Taiwan National Newborn Screening Program by Tandem Mass Spectrometry for Mucopolysaccharidoses Types I, II, and VI

Abstract

Objective: The first live and large-scale newborn screening program of multiple mucopolysaccharidoses (MPS) was developed in Taiwan. The initial cutoff values, rates of screen positives, and genotypes were evaluated. Study Design: More than 100,000 dried blood spots (DBSs) were collected consecutively as part of the national Taiwan newborn screening programs. Enzyme activities were measured by tandem mass spectrometry (MS/MS) from DBS punches. Genotypes were obtained when a second newborn screening specimen again had a reduced enzyme activity. Additional clinical evaluation was then initiated based on enzyme activity and/or genotype. Results: Molecular genetic analysis for cases with low enzyme activity revealed 5 newborns with pathogenic IDUA mutations, 3 newborns with pathogenic IDS mutations, and one newborn was a carrier of an ARSB mutation. Several variants of unknown pathogenic significance were also identified, most likely causing pseudodeficiency. Conclusions: The highly robust MS/MS-based enzyme assays for MPS I, MPS II and MPS VI allow for high throughput newborn screening for these lysosomal storage disorders (LSDs). Optimized cutoff values combined with second tier testing could largely eliminate false positive results. Accordingly, newborn screening for these LSDs is possible.

Incorporation of Second-Tier Biomarker Testing Improves the Specificity of Newborn Screening for Mucopolysaccharidosis Type I

“…Similar results were reported by Burton et al [5], with 151 infants out of 219,793 screened referred for confirmatory MPS I testing and an incidence of 1/7326 for IDUA pseudodeficiency and 1/219,793 for MPS I. These findings are reproduced in several additional reports [24][25][26][27][28]. With the overall incidence of pseudodeficiency being approximately 16 times higher than true disease, newborn screening programs and clinicians involved in the evaluation of referred infants will continue to be overwhelmed with false-positive results if the enzymatic screen alone is utilized.…”

“…Several states have recently added MPS II, also known as Hunter syndrome, to their testing panels and newborn screening has already been underway in Japan and Taiwan for several years. Both published and recent/stated experience [32] has shown a high false-positive rate for MPS II newborn screening, attributable to the high frequency of pseudo and pseudo-like alleles in the IDS gene [25].…”

Genotype‐phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry

“…5,6 The recent initiation of newborn screening for MPS I as well as other programs to identify individuals with MPS I at an age when CNS and somatic involvement may be minimal, highlight the need for accurate delineation of patients so effective therapies can be initiated early. [7][8][9][10][11][12] Unfortunately, no currently available biochemical assessments allow for accurate classification of patients as either severe or attenuated. 13 Published diagnosis and management guidelines suggest a role for IDUA genotype in management decision making.…”

Early detection of lysosomal diseases by screening of cases of idiopathic splenomegaly and/or thrombocytopenia with a next‐generation sequencing gene panel

“…To reduce this diagnostic delay, universal newborn screening for LD has been implemented in some health systems . These newborn screening programs, which rely on high‐throughput enzymatic assays on dried blood spots (DBS), are limited to just a handful of LD with available treatment for which early detection provides demonstrable benefits.…”

“…To reduce this diagnostic delay, universal newborn screening for LD has been implemented in some health systems. [4][5][6] These newborn screening programs, which rely on high-throughput enzymatic assays on dried blood spots (DBS), are limited to just a handful of LD with available treatment for which early detection provides demonstrable benefits. For all other LD, the diagnostic strategy is traditionally based, upon clinical suspicion, on assaying enzymatic activities on cultured cells (the gold standard) 7 or DBS, followed by molecular genetic testing of positive cases to identify the underlying mutations.…”