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

Vincenza Gragnaniello; Pim W W M Pijnappel; Alessandro P Burlina; Stijn L M In 't Groen; Daniela Gueraldi; Chiara Cazzorla; Evelina Maines; Giulia Polo; Leonardo Salviati; Giovanni Di Salvo; Alberto B Burlina

doi:10.1016/j.ymgmr.2022.100929

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. eCollection 2022 Dec.

Authors

Affiliations

¹ Division of Inherited Metabolic Diseases, Department of Diagnostic Services, University Hospital, Padua, Italy.
² Department of Pediatrics, Erasmus University Medical Center, Rotterdam, the Netherlands.
³ Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁴ Center for Lysosomal and Metabolic Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁵ Neurology Unit, St Bassiano Hospital, 36061 Bassano del Grappa, Italy.
⁶ Division of Pediatrics, S. Chiara General Hospital, Trento, Italy.
⁷ Clinical Genetics Unit, Department of Women's and Children's Health, and Myology Center, University of Padova, Padova, Italy.
⁸ Division of Paediatric Cardiology, Department of Women's and Children's Health, University Hospital Padua, Padua, Italy.

Abstract

Pompe disease (PD) is a progressive neuromuscular disorder caused by a lysosomal acid α-glucosidase (GAA) deficiency. Enzymatic replacement therapy is available, but early diagnosis by newborn screening (NBS) is essential for early treatment and better outcomes, especially with more severe forms. We present results from 7 years of NBS for PD and the management of infantile-onset (IOPD) and late-onset (LOPD) patients, during which we sought candidate predictive parameters of phenotype severity at baseline and during follow-up. We used a tandem mass spectrometry assay for α-glucosidase activity to screen 206,741 newborns and identified 39 positive neonates (0.019%). Eleven had two pathogenic variants of the GAA gene (3 IOPD, 8 LOPD); six carried variants of uncertain significance (VUS). IOPD patients were treated promptly and had good outcomes. LOPD and infants with VUS were followed; all were asymptomatic at the last visit (mean age 3.4 years, range 0.5-5.5). Urinary glucose tetrasaccharide was a useful and biomarker for rapidly differentiating IOPD from LOPD and monitoring response to therapy during follow-up. Our study, the largest reported to date in Europe, presents data from longstanding NBS for PD, revealing an incidence in North East Italy of 1/18,795 (IOPD 1/68,914; LOPD 1/25,843), and the absence of mortality in IOPD treated from birth. In LOPD, rigorous long-term follow-up is needed to evaluate the best time to start therapy. 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; DMF, digital microfluidics; ECG, electrocardiogram; EF, ejection fraction; EMG, electromyography; ERT, enzyme replacement therapy; Enzyme replacement therapy; GAA, acid α-glucosidase; GMFM-88, Gross Motor Function Measure; Glc4, glucose tetrasaccharide; IOPD, infantile-onset Pompe disease; ITI, immunotolerance induction; LOPD, late-onset Pompe disease; LVMI, left ventricular max index; MFM-20, motor function measurement; MRC, Medical Research Council Scale; MRI, magnetic resonance imaging; MS/MS, tandem mass spectrometry; NBS, newborn screening; Newborn screening; PBMC, peripheral blood mononuclear cells; PD, Pompe disease; PPV, positive predictive value; Pompe disease; RUSP, Recommended Uniform Screening Panel; Tandem mass-spectrometry; Urinary tetrasaccharide; VUS, variants of uncertain significance.; nv, normal values; rhGAA, recombinant human GAA.