Department of Chemistry, University of Washington, Seattle, WA, USA.
Utah Public Health Laboratory, Salt Lake City, UT, USA.
Genet Med. 2021 Mar;23(3):555-561. doi: 10.1038/s41436-020-01017-5. Epub 2020 Nov 20.
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.
异染性脑白质营养不良（MLD）是一种溶酶体贮积病，由芳基硫酸酯酶 A（ARSA）缺乏引起，导致硫酸脂的积累。由于创新疗法的不断推进，未来可能会考虑对 MLD 进行新生儿筛查。我们开展了一项研究，旨在评估使用未经身份识别的新生儿干血斑（DBS）筛查 MLD 的可行性。
为了最大限度地降低假阳性率，设计了两阶段筛查算法。初级检测是通过超高效液相色谱-串联质谱法（UPLC-MS/MS）对 DBS 中的 C16:0-硫酸脂进行定量。根据 15 名 MLD 新生儿的结果确定筛查截止值，以实现 100%的灵敏度。二级检测是测量 DBS 中 ARSA 活性，针对 C16:0-硫酸脂水平异常的新生儿。只有同时显示 C16:0-硫酸脂丰度和 ARSA 活性异常的新生儿才被视为筛查阳性。
使用这种两阶段算法共筛查了 27335 名新生儿，发现了 2 例高危病例。ARSA 基因测序确定这 2 例高危个体为 MLD 患者和杂合子。
我们的研究表明，在实际情况下，使用近 100%的检测特异性对 MLD 进行新生儿筛查是非常可行的。
