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

Gragnaniello, Vincenza; Pijnappel, Pim W.W.M.; Groen, Stijn L.M. in ‘t; Gueraldi, Daniela; Cazzorla, Chiara; Maines, Evelina; Polo, Giulia; Salviati, Leonardo; Salvo, Giovanni Di; Burlina, Alberto

doi:10.1016/j.ymgmr.2022.100929

Cited by 18 publications

(17 citation statements)

References 103 publications

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“…While working through publication of this manuscript, additional data were published about incidence of PD in Italy ( 12 ), as well as updated data made available by the Tennessee Department of Health NBS program, and data shared by both Colorado newborn screening program and North Carolina department of health and human services via posters at the APHL/ISNS NBS Symposium in Sacramento, October 15–19, 2023. An updated binomial analysis, inclusive of this additional data is available in Appendix E .…”

Section: Discussionmentioning

confidence: 99%

An analysis of Pompe newborn screening data: a new prevalence at birth, insight and discussion

Colburn,

Lapidus

2024

Front. Pediatr.

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This study includes over 11.6M newborns screened (NBS) for Pompe Disease (PD) from 29 distinct universal screening programs across 8 countries and 4 continents. The birth prevalence of PD is 1:18,711, with no evidence of difference across populations of European, Latin American, or Asian ancestry, though differences may exist for PD subtypes. This study also compares these results, based on direct detection of disease and analyzed using a binomial method along with power analysis, with other methods for estimating the ‘frequency’ of rare genetic diseases (such as utilizing Hardy-Weinberg equilibrium on allele frequency and confidence interval analysis). This comparison demonstrates the implications of sample size and frames a discussion on its influence on the reliability of results when extrapolating to a population beyond the study dataset.ObjectivesPrimary: Establish a new figure for prevalence at birth for Pompe disease by collecting and analyzing the largest relevant dataset to date and using that result to project population prevalence at birth in a novel way. Secondary: Compare these results to previous analyses to offer a framework for evaluating ‘frequency’ data that can be applied to other rare, genetic diseases, along with methods to assess quality of estimates.

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Section: Discussionmentioning

confidence: 99%

An analysis of Pompe newborn screening data: a new prevalence at birth, insight and discussion

Colburn,

Lapidus

2024

Front. Pediatr.

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“…Newborn screenings for a number of different diseases are becoming more common in recent years, and the largest screening for Pompe disease has been recently reported [ 24 ]. The authors have extensively addressed the problem of newborns carrying mutations that are associated with late-onset disease, and have provided their suggestions for the clinical follow-up of these cases.…”

Section: Discussionmentioning

confidence: 99%

Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD)

Filippi¹,

Errichiello

Toscano

et al. 2023

CIMB

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Pompe disease (PD) is a monogenic autosomal recessive disorder caused by biallelic pathogenic variants of the GAA gene encoding lysosomal alpha-glucosidase; its loss causes glycogen storage in lysosomes, mainly in the muscular tissue. The genotype–phenotype correlation has been extensively discussed, and caution is recommended when interpreting the clinical significance of any mutation in a single patient. As there is no evidence that environmental factors can modulate the phenotype, the observed clinical variability in PD suggests that genetic variants other than pathogenic GAA mutations influence the mechanisms of muscle damage/repair and the overall clinical picture. Genes encoding proteins involved in glycogen synthesis and catabolism may represent excellent candidates as phenotypic modifiers of PD. The genes analyzed for glycogen synthesis included UGP2, glycogenin (GYG1-muscle, GYG2, and other tissues), glycogen synthase (GYS1-muscle and GYS2-liver), GBE1, EPM2A, NHLRC1, GSK3A, and GSK3B. The only enzyme involved in glycogen catabolism in lysosomes is α-glucosidase, which is encoded by GAA, while two cytoplasmic enzymes, phosphorylase (PYGB-brain, PGL-liver, and PYGM-muscle) and glycogen debranching (AGL) are needed to obtain glucose 1-phosphate or free glucose. Here, we report the potentially relevant variants in genes related to glycogen synthesis and catabolism, identified by whole exome sequencing in a group of 30 patients with late-onset Pompe disease (LOPD). In our exploratory analysis, we observed a reduced number of variants in the genes expressed in muscles versus the genes expressed in other tissues, but we did not find a single variant that strongly affected the phenotype. From our work, it also appears that the current clinical scores used in LOPD do not describe muscle impairment with enough qualitative/quantitative details to correlate it with genes that, even with a slightly reduced function due to genetic variants, impact the phenotype.

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“…Our data demonstrate a high incidence of pseudodeficiencies, especially of the Asiatic variant p.Glu689Lys, alone ( n = 1) or in the complex allele p.(Gly576Ser; Glu689Lys) ( n = 7). Moreover, five European newborns carried the predicted non-pathogenic variant p.Val222Met [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Light and Shadows in Newborn Screening for Lysosomal Storage Disorders: Eight Years of Experience in Northeast Italy

Gragnaniello,

Cazzorla,

Gueraldi

et al. 2023

IJNS

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In the last two decades, the development of high-throughput diagnostic methods and the availability of effective treatments have increased the interest in newborn screening for lysosomal storage disorders. However, long-term follow-up experience is needed to clearly identify risks, benefits and challenges. We report our 8-year experience of screening and follow-up on about 250,000 neonates screened for four lysosomal storage diseases (Pompe disease, mucopolysaccharidosis type I, Fabry disease, Gaucher disease), using the enzyme activity assay by tandem mass spectrometry, and biomarker quantification as a second-tier test. Among the 126 positive newborns (0.051%), 51 infants were confirmed as affected (positive predictive value 40%), with an overall incidence of 1:4874. Of these, three patients with infantile-onset Pompe disease, two with neonatal-onset Gaucher disease and four with mucopolysaccharidosis type I were immediately treated. Furthermore, another four Gaucher disease patients needed treatment in the first years of life. Our study demonstrates the feasibility and effectiveness of newborn screening for lysosomal storage diseases. Early diagnosis and treatment allow the achievement of better patient outcomes. Challenges such as false-positive rates, the diagnosis of variants of uncertain significance or late-onset forms and the lack of treatment for neuronopathic forms, should be addressed.

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

Cited by 18 publications

References 103 publications

An analysis of Pompe newborn screening data: a new prevalence at birth, insight and discussion

An analysis of Pompe newborn screening data: a new prevalence at birth, insight and discussion

Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD)

Light and Shadows in Newborn Screening for Lysosomal Storage Disorders: Eight Years of Experience in Northeast Italy

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