all. Consequently, accumulated glycogen builds up to toxic levels within cells, particularly in the muscles.
Mutations that cause the GAA enzyme to be completely absent or nonfunctional — where enzyme activity is less than 1% of normal — usually cause infantile-onset Pompe disease. Mutations that partially limit enzyme activity — usually between 2% and 40% of normal activity — are associated with the late-onset form of the disease.
More than 560 mutations spread throughout the GAA gene have been reported on the Pompe Registry, which is the largest global collection of Pompe disease data.
How is the GAA gene inherited?
Each person has two copies of the GAA gene. Pompe disease is inherited in an autosomal recessive pattern, which means that a person must receive two mutated copies of the GAA gene, one from each biological parent, in order to develop the disease.
If a person only has one mutated copy of the gene (and one nonmutated copy) then they are known as a “carrier.” They will not develop any symptoms, but they may pass the disease-causing mutation on to their biological children.
If two people who are both carriers have children, there is a 25% chance each child will develop the disease, while there is a 50% chance their children will be carriers. The child of two carriers would have a 25% chance of not inheriting any mutated copies of the gene.
When only one of the parents is a carrier, the child will have a 50% chance of carrying a mutated copy of the gene, but none of the offspring will develop the disease.
In families in which one child has been already diagnosed with Pompe disease, it’s important to check siblings of the affected child to see if they may also have the disease or be carriers.
What tests are used to diagnose Pompe disease?
Pompe disease is primarily diagnosed through genetic analysis and enzyme activity tests. Blood tests, analysis measuring heart and muscle function, and breathing and sleeping tests are also used as part of the diagnostic process.
Screening among at-risk populations can identify carriers, and newborn screening can ensure treatment is started as soon as possible.
Enzyme activity tests
A dried blood spot or liquid blood sample is used to look for a deficiency of the GAA enzyme. Enzyme activity tests also can be performed on a person’s cells, collected through a muscle or skin biopsy.
People with infantile-onset Pompe disease usually have enzyme activity that is less than 1% of normal, whereas those with late-onset disease typically have enzyme activity levels up to 40% of normal.
Genetic testing
Genetic testing is used to identify mutations in the GAA gene. This often is done by taking blood or saliva samples.
Identifying family members who carry GAA mutations is important, as it can allow for genetic counseling. This can help people make informed decisions about having children. Prenatal testing is an option for future parents who are at a high risk of having a child with Pompe disease. This can be done during pregnancy.
Prenatal diagnosis is done through analysis of DNA extracted from fetal cells obtained by amniocentesis (analysis of the amniotic fluid that surrounds the fetus), typically performed between 15 and 18 weeks gestation or through chorionic villus sampling (to collect a tissue sample from the placenta) at 10 to 12 weeks gestation.
Other tests
Babies with classic infantile-onset Pompe disease display a form of heart muscle damage called cardiomyopathy. There are a number of tests that can identify heart damage:
- chest X-rays can determine if the heart is enlarged, a sign of heart damage
- electrocardiogram (EKG or ECG) identifies abnormal heartbeat patterns
- echocardiogram tests whether the heart muscle is functioning properly.
As Pompe mainly affects muscles, tests that check muscle function are often used as part of the diagnosis process, including:
- MRI to track muscle degeneration
- electromyogram to detect alterations in electrical activity in the muscles.
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 GAA gene
The GAA gene encodes instructions for the production of an enzyme called acid alpha-glucosidase, also known as the GAA enzyme.This enzyme is used in lysosomes, which are intracellular compartments that serve as recycling centers. Lysosomes use digestive enzymes to break down complex sugar molecules into simpler ones that can be used for energy.
If both parents are carriers of a mutated GAA gene, the baby has a 25% chance of inheriting two copies of the nonworking GAA gene, leading to Pompe disease. The infant also has a 50% chance of becoming a Pompe disease carrier. If only one of the parents carries a mutated GAA gene, then the child will not develop the disease but has a 50% chance of carrying a mutated copy of the gene.
Mutations in the GAA gene are identified through genetic tests, often done by testing a sample of blood or saliva.
Newborn screening is done for Pompe disease, usually by taking a blood sample from the baby’s heel, in 37 of the 50 U.S. states as of December 2022.
Both infantile-onset and late-onset Pompe disease are caused by mutations in the GAA gene, which results in symptoms including muscle weakness and delayed motor development. People with the most severe form of Pompe disease, classic infantile-onset, typically have mutations that lead to the absence or near-total absence of the GAA enzyme. In contrast, those with late-onset Pompe disease usually have mutations that allow more of the functional GAA enzyme to be produced.
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