Pompe Disease and Family Genetics

Pompe is classified as an autosomal recessive genetic disease that is acquired when a child inherits 2 altered GAA genes, 1 from each parent.

Introduction to the Genetic Nature of Pompe

Mutations are variations or changes in a gene that result in changes to the sequence of that gene. The genes that make up our DNA are composed of 4 bases: A, T, G, and C. The 4 bases pair up in a specific way such that A can only pair with T and G can only pair with C. Even so, these 4 bases and 2 base pairing combinations can form many, many different arrangements that create our genes. Each gene has a specific sequence of these bases, like words have a specific order of letters. Like how words can be misspelled, genes can have “mistakes”: base substitutions, deletions, additions, that alter the normal sequence of the gene. The result of the various types of gene variants can range from those that change the sequence of the gene while partially preserving its function to those that cause complete loss of function. In Pompe disease, depending on the type of variant , GAA gene function can be deficient or completely absent.

GAA has the important function of breaking down glycogen (a complex sugar) into glucose (a simple sugar) inside cell lysosomes (small structures within the cells). When GAA is absent or lacking, glycogen accumulates in the muscles, resulting in symptoms of Pompe disease. Depending on both the extent of deficiency and residual enzyme activity, symptoms can appear as early as the first few months of life or years to decades later.

Illustration of two muscle cells are presented: one is normal and the other is affected by Pompe disease. Each muscle cell shows a nucleus, glycogen, and a lysosome. Impaired breakdown of glycogen to glucose is illustrated in the muscle cell affected by Pompe disease

Autosomal Inheritance, Ethnicity and Genetic Variations

Pompe disease is rare, and current estimates put the incidence of occurrence at around 1 in 40,000 live births in the United States.

The incidence of a disease refers to the rate, or number, of new cases diagnosed in a given time period. The prevalence of a disease refers to the overall number of people affected with a particular disease. As with any rare disease, it is difficult to know exactly how many people are actually affected. It is estimated that the prevalence of Pompe disease may be 5,000 to 10,000 people worldwide. It occurs equally in males and females but varies depending on race and geographic location.

Genetic Variations

Many different genetic mutations or variations can affect the GAA gene. There are more than 500 gene variants although only about half are considered pathogenic, or disease-causing. Pathogenic variants that have been identified around the world are catalogued at the Pompe Centre at Erasmus MC. Individuals with Pompe disease may have the same gene variant (homozygous) or different gene variants (heterozygous), but most patients are likely to have more than 1 kind of GAA gene variant.

A carrier does not show any signs and symptoms of Pompe disease and is healthy. A carrier can, however, pass on the altered gene to their offspring. Let us look at a few possible scenarios.

A diagram showing the scenario when two healthy carriers of the GAA gene variant have a child. Silhouettes of parents and a pair of their chromosomes illustrate that they both have a copy of the variant GAA gene. Silhouettes of four children and a pair of their chromosomes illustrate the possibilities of being an affected child, an unaffected child, or an unaffected child who is a carrier.

When 2 healthy carriers of the GAA gene variant have a child, with each pregnancy their offspring have:

  • a 25% chance of inheriting 2 copies of the GAA gene variant (1 from each parent) and having Pompe disease
  • a 25% chance of inheriting 2 copies of the normal GAA gene (1 from each parent) and being unaffected
  • a 50% chance of inheriting only 1 copy of the GAA gene variant (from either parent) and being an unaffected carrier of the disease

A diagram showing the scenario when a father with Pompe disease has a child with a person who is a carrier of Pompe disease. Silhouettes of parents and a pair of their chromosomes illustrate that the father has two copies of a variant GAA gene while the mother has one. Silhouettes of four children and a pair of their chromosomes illustrate the possibilities of being an affected child or an unaffected child who is a carrier.

When a person with Pompe disease has a child with a person who is a carrier of Pompe disease, with each pregnancy their offspring have:

  • a 50% chance of inheriting 2 copies of the GAA gene variant (1 from each parent) and having Pompe disease
  • a 50% chance of inheriting only 1 copy of the GAA gene variant (from either parent) and being an unaffected carrier of the disease

A diagram showing the scenario when a father with Pompe disease has a child with a person who is unaffected by Pompe disease. Silhouettes of parents and a pair of their chromosomes illustrate that the father has two copies of a variant GAA gene while the mother does not have a variant GAA gene. Silhouettes of four children and a pair of their chromosomes illustrate that all children will be unaffected children that are carriers.

When a person with Pompe disease has a child with a person who is not a carrier of Pompe disease, with each pregnancy their offspring have:

  • a 100% chance of inheriting only 1 copy of the GAA gene variant (from the parent with Pompe) and being an unaffected carrier of the disease