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. 2024 May;142(1):108436.
doi: 10.1016/j.ymgme.2024.108436. Epub 2024 Mar 22.

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

Soumeya Bekri  1 , Annette Bley  2 , Heather A Brown  3 , Charlotte Chanson  4 , Heather J Church  3 , Michael H Gelb  5 , Xinying Hong  6 , Nils Janzen  7 , David C Kasper  8 , Thomas Mechtler  9 , Georgina Morton  10 , Simona Murko  11 , Petra Oliva  8 , Abdellah Tebani  12 , Teresa H Y Wu  13
Affiliations

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

Soumeya Bekri et al. Mol Genet Metab. 2024 May.

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.

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Conflict of interest statement

Declaration of competing interest None.

Figures

Figure 1.
Figure 1.
(A) Levels of sulfatide molecular species in newborn DBS measured by LC-MS/MS at the University of Washington. All species were quantified with the single internal standard d5-16:0-sulfatide and are reported as "apparent" values (assuming all MS/MS relative response factors are unity). Mean values are shown as dotted lines, and the cutoffs are shown as solid lines. For each sulfatide species, non-MLD samples (n = 592) are on the left and MLD samples are on the right. (B) Same as (A) but for sum of 4 sulfatide species.
Figure 1.
Figure 1.
(A) Levels of sulfatide molecular species in newborn DBS measured by LC-MS/MS at the University of Washington. All species were quantified with the single internal standard d5-16:0-sulfatide and are reported as "apparent" values (assuming all MS/MS relative response factors are unity). Mean values are shown as dotted lines, and the cutoffs are shown as solid lines. For each sulfatide species, non-MLD samples (n = 592) are on the left and MLD samples are on the right. (B) Same as (A) but for sum of 4 sulfatide species.
Figure 2.
Figure 2.
Multiple-of-the-Median (MoM)values for 16:0- and 16:1-OH-sulfatide species for 40 newborn DBS from clinically-confirmed, MLD patients. The solid lines are the cutoff values listed in Table 1.
See this image and copyright information in PMC

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