Diagnosis of Pompe Disease

Pompe disease is a rare genetic condition caused by mutations in the GAA gene, which contains the information necessary to produce the acid alpha-glucosidase enzyme. This enzyme normally breaks down a complex sugar molecule called glycogen. Without a working version of this enzyme, glycogen accumulates inside cells, damaging them and leading to symptoms that include muscle weakness, breathing problems, and eating difficulties.

Typically, patients with less of the enzyme are younger at disease onset and experience greater clinical severity.

Diagnosing Pompe disease can be complicated, and it may take time for a definitive diagnosis to be reached. Typical symptoms, such as muscle weakness and heart disease, also are found in other conditions. In addition, early symptoms can be different for each patient and may appear at any age.

Further complicating matters, because Pompe disease is rare, healthcare providers may struggle to recognize the condition. Still, a number of tests exist to confirm a Pompe disease diagnosis.

Differential diagnosis

Many of the hallmark signs and symptoms of Pompe disease, like poor muscle tone, an enlarged heart or frequent chest infections, are found in other conditions. As such, a thorough evaluation is needed to distinguish between Pompe disease and other disorders, a process called differential diagnosis. Specialists such as neurologists, cardiologists, geneticists, pediatricians, and general practitioners may be involved in a differential diagnosis.

If this procedure concludes that symptoms point to the possibility of Pompe disease, further testing is necessary to confirm the diagnosis.

Enzyme activity tests

Upon suspicion of Pompe disease, the levels and activity of the acid alpha-glucosidase enzyme can be measured using several different methods. A test showing clear enzyme deficiency reveals the existence of Pompe even if disease-causing mutations are not found.

One minimally invasive way is checking for the enzyme’s presence through a skin biopsy. From the biopsy, cells called fibroblasts are the best source to test for enzyme activity. In people with Pompe disease, enzyme activity typically ranges from 40% to less than 1% of normal values. Enzyme activity also can be measured directly on a muscle biopsy based on tissue pathology, but this is a more invasive approach.

Blood tests are another non-invasive way of determining the activity of acid alpha-glucosidase. Testing in white blood cells isolated from a blood sample is one such approach. A blood spot test, where a blood sample from the patient is dried on a filter paper, also is an effective way of screening for Pompe disease. Blood spot tests often are used in newborn screening for various diseases.

Blood tests to measure enzyme activity are reported to be increasingly replacing biopsies, especially muscle biopsies, as a diagnostic approach, because of their faster and reliable results.

Genetic testing

While enzyme activity tests are the main diagnostic approaches when Pompe disease is suspected, genetic testing also may be requested. The aim of genetic testing is to identify disease-causing mutations in the GAA gene; this is often done with a sample of blood or saliva.

Because Pompe is an inherited disease, identifying family members who carry GAA mutations is important for the genetic counseling that can help them make informed decisions about family planning. Prenatal testing done prior to childbirth also is available for expectant parents who are at a high risk of having a child with Pompe disease.

Additional tests

Healthcare providers may ask for additional tests to complement and confirm previous test results.

One symptom of classic infantile Pompe disease is heart muscle damage, called cardiomyopathy, that impairs cardiac function. Doctors may need to take chest X-rays frequently to determine if the heart is enlarged (a sign of heart damage), an electrocardiogram to detect abnormal heartbeat patterns, and/or an echocardiogram (Echo) to test whether the heart muscle is functioning properly.

Another test that may be used is an electromyogram, which can detect abnormalities in muscle function that occur in Pompe patients. Muscle MRI also may help to detect muscle damage.

A common laboratory test is measuring levels of creatine kinase (CK) in the blood; high CK levels are indicative of muscle damage. Levels of liver enzymes also may be elevated.

People with Pompe disease may experience breathing difficulties due to weakness in the muscles needed for respiration, and these difficulties can cause sleep problems. Breathing tests and sleep studies help to assess these complications.


Last updated: May 20, 2021


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