Causes of Pompe disease
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Pompe disease is a rare genetic disorder caused by a toxic buildup of the sugar molecule glycogen inside cells, primarily affecting muscle cells. The disease causes progressive muscle weakness and poor muscle tone. It is also known as acid alpha-glucosidase deficiency, acid maltase deficiency, or glycogen storage disease type 2.
What causes Pompe disease?
Pompe is caused by mutations in the GAA gene, which provides instructions for making an enzyme called acid alpha-glucosidase (abbreviated GAA). Genetic testing to identify disease-causing mutations in the GAA gene is one of the tools used for Pompe disease diagnosis.
The GAA enzyme is normally responsible for breaking down glycogen, a complex sugar molecule. When the body needs energy, the GAA enzyme breaks down glycogen into a simpler sugar called glucose, which can then be used to generate energy. Muscle cells, in particular, use glycogen to help provide the energy needed to power muscle movements.
If the GAA enzyme is absent or defective, glycogen accumulates within cells and reach levels that are toxic and can cause cell damage. Cell damage can ultimately lead to an impairment in the functioning of different organs and tissues.
How do mutations cause Pompe disease?
In Pompe, mutations in the GAA gene either lead to the production of a GAA enzyme that doesn’t work properly or stop any enzyme from being made at all. Consequently, glycogen cannot be broken down into glucose, instead building up to toxic levels within cells.
The breakdown of glycogen by GAA enzymes occurs within lysosomes, which are cellular compartments that act as a cell “recycling center” where specialized lysosomal enzymes help to break down complex molecules into simple components. Pompe is therefore considered a type of lysosomal storage disorder.
Glycogen accumulation can mechanically interfere with the proper functioning of lysosomes and cells. The buildup of glycogen in muscle cells, in particular, may interfere with a number of signaling and metabolic pathways that are essential for normal muscle function. This damage to muscles ultimately results in the disease’s symptoms and necessitates treatment.
How is Pompe disease inherited?
Each person inherits two copies of the GAA gene. Pompe 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.
A person who has only one mutated copy of the gene (and one nonmutated copy) is referred to as a “carrier.” These individuals will not develop any symptoms of the disorder, but they carry the disease-causing mutation and may pass it on to their biological children.
In terms of inheritance, if two people who are both carriers have biological children, there is a 25% chance that each child will develop the disease. There is a 50% chance that any children will be carriers 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 of the mutated copy, the child will have a 50% chance of being a carrier, but none of the offspring will develop the disease.
| Parents | Impact to offspring |
|---|---|
| One parent with mutated copy of GAA gene |
|
| Both parents with mutated copy of GAA gene |
|
How do mutations affect disease severity?
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 nongenetic factors that aren’t completely understood.
Mutations that cause the GAA enzyme to be completely absent or nonfunctional (enzyme activity less than 1% of normal) usually cause infantile-onset Pompe disease. This generally is the most severe type of Pompe. By comparison, mutations that partially limit enzyme activity, usually between 2% and 40% of normal activity, are associated with late-onset forms that are generally less severe.
Some specific GAA mutations tend to cause a particular disease course, though these associations are not absolute. These include:
- p.Glu176ArgfsTer45 and p.Gly828_Asn882del, both of which tend to cause severe infantile-onset disease and are common in Dutch populations
- p.Asp645Glu, commonly associated with infantile-onset disease among patients in Taiwan and China
- p.Arg854Ter, frequently linked with infantile-onset disease in people of African descent
- c.-32-13T>G, reported in a large percentage of people with late-onset Pompe.
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 disease causes
Pompe disease is caused by genetic mutations that are inherited from a person’s biological parents. The disease-causing mutations are present from the moment of conception, though disease symptoms may not become apparent until later in life.
While individuals with infantile-onset Pompe usually have obvious abnormalities within the first few months after birth, some people with late-onset forms of Pompe disease do not experience any overt symptoms of the disease until adulthood. The onset and course of Pompe depend on the severity of functional defects resulting from mutations in the GAA gene. These mutations lead to altered GAA enzyme activity, and consequently to glycogen accumulation inside cells to toxic levels. When GAA enzyme activity is impaired but not absent, glycogen builds up more slowly, and so the disease symptoms take longer to develop and progress. Late-onset Pompe patients may have up to 40% of normal levels of the functional enzyme, which may be sufficient for them to have a symptom-free life for decades.
All forms of Pompe disease are life-threatening. This is because the disease can cause problems with the muscles of the heart and/or the muscles that are needed to control breathing. These problems can ultimately lead to heart or respiratory failure in patients.
Life expectancy depends on the type of Pompe disease. In general, later age at symptom onset is associated with a longer life expectancy. If untreated, babies with infantile-onset Pompe usually die from heart failure within the first year of life, whereas patients with late-onset disease who don’t develop symptoms until adulthood may live into their 50s. Modern treatments, particularly enzyme replacement therapy, are improving survival outcomes for people with Pompe.
Pompe disease is equally common in male and female patients. The GAA gene, the mutated gene in Pompe, is not located in sex-associated chromosomes.
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