Higher precision, first tier newborn screening for metachromatic leukodystrophy using 16:1-OH-sulfatide

Soumeya Bekri; Annette Bley; Heather A Brown; Charlotte Chanson; Heather J Church; Michael H Gelb; Xinying Hong; Nils Janzen; David C Kasper; Thomas Mechtler; Georgina Morton; Simona Murko; Petra Oliva; Abdellah Tebani; Teresa H Y Wu

doi:10.1016/j.ymgme.2024.108436

Higher precision, first tier newborn screening for metachromatic leukodystrophy using 16:1-OH-sulfatide

Mol Genet Metab. 2024 Mar 22;142(1):108436. doi: 10.1016/j.ymgme.2024.108436. Online ahead of print.

Authors

Affiliations

¹ Hospital Charles Nicolle, UNIROUEN INSERM U1245, CHU Rouen, Referral Center for Lysosomal Diseases, Department of Metabolic Biochemistry, 76000 Rouen, France.. Electronic address: Soumeya.Bekri@chu-rouen.fr.
² Department of Pediatrics, University Medical Center, Hamburg Eppendorf, Hamburg, Germany.
³ Willink Biochemical Genetics Laboratory, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK.
⁴ Orchard Therapeutics Limited, 245 Hammersmith Rd, London W6 8PW, UK.
⁵ Dept. of Chemistry, University of Washington, Seattle, WA 98195, USA. Electronic address: gelb@uw.edu.
⁶ Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁷ Screening-Laboratory Hannover, Hannover 30430, Germany; Department of Clinical Chemistry, Hannover Medical School, Hannover, Germany; Centre for Children and Adolescents, Kinder- and Jugenbrankenhaus Auf der Bult, Hannover, Germany.
⁸ Archimedlife, Vienna, Austria.
⁹ Archimedlife, Vienna, Austria. Electronic address: t.mechtler@archimedlife.com.
¹⁰ ArchAngel MLD Trust, 506 Betula House, North Wharf Road, London W1 2DT, UK.
¹¹ Newborn Screening and Metabolic Laboratory, Department of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany.
¹² Hospital Charles Nicolle, UNIROUEN INSERM U1245, CHU Rouen, Referral Center for Lysosomal Diseases, Department of Metabolic Biochemistry, 76000 Rouen, France.
¹³ Willink Biochemical Genetics Laboratory, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK. Electronic address: hoiyee.wu@mft.nhs.uk.

PMID: 38552449
DOI: 10.1016/j.ymgme.2024.108436

Abstract

Newborn screening (NBS) for metachromatic leukodystrophy (MLD) is based on first-tier measurement of sulfatides in dried blood spots (DBS) followed by second-tier measurement of arylsulfatase A in the same DBS. This approach is very precise with 0-1 false positives per ∼30,000 newborns tested. Recent data reported here shows that the sulfatide molecular species with an α-hydroxyl, 16‑carbon, mono-unsaturated fatty acyl group (16:1-OH-sulfatide) is superior to the original biomarker 16:0-sulfatide in reducing the number of first-tier false positives. This result is consistent across 4 MLD NBS centers. By measuring 16:1-OH-sulfatide alone or together with 16:0-sulfatide, the estimated false positive rate is 0.048% and is reduced essentially to zero with second-tier arylsulfatase A activity assay. The false negative rate is predicted to be extremely low based on the demonstration that 40 out of 40 newborn DBS from clinically-confirmed MLD patients are detected with these methods. The work shows that NBS for MLD is extremely precise and ready for deployment. Furthermore, it can be multiplexed with several other inborn errors of metabolism already tested in NBS centers worldwide.

Keywords: Biochemical genetics; Leukodystrophy; Lysosomal storage disease; Mass spectrometry; Newborn screening; Sulfatides.