Pompe disease is a rare genetic disorder that impacts muscle function due to a deficiency of a specific enzyme. Newborn screening programs identify treatable conditions early. Sometimes, these screenings yield a “false positive” result, indicating a potential issue that is not actually present.
Understanding a Pompe Disease False Positive
A “false positive” in Pompe disease newborn screening means the initial test suggests low acid alpha-glucosidase (GAA) enzyme activity, but the baby does not have the condition. Newborn screening tests are highly sensitive to minimize missing true cases, which can lead to more initial positive results later found to be negative.
The screening test measures GAA enzyme activity in a dried blood spot from the baby’s heel. If this activity falls below a predetermined cutoff level, the result is considered positive, even if the baby’s body produces normal enzyme levels. Such a result does not confirm Pompe disease; it means further investigation is needed to determine the baby’s health status.
Factors Contributing to False Positives
Several factors can lead to a false positive result for Pompe disease during newborn screening, often stemming from genetic variations or technical aspects of the testing process. These factors do not indicate a health problem for the baby.
Genetic Variations
A common reason for a false positive is the presence of “pseudodeficiency alleles” or “benign variants” in the GAA gene. These common genetic changes can cause GAA enzyme activity to appear lower in the screening test without leading to Pompe disease symptoms. A pseudodeficiency allele like c.[1726A; 2065A] can result in GAA activity levels as low as those seen in Pompe disease. These mutations are observed more frequently in certain populations, approximately 4% in East Asian populations.
Technical and Laboratory Factors
Blood spot sample issues can also contribute to false positives. Insufficient sample volume or contamination interferes with accurate enzyme activity measurement. Sample handling, transport, or storage conditions, like extreme temperatures, can affect GAA enzyme stability, leading to an artificially low reading. Inherent limitations or variability within the screening assay can produce results below the established cutoff, even when enzyme activity is healthy.
Next Steps After a False Positive Result
A false positive screening result for Pompe disease can be concerning for parents. Subsequent steps involve confirmatory testing and support.
Confirmatory Testing
Specialists perform more precise tests to confirm or rule out Pompe disease. A repeat enzyme activity measurement uses a different blood sample, such as plasma or white blood cells, for a more accurate assessment of GAA enzyme activity.
Genetic (DNA) testing of the GAA gene is a definitive diagnostic step. This analysis examines the baby’s DNA to identify specific mutations associated with Pompe disease. If only a pseudodeficiency allele is found through GAA gene sequencing, and no disease-causing mutations are present, the screen is considered negative, and no further follow-up is recommended.
Other tests, including a heart exam (chest X-ray or echocardiogram) and blood or urine tests, may evaluate health. A blood test for creatine kinase (CK) levels, which can be elevated in Pompe disease, may be performed; however, elevated CK can also be caused by other conditions. Urine analysis for carbohydrates like glucose tetrasaccharides can provide additional information, as individuals with Pompe disease may have increased levels.
Process and Timeline
Parents are contacted by a healthcare specialist, a metabolic geneticist or genetic counselor, to discuss initial screening results and outline next steps. Confirmatory tests and results take time, and healthcare providers guide families through this waiting period.
Parental Support
Genetic counseling helps parents understand results, implications, and inheritance patterns of Pompe disease. Most false positive newborn screening results for Pompe disease are confirmed as negative. Attending all recommended follow-up appointments ensures thorough evaluation and accurate diagnosis.