Improving newborn screening test performance for metachromatic leukodystrophy: Recommendation from a pre-pilot study that identified a late-infantile case for treatment

• Published in: Molecular genetics and metabolism 2024-05, Vol.142 (1), p.108349-108349, Article 108349
• Main Authors: WU, Teresa H.Y., Brown, Heather A., Church, Heather J., Kershaw, Christopher J., Hutton, Rebekah, Egerton, Christine, Cooper, James, Tylee, Karen, Cohen, Rebecca N., Gokhale, David, Ram, Dipak, Morton, Georgina, Henderson, Michael, Bigger, Brian W., Jones, Simon A.
• Format: Article
• Language: English
• Subjects: Dried bloodspot; Lysosomal storage disorder; Metachromatic leukodystrophy; Newborn screening; Pilot study; Sphingolipidosis; Sulphatide
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2024.108349

Metachromatic leukodystrophy (MLD) is a devastating rare neurodegenerative disease. Typically, loss of motor and cognitive skills precedes early death. The disease is characterised by deficient lysosomal arylsulphatase A (ARSA) activity and an accumulation of undegraded sulphatide due to pathogenic variants in the ARSA gene. Atidarsagene autotemcel (arsa-cel), an ex vivo haematopoietic stem cell gene therapy was approved for use in the UK in 2021 to treat early-onset forms of pre- or early-symptomatic MLD. Optimal outcomes require early diagnosis, but in the absence of family history this is difficult to achieve without newborn screening (NBS). A pre-pilot MLD NBS study was conducted as a feasibility study in Manchester UK using a two-tiered screening test algorithm. Pre-established cutoff values (COV) for the first-tier C16:0 sulphatide (C16:0-S) and the second-tier ARSA tests were evaluated. Before the pre-pilot study, initial test validation using non‑neonatal diagnostic bloodspots demonstrated ARSA pseudodeficiency status was associated with normal C16:0-S results for age (n = 43) and hence not expected to cause false positive results in this first-tier test. Instability of ARSA in bloodspot required transfer of NBS bloodspots from ambient temperature to −20°C storage within 7–8 days after heel prick, the earliest possible in this UK pre-pilot study. Eleven of 3687 de-identified NBS samples in the pre-pilot were positive for C16:0-S based on the pre-established COV of ≥170 nmol/l or ≥ 1.8 multiples of median (MoM). All 11 samples were subsequently tested negative determined by the ARSA COV of