Newborn screening finds more presumed LOPD cases than expected
North Carolina data also point to ways to refine testing after positive screens
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Newborn screening (NBS) for Pompe disease in North Carolina identified more babies with presumed late-onset Pompe disease (LOPD) than previous estimates suggested, a study found.
Among more than 228,000 newborns screened over 20 months, 52 tested positive for possible Pompe. After additional testing, about one-third were ultimately classified as having presumed LOPD. That translated to about one case per 12,700 newborns, a higher rate than previously reported. No cases of infantile-onset Pompe disease (IOPD) were identified.
Screening process highlights areas for improvement
The researchers also identified parts of the screening process that could be improved and developed two step-by-step guides: one to “enable timely treatment of the infantile onset form of Pompe disease” and another to help reach “a clinical designation after a positive NBS for Pompe disease,” they wrote.
The study, “Early detection in action: developing and refining newborn screening for Pompe disease in North Carolina,” was published in Molecular Genetics and Metabolism.
Pompe is caused by mutations in the GAA gene that result in too little or poorly working acid alpha-glucosidase (GAA), an enzyme needed to break down glycogen, a stored form of sugar. Without enough working GAA, glycogen builds up inside cells, particularly muscle cells, causing progressive damage.
IOPD, the most severe Pompe type, typically causes Pompe symptoms within the first months of life and can rapidly lead to severe muscle weakness, heart problems, and feeding difficulties. LOPD has a much more variable course, with symptoms appearing anytime from infancy to adulthood.
NBS can help identify affected babies early, allowing prompt evaluation and timely treatment when needed. Pompe was added to the recommended U.S. NBS panel in 2015, although individual states introduced screening at different times. North Carolina added Pompe to its NBS program in February 2023.
In this study, a team of researchers in North Carolina analyzed outcomes from the first 20 months of screening in the state, through October 2024. Their goal was to add North Carolina’s real-world experience to the growing body of evidence on NBS for Pompe and identify ways to improve the screening process.
Presumed LOPD rate higher than earlier estimates
Of the 228,474 babies screened, 52 had a positive result that required further evaluation. After follow-up testing, 18 (35%) were classified as having presumed LOPD, or one case per 12,693 births — higher than the roughly one in 21,900 estimate from an earlier analysis of NBS studies.
The remaining babies were classified as having false-positive results (17), being carriers (seven), or having pseudodeficiency — genetic changes that lower measured GAA activity without causing Pompe (five). Five had uncertain results. A carrier has only one mutated copy of the GAA gene, while people with Pompe have mutations in both copies.
No babies with IOPD were identified during the study period. The researchers were also unaware of any babies with Pompe who had been missed since North Carolina began screening. However, they cautioned that it is too early to determine the program’s sensitivity “given that individuals with LOPD may not develop symptoms until later in childhood or adulthood.”
The team also examined how well the different steps in the screening process distinguished babies likely to have Pompe from those who tested positive for other reasons.
Screening begins by measuring GAA activity in a small dried blood sample collected from the baby. In North Carolina’s NBS program, babies with very low activity undergo urgent follow-up testing for possible IOPD. For babies with less severely reduced activity who appear well, clinicians can wait for results from additional screening tests, including genetic analysis, before moving to follow-up testing.
The researchers found that GAA activity tended to be lower during warmer months and higher during colder ones. Clinicians in North Carolina account for these fluctuations by comparing each baby’s result with the median value measured in samples tested that same day. This approach kept the number of positive screens relatively consistent across seasons.
The timing of sample collection also mattered. GAA activity changed depending on how many days after birth the blood sample was collected, suggesting that a baby’s age at testing may need to be considered when interpreting the result.
Additional tests show mixed value in follow-up
Among the additional screening measurements evaluated, a test combining GAA activity with levels of the molecules creatine and creatinine in the original blood sample added little useful information. It spared only two babies from subsequent genetic testing and generally could not distinguish presumed LOPD cases from false-positive results. North Carolina has since stopped using the test.
By contrast, comparing GAA activity with that of another enzyme, called IDUA, better distinguished among groups of babies with different outcomes after a positive screen. The researchers said this GAA/IDUA ratio could help refine screening, although further research is needed to ensure it would not cause affected babies to be missed.
Drawing on their experience, the researchers developed two step-by-step guides for evaluating babies after a positive screen.
The first is designed to quickly evaluate babies with very low GAA activity who may have IOPD. These babies can undergo heart tests, repeat enzyme testing, urine testing, and genetic analysis to help establish a Pompe diagnosis, while allowing treatment to begin quickly when IOPD is strongly suspected.
The second provides a broader roadmap to help doctors interpret the full set of follow-up results and decide whether a baby most likely has Pompe, is a carrier, has pseudodeficiency or a false-positive result, or needs continued monitoring because the findings remain uncertain.
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