Lessons from late-onset Pompe disease identified by Newborn screening: A systematic review

Late-onset Pompe disease (LOPD) is a lysosomal disease characterized by progressive weakness primarily in skeletal and respiratory muscles with symptom onset ranging from infancy to adulthood. The distinguishing feature between infantile-onset Pompe disease (IOPD) and LOPD is the absence of cardiomyopathy in the first year of life in LOPD. Newborn screening (NBS) has facilitated earlier detection, revealing an earlier disease spectrum than previously understood.

To systematically review NBS data from countries with published long-term follow-up, specifically Taiwan and the United States, focusing on clinical manifestations, genotypes, biomarkers, treatments, and follow-up data of LOPD.

A systematic search of PubMed was conducted up to January 2026 using the terms "Pompe disease," "late-onset Pompe disease," and "newborn screening."

Studies were included if they reported individuals diagnosed with LOPD through NBS. Exclusion criteria included non-English articles and studies limited to infantile-onset Pompe disease.

18 studies were included. Data extracted included genotype, biomarkers, muscle imaging, enzyme replacement therapy (ERT) status, and outcomes. Given the descriptive nature of the included studies, no risk of bias assessment was applied.

Results were synthesized narratively due to heterogeneity in outcome reporting. In Taiwan, the common splice site variant c.-32-13 T > G (IVS1) in GAA was not observed, whereas IVS1 homozygosity was frequent in U.S. cohorts and generally associated with milder phenotypes. Individuals who were compound heterozygous for the IVS1 variant and a second pathogenic GAA variant demonstrated more variable presentations, with some exhibiting elevated biomarkers and early motor signs. In Taiwan, 21% (8/39 cases) initiated ERT between 1.6 months and 3 years, representing the only population-level data with longer-term follow-up to date. In the United States, early post-NBS clinical experience has been reported, including a case series describing infants with LOPD who initiated ERT following identification by NBS, as well as a case series describing symptomatic infants also identified by NBS harboring the IVS1 variant in trans with a second pathogenic variant who demonstrated biochemical and motor improvement following early ERT initiation. While many NBS-identified individuals who did not meet criteria for early treatment remained clinically stable under surveillance, emerging evidence suggests that a subset of infants with early biochemical and functional abnormalities may benefit from timely initiation of ERT.

Heterogeneous follow-up, lack of unified diagnostic criteria, and limited long-term data.

NBS has expanded our understanding of emerging phenotypes that were not previously recognized. Future efforts should prioritize long term follow-up, phenotyping, and clearer ERT initiation guidelines. No datasets were created or analyzed for this study.