Status of newborn screening and follow up investigations for Mucopolysaccharidoses I and II in Taiwan

Abstract

BackgroundMucopolysaccharidoses (MPS) are lysosomal storage diseases in which mutations of genes encoding for lysosomal enzymes cause defects in the degradation of glycosaminoglycans (GAGs). The accumulation of GAGs in lysosomes results in cellular dysfunction and clinical abnormalities. The early initiation of enzyme replacement therapy (ERT) can slow or prevent the development of severe clinical manifestations. MPS I and II newborn screening has been available in Taiwan since August 2015. Infants who failed the recheck at recall were referred to MacKay Memorial Hospital for a detailed confirmatory diagnosis.MethodsFrom August 2015 to November 2017, 294,196 and 153,032 infants were screened using tandem mass spectrometry for MPS I and MPS II, respectively. Of these infants, 84 suspected cases (eight for MPS I; 76 for MPS II) were referred for confirmation. Urinary first-line biochemistry examinations were performed first, including urinary GAG quantification, two-dimensional electrophoresis, and tandem mass spectrometry assay for predominant disaccharides derived from GAGs. If the results were positive, a confirmative diagnosis was made according to the results of leukocyte enzymatic assay and molecular DNA analysis. Leukocyte pellets were isolated from EDTA blood and used for fluorescent α-iduronidase (IDUA) or iduronate-2-sulfatase (IDS) enzymatic assay. DNA sequencing analysis was also performed.ResultsNormal IDS and IDUA enzyme activities were found in most of the referred cases except for four who were strongly suspected of having MPS I and three who were strongly suspected of having MPS II. Of these infants, three with novel mutations of the IDS gene (c.817C > T, c.1025A > G, and c.311A > T) and four with two missense mutations of the IDUA gene (C.300-3C > G, c.1874A > C; c.1037 T > G, c.1091C > T) showed significant deficiencies in IDS and IDUA enzyme activities (< 5% of mean normal activity), respectively. Urinary dermatan sulfate and heparan sulfate quantitative analyses by tandem mass spectrometry also demonstrated significant elevations. The prevalence rates of MPS I and MPS II in Taiwan were 1.35 and 1.96 per 100,000 live births, respectively.ConclusionsThe early initiation of ERT for MPS can result in better clinical outcomes. An early confirmatory diagnosis increases the probability of receiving appropriate medical care such as ERT quickly enough to avoid irreversible manifestations. All high risk infants identified in this study so far remain asymptomatic and are presumed to be affected with the attenuated disease variants.

Development of a newborn screening tool for mucopolysaccharidosis type I based on bivariate normal limits: Using glycosaminoglycan and alpha‐L‐iduronidase determinations on dried blood spots to predict symptoms

“…However, the choice of low (and therefore sensitive) enzyme thresholds is partially responsible for the lack of an acceptable balance between false positive and negative screens in NBS, as reported for the two disorders to which BVNL diagnostic tools have now been applied: KD 13,33 and MPSI. [14][15][16][17][18][19] There is also ethically motivated urgency to reduce high false positive rates. 32 Using more aggressive thresholds to reduce false positive screens in a univariate test may, however, increase false negative screens.…”

“…This would represent a remarkable improvement in NBS for MPSI. [14][15][16][17][18][19] No new case was identified among the 5000 prospective screens from the Gifu prefecture. New York State recently reported the results of 65 000 LSDs newborn screens.…”

“…Pilot studies were, for example, performed with dried blood spots (DBS) in Taiwan and in Italy . The PPV values for MPSI were 26.7% and 7.7%, respectively.…”

Identification and Functional Characterization of IDS Gene Mutations Underlying Taiwanese Hunter Syndrome (Mucopolysaccharidosis Type II)

“…As mentioned above, the variation allele, c.103 + 34_56dup, a novel IDS variation located between exon 1 and exon 2 (intron-1) downstream of the 34 to 56 regions, had a repeat sequence, CCTTCCTCCCTCCCTTCCTTCCT. The cDNA sequencing analysis was normal, and there was no significant difference in RNA expression in real-time PCR analysis [41]. Most of the cases also showed other IDS mutations, including c.851C>T (P284L) in exon 6, c.1180 + 184T>C (splicing) in intron 8, and c.684A>G (p.Pro228 =) in exon 5 (silent mutation).…”

“…Most of the cases also showed other IDS mutations, including c.851C>T (P284L) in exon 6, c.1180 + 184T>C (splicing) in intron 8, and c.684A>G (p.Pro228 =) in exon 5 (silent mutation). The patients with these combinations of variation alleles had pseudo-deficiencies of leukocyte IDS enzyme activities, ranging from 0.56 to 14.69 µmol/g protein/4 h, but no significant signs or symptoms were noted when surveying the family members who had the same variation alleles [41]. Chang et al reported that the c.240 + 1G>C variation in intron 2 resulted in false splicing that caused the deletion of 105 amino acids and caused the severe form of MPS II [14].…”