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

Genetics in Medicine (2020)Cite this article

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

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Acknowledgements

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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Author notes

  1. These authors contributed equally and should both be considered as first authors: Xinying Hong, Jessica Daiker.

Affiliations

  1. Department of Chemistry, University of Washington, Seattle, WA, USA

    Xinying Hong PhD, Jessica Daiker BS, Martin Sadilek PhD, Arun Babu Kumar PhD & Michael H. Gelb PhD

  2. Utah Public Health Laboratory, Salt Lake City, UT, USA

    Nicole Ruiz-Schultz PhD, Stevie Norcross PhD, Warunee Dansithong PhD & Andreas Rohrwasser PhD

  3. MLD Foundation, West Linn, OR, USA

    Teryn Suhr RN

  4. The Program for the Study of Neurodevelopment in Rare Disorders, University of Pittsburgh, Pittsburgh, PA, USA

    Maria L. Escolar MD

  5. Department of Pediatrics, University of Washington, Seattle, WA, USA

    C. Ronald Scott MD

  6. Department of Biochemistry, University of Washington, Seattle, WA, USA

    Michael H. Gelb PhD

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  1. Xinying Hong PhD
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  2. Jessica Daiker BS
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Correspondence to Michael H. Gelb PhD.

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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.

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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

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