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. 2021 Mar;23(3):555-561.
doi: 10.1038/s41436-020-01017-5. Epub 2020 Nov 20.

Toward newborn screening of metachromatic leukodystrophy: results from analysis of over 27,000 newborn dried blood spots

Xinying Hong #  1 , Jessica Daiker #  1 , Martin Sadilek  1 , Nicole Ruiz-Schultz  2 , Arun Babu Kumar  1 , Stevie Norcross  2 , Warunee Dansithong  2 , Teryn Suhr  3 , Maria L Escolar  4 , C Ronald Scott  5 , Andreas Rohrwasser  2 , Michael H Gelb  6   7
Affiliations

Toward newborn screening of metachromatic leukodystrophy: results from analysis of over 27,000 newborn dried blood spots

Xinying Hong et al. Genet Med. 2021 Mar.

Abstract

Purpose: Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A (ARSA), which results in the accumulation of sulfatides. Newborn screening for MLD may be considered in the future as innovative treatments are advancing. We carried out a research study to assess the feasibility of screening MLD using dried blood spots (DBS) from de-identified newborns.

Methods: To minimize the false-positive rate, a two-tier screening algorithm was designed. The primary test was to quantify C16:0-sulfatide in DBS by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The screening cutoff was established based on the results from 15 MLD newborns to achieve 100% sensitivity. The secondary test was to measure the ARSA activity in DBS from newborns with abnormal C16:0-sulfatide levels. Only newborns that displayed both abnormal C16:0-sulfatide abundance and ARSA activity were considered screen positives.

Results: A total of 27,335 newborns were screened using this two-tier algorithm, and 2 high-risk cases were identified. ARSA gene sequencing identified these two high-risk subjects to be a MLD-affected patient and a heterozygote.

Conclusion: Our study demonstrates that newborn screening for MLD is highly feasible in a real-world scenario with near 100% assay specificity.

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Conflict of interest statement

DISCLOSURE

M.H.G. is a consultant for PerkinElmer Corp. PerkinElmer was not involved in any aspects of the study described in this paper. The other authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1. Sulfatide analysis in DBS.
a UPLC-MS/MS chromatogram of four sulfatide species in DBS from a random newborn. The x-axis is time (min) and the y-axis is the MS/MS intensity. Peak 1 at 1.22 min is C16:1-OH-sulfatide, peak 2 at 1.31 min is C16:0-OH-sulfatide, peak 3 at 1.35 min is C16:0-sulfatide and peak 4 at 1.46 min is C18:0-sulfatide. b C16:0-sulfatide abundance (μM) in DBS from 15 MLD newborns (median: 0.32 μM, range: 0.18–0.47 μM) and 2000 random newborns (median: 0.094 μM, range: 0.020–0.23 μM). The solid line is the median of the MLD group. The dash line is the screening cutoff at 0.17 μM. The crosses indicate MLD newborns without normalized C16:0-sulfatide data available (see text). The circles indicate MLD newborns with normalized C16:0-sulfatide data available and the data are presented in (c). c Normalized C16:0-sulfatide level in DBS from 6 MLD newborns (median: 1.24, range: 0.68–0.48) and 2000 random newborns (median: 0.34, range: 0.11–0.86). The dash line is the screening cutoff at 0.64 after normalization.
Fig. 2
Fig. 2. Proposed algorithms for the newborn screening of MLD.
a The C16:0-sulfatide DBS assay is the primary screening test and the ARSA DBS activity assay is the secondary test; b the ARSA DBS activity assay is the primary screening test and the C16:0-sulfatide DBS assay is the secondary test.
See this image and copyright information in PMC

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