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.
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.
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.
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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We are grateful for Giancarlo la Marca for providing part of the MLD newborn DBS used in the study. Funding is provided by Takeda and National Institutes of Health (R01 DK067859).
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.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Hong, X., Daiker, J., Sadilek, M. et al. Toward newborn screening of metachromatic leukodystrophy: results from analysis of over 27,000 newborn dried blood spots. Genet Med (2020). https://doi.org/10.1038/s41436-020-01017-5