Newborn screening for Pompe disease in Italy: Long-term results and future challenges

Mol Genet Metab Rep. 2022 Oct 22;33:100929. doi: 10.1016/j.ymgmr.2022.100929.

PMID: 36310651

Vincenza Gragnaniello, Pim W W M Pijnappel, Alessandro P Burlina

Highlights: This study presents the results from 7 years of newborn screening (NBS) for Pompe disease (PD) and the management of infantile-onset (IOPD) and late-onset (LOPD) patients.

Abstract

Background: A deficiency of lysosomal acid α-glucosidase (GAA) results in Pompe disease (PD), a degenerative neuromuscular condition. Enzymatic replacement therapy is available, however for better outcomes, especially with more severe types, early detection through newborn screening (NBS) is crucial.

Objective and results: The therapy of patients with infantile-onset (IOPD) and late-onset (LOPD) PD, as well as the outcomes from seven years of NBS, are presented. Throughout this time, we looked for possible predictive markers of phenotypic severity at baseline and throughout follow-up. We screened 206,741 infants using a tandem mass spectrometry assay for α-glucosidase activity, and 39 positive neonates (0.019%) were found. Eleven had two GAA gene pathogenic variants (3 IOPD, 8 LOPD), and six had variants of uncertain significance (VUS). IOPD patients received quick care and experienced positive results. All of the infants with VUS and LOPD who were being monitored at the time were asymptomatic (mean age 3.4 years, range 0.5-5.5). A helpful biomarker for quickly distinguishing IOPD from LOPD and tracking treatment response during follow-up was urinary glucose tetrasaccharide.

Conclusion: The data in our analysis, the greatest to date in Europe, comes from long-standing NBS for PD and shows an incidence of 1/18,795 in North East Italy (IOPD 1/68,914; LOPD 1/25,843) and no mortality in IOPD treated from birth. With LOPD, a thorough long-term follow-up is required to determine when therapy should be started. The high pseudodeficiency frequency, ethical issues with early LOPD diagnosis, and difficulty predicting phenotypes based on biochemical parameters and genotypes, especially in LOPD, need further study.

Keywords: Acid α-glucosidase, CLIR, Collaborative Laboratory Integrated Reports, CRIM, cross-reactive immunological material, DBS, dried blood spot