Pompe disease (also known as acid-maltase disease and glycogen storage disease II) is a rare genetic disorder that causes progressive weakness to the heart and skeletal muscles. It is caused by mutations in a gene that makes an enzyme called acid alpha-glucosidase (GAA), which the body uses to break down glycogen, a stored form of sugar used for energy. The enzyme performs its function in intracellular compartments called lysosomes, which function as cellular clearinghouses. Lysosomes ingest multiple substances including glycogen, which is converted by the GAA into glucose, a sugar that fuels muscles.

In Pompe disease, mutations in the GAA gene reduce or completely eliminate this essential enzyme, which causes buildup that damages the muscles of the skeletal muscles and heart most seriously. The severity of the disease and the age of onset, which varies widely, are related to the degree of enzyme deficiency.

There are two forms of Pompe disease:

1. Early onset (infantile form) is caused by the complete or near complete deficiency of GAA. Symptoms begin in the first months of life, with feeding problems, poor weight gain, trouble breathing, muscle weakness, enlarged heart, floppiness, and head lag. Many infants with Pompe disease also have enlarged tongues. Without enzyme replacement therapy, most babies die from cardiac or respiratory complications before their first birthday.
2. Late onset (juvenile/adult) results from partial deficiency of GAA and can begin as early as the first decade of childhood or well into adulthood. Muscle weakness progresses to death from respiratory failure after several years. The heart is usually not involved.

Enzyme replacement therapy can help improve muscle tone and reduce glycogen storage in individuals with Pompe disease. The following drugs have been approved:

• Alglucosidase alfa (Myozyme©) to treat infantile-onset Pompe disease
• Lumizyme© to treat individuals of all ages with Pompe disease
• Avalglucosidare alfa-ngpt (Nexviazyme©) for individuals age 1 and older with late-onset Pompe disease

Mutations in the GAA gene cause Pompe disease. The GAA gene provides instructions for producing an enzyme called acid alpha-glucosidase (also known as acid maltase). This enzyme is active in lysosomes, which are structures that serve as recycling centers within cells. The enzyme normally breaks down glycogen into a simpler sugar called glucose, which is the main energy source for most cells.

Mutations in the GAA gene prevent acid alpha-glucosidase from breaking down glycogen effectively, which allows this sugar to build up to toxic levels in lysosomes. This buildup damages organs and tissues throughout the body, particularly the muscles, leading to the progressive signs and symptoms of Pompe disease.

Normal Function

The GAA gene provides instructions for producing an enzyme called acid alpha-glucosidase (also known as acid maltase). This enzyme is active in lysosomes, which are structures that serve as recycling centers within cells. Lysosomes use digestive enzymes to break down complex molecules into simpler ones that can be used by cells. Acid alpha-glucosidase normally breaks down a complex sugar called glycogen into a simpler sugar called glucose. Glucose is the main energy source for most cells.

Health Conditions Related to Genetic Changes

Pompe disease

More than 200 mutations in the GAA gene have been identified in people with Pompe disease. Many of these mutations change one of the protein building blocks (amino acids) used to make acid alpha-glucosidase. Other mutations insert or delete genetic material in the GAA gene. Mutations in this gene significantly reduce the activity of acid alpha-glucosidase, preventing the enzyme from breaking down glycogen effectively. As a result, this complex sugar can build up to toxic levels in lysosomes. The abnormal buildup of glycogen damages organs and tissues throughout the body, particularly the muscles, leading to progressive muscle weakness, heart problems, and the other features of Pompe disease.

Other Names for This Gene

• acid alpha-glucosidase
• acid alpha-glucosidase preproprotein
• acid maltase
• Aglucosidase alfa
• Alpha-1,4-glucosidase
• Amyloglucosidase
• Glucoamylase
• glucosidase, alpha; acid
• glucosidase, alpha; acid (Pompe disease, glycogen storage disease type II)
• LYAG
• LYAG_HUMAN
• lysosomal alpha-glucosidase

Genomic Location

Pompe disease is a genetic condition. Babies inherit it from their biological (birth) parents.

• Pompe disease is an autosomal recessive condition. Babies inherit the condition when each parent passes down a nonworking GAA gene to their baby. Only babies with two nonworking GAA genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the GAA gene are called carriers.
  • Carriers do not have or develop the condition. However, they may pass down a nonworking copy of the gene to their children.
  • If two parents are carriers of a nonworking copy of the GAA gene, they have a 1 in 4 chance of having a child with Pompe disease.
  • Carriers for Pompe disease often do not know they are carriers before having a child with the condition. In most cases, families have no history of the condition until the birth of a child with Pompe disease.
  • Parents who already have a child with Pompe disease still have a 1 in 4 chance of having another child with Pompe disease. This 1 in 4 chance stays the same for all future children.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

Newborn screening for Pompe disease is done using a small amount of blood collected from your baby’s heel. During screening, a special machine measures how much of a certain enzyme (called acid alpha-glucosidase or GAA) is in your baby’s blood. This enzyme is responsible for breaking down glycogen. Babies with a low level of this enzyme might have Pompe disease.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for Pompe disease is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Heart exam that may include a chest X-ray or an echocardiogram
• Blood and/or urine tests
• Genetic testing using a blood sample

You should complete any recommended follow-up testing as soon as possible. Babies with this condition can have serious health problems soon after birth if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition may happen. Some babies with positive newborn screening results for Pompe disease have “pseudodeficiency.” Pseudodeficiency means that a baby’s enzyme levels are low on the screening but are normal in their body. These babies do not have and will never develop Pompe disease.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

Signs of Pompe disease can appear shortly after birth (particularly in the classic infantile-onset form). Other forms of Pompe disease (nonclassic infantile-onset and late-onset forms) may not appear until later in infancy, adolescence, or adulthood.

Signs of the condition may include the following:

• Heart problems (cardiomyopathy)
• Muscle weakness (myopathy)
• Floppy arms and legs (hypotonia)
• Enlarged liver (hepatomegaly)
• Failure to gain weight and grow (failure to thrive)
• Breathing problems
• Hearing problems

It is important to talk to your health care provider about which treatment(s) are best for your baby. The goal of treatment is to prevent the health problems caused by this condition.

Treatments may include the following:

• Enzyme replacement therapy (ERT)
• Physical therapy
• Respiratory therapy and breathing support
• Nutritional and feeding support

Children who receive early and ongoing treatment for Pompe disease can live longer and have better growth.

Pompe disease affects about 1 in 40,000 people in the United States. The incidence of this disorder varies among different ethnic groups.