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



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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Fig. 1: Sulfatide analysis in DBS.
Fig. 2: Proposed algorithms for the newborn screening of MLD.


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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).

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Correspondence to Michael H. Gelb PhD.

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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.

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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).

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