The Diagnostic Journey of Infantile-Onset Pompe Disease

A diagnosis of infantile-onset Pompe disease, or IOPD, for your baby could be made through multiple pathways.

If you have a family history of Pompe disease, you may have received genetic counseling or in-utero testing of your baby. There’s also the possibility that IOPD has been identified through newborn screening after your baby was born.

If your baby has shown signs and symptoms of IOPD, your primary healthcare provider or a specialist may have performed tests to further investigate.

Below is some information on tests that you may encounter if your child is suspected to have Pompe disease.

When diagnosing a patient with Pompe disease, healthcare providers will create a list of disorders they believe could be causing those symptoms. This process is called differential diagnosis because medical professionals try to “differentiate” the signs and symptoms of various diseases from Pompe disease. Healthcare providers use a variety of tests to investigate patients’ symptoms, rule out other diseases, and arrive at a diagnosis.

Pompe disease can affect many of the body’s systems, and the following are common tests for IOPD in some parts of the body commonly affected by IOPD:


Healthcare providers may monitor your baby’s heart with an electrocardiogram, or ECG for short, to measure the heart’s electrical activity and test for problems with heart rate and rhythm. This is a simple, non-invasive test which uses adhesive electrodes on multiple places of the body to record, not transmit, electrical activity. Healthcare providers may also perform an echocardiogram, or ECHO, to visualize the heart and to investigate how the blood is being pumped through the heart. This test is also simple and noninvasive, and uses a handheld device to make images of the heart. A chest x-ray may also be performed to investigate if the heart is larger than normal.

Respiratory System

Babies cannot use the typical device (spirometer) that is used to measure the amount of air coming and going from the lungs. In addition to checking for outward, physical signs of breathing problems, your baby’s healthcare provider could measure respiration with a blood test that monitors a compound (bicarbonate) that may be elevated in the blood.


Your baby’s pediatrician monitors your baby’s growth, but he or she will pay special attention to monitoring height and weight if your baby is not gaining weight appropriately for development, which healthcare providers may call a “failure to thrive.” Additionally, the pediatrician may make assessments to investigate if your baby has any delays in their motor development, which is the ability to control and coordinate movement. Potential tests of this motor development, cognitive development or both include:

  • Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders
  • Denver Developmental Screening test
  • Alberta Infant Motor Scale
  • Test of Infant Motor Performance

Laboratory Tests

Your baby’s healthcare provider may order some additional laboratory tests that will help determine if your infant has Pompe disease. The healthcare provider may order a urine test (Hex4 fraction of glucose tetrasaccharide) that is indicative of the glycogen accumulation occurring in Pompe disease, as well as blood tests that are indicators of damage to the tissues affected by Pompe disease. The following blood tests can be indicative of muscle damage and may be elevated in patients with Pompe disease:

  • Creatine kinase (CK)
  • Creatine kinase of myocardial band (CK-MB)
  • Aspartate aminotransferase (AST)
  • Alanine aminotransferase (ALT)

One of the big challenges in diagnosing IOPD is that many of its symptoms are shared with other diseases, and a misdiagnosis can delay management.

Check the infographic below, which demonstrates how IOPD could easily be misdiagnosed. The symptoms listed below are not an exhaustive list and may not be inclusive of all symptoms that someone with these diseases may encounter.

Disorders That Mimic IOPD

Absent reflexes

Biventricular hypertrophy (thickening of heart ventricle walls)


Cardiomegaly (enlarged heart)

Cardiomyopathy (heart muscle disease)

Elevated creatine kinase (CK), an indicator of muscle damage

Feeding difficulties

Heart failure

Hepatomegaly (enlarged liver)

Hypertrophic cardiomyopathy (abnormally thick heart muscle)

Hypotonia (low muscle tone)

Hypotonia-severe (very low muscle tone)

Macroglossia (enlarged tongue)

Muscle weakness

Myopathy (muscle disease)

Progressive proximal muscle weakness

Skeletal muscle myopathy (skeletal muscle disease)

Vacuolar glycogen storage

After your healthcare provider suspects that your baby may have IOPD, healthcare providers will need to perform confirmatory testing to be certain of the diagnosis. As the introduction to Pompe disease explains, the symptoms of IOPD are due to a very low (<1%) level of acid alpha-glucosidase, or GAA enzyme. Healthcare providers may test for this enzyme, and use genetic testing for a confirmatory diagnosis.

Infantile-onset Pompe disease is an inherited disorder. The typical confirmatory test is a blood-based test that uses genetics to determine if there is a problem with the gene for the GAA enzyme. In this test, the GAA gene is tested for known defects referred to as pathogenic variants or known alterations. The presence of two pathogenic variants confirms Pompe disease.

Blood-based tests, skin biopsy, and muscle biopsy are used to confirm IOPD, with blood-based tests being used more frequently over time.

Blood-based Tests

In infants, the typical blood-based test for GAA enzyme level is the dried blood spot sample. The dried blood spot sample consists of blood that is typically obtained by heel prick and placed on filter paper. Another form of blood-based testing is analysis of white blood cells for GAA enzyme activity. This test is performed on a whole blood sample.

Genetic testing of the blood sample is recommended to confirm alterations in the gene responsible for production of the GAA enzyme.

Skin Biopsy

To measure GAA enzyme activity from the skin, a small amount of skin is removed and sent to a laboratory where connective tissue cells of the skin called fibroblasts are the focus of testing. These fibroblasts are grown in the laboratory, or cultured, for approximately 4 to 6 weeks so that enough tissue is available to test for GAA enzyme levels.

Muscle Biopsy

Muscle biopsies are uncommon in IOPD. Muscle biopsy is a surgical removal of muscle tissue, is invasive, requires anesthesia, and involves shipping to a laboratory for possibly both GAA enzyme analysis and inspection of muscle tissue. This inspection of the muscle tissue can reveal glycogen accumulation to confirm Pompe disease; however, absence of glycogen accumulation in the muscle tissue selected does not rule out Pompe disease.