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Newborn screening for Pompe disease in Italy: Long-term results and future challenges
Vincenza Gragnaniello1, Pim W W M Pijnappel2,3,4, Alessandro P Burlina5
1Division of Inherited Metabolic Diseases, Department of Diagnostic Services, University Hospital, Padua, Italy.
Insights
Newborn screening for Pompe disease (PD) identifies infantile-onset (IOPD) and late-onset (LOPD) cases. Early diagnosis and treatment of IOPD via newborn screening (NBS) significantly improve outcomes, with no mortality observed in treated infants.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Pompe disease (PD) is a progressive neuromuscular disorder caused by acid α-glucosidase (GAA) deficiency.
- Early diagnosis through newborn screening (NBS) is crucial for timely intervention and improved patient outcomes, particularly for severe forms.
- Enzymatic replacement therapy is an available treatment option.
Purpose of the Study:
- To present results from a 7-year newborn screening (NBS) program for Pompe disease (PD).
- To analyze the management of infantile-onset (IOPD) and late-onset (LOPD) PD patients identified through NBS.
- To identify predictive parameters for phenotype severity in PD patients.
Main Methods:
- Tandem mass spectrometry assay for α-glucosidase activity used to screen 206,741 newborns.
- Genetic analysis of the *GAA* gene for pathogenic variants and variants of uncertain significance (VUS).
- Clinical follow-up of identified patients, including monitoring with urinary glucose tetrasaccharide.
Main Results:
- Identified 39 positive neonates (0.019%) from 206,741 screened.
- Eleven neonates had pathogenic *GAA* variants (3 IOPD, 8 LOPD); six had VUS.
- Promptly treated IOPD patients showed good outcomes; LOPD and VUS infants were asymptomatic at follow-up (mean age 3.4 years).
- Urinary glucose tetrasaccharide proved a useful biomarker for differentiating IOPD/LOPD and monitoring therapy response.
- Study revealed PD incidence in North East Italy as 1/18,795 (IOPD 1/68,914; LOPD 1/25,843).
- No mortality observed in IOPD cases treated from birth.
Conclusions:
- Longstanding NBS for PD is effective, with early treatment of IOPD preventing mortality.
- Rigorous long-term follow-up is necessary for LOPD to determine optimal treatment timing.
- Further research is needed on high pseudodeficiency frequency, ethical considerations in early LOPD diagnosis, and predicting PD phenotypes.
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.
