Newborn screening in metachromatic leukodystrophy - European consensus-based recommendations on clinical management.

Introduction: Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder resulting from arylsulfatase A enzyme deficiency, leading to toxic sulfatide accumulation. As a result affected individuals exhibit progressive neurodegeneration. Treatments such as hematopoietic stem cell transplantation (HSCT) and gene therapy are effective when administered pre-symptomatically. Newborn screening (NBS) for MLD has recently been shown to be technically feasible and is indicated because of available treatment options. However, there is a lack of guidance on how to monitor and manage identified cases. This study aims to establish consensus among international experts in MLD and patient advocates on clinical management for NBS-identified MLD cases.
Methods: A real-time Delphi procedure using eDELPHI software with 22 experts in MLD was performed. Questions, based on a literature review and workshops, were answered during a seven-week period. Three levels of consensus were defined: A) 100%, B) 75-99%, and C) 50-74% or >75% but >25% neutral votes. Recommendations were categorized by agreement level, from strongly recommended to suggested. Patient advocates participated in discussions and were involved in the final consensus.
Results: The study presents 57 statements guiding clinical management of NBS-identified MLD patients. Key recommendations include timely communication by MLD experts with identified families, treating early-onset MLD with gene therapy and late-onset MLD with HSCT, as well as pre-treatment monitoring schemes. Specific knowledge gaps were identified, urging prioritized research for future evidence-based guidelines.
Discussion: Consensus-based recommendations for NBS in MLD will enhance harmonized management and facilitate integration in national screening programs. Structured data collection and monitoring of screening programs are crucial for evidence generation and future guideline development. Involving patient representatives in the development of recommendations seems essential for NBS programs.
Competing Interests: Declaration of competing interest L. A. Adang is a consultant to Takeda Pharmaceuticals, Orchard Therapeutics, and is a site sub-investigator for the Takeda trial. G. Bernard is/was a consultant for Calico (2023-present), Orchard Therapeutics (2023-present), Passage Bio Inc (2020–2022) and Ionis (2019). She is/was a site investigator for the Alexander's disease trial of Ionis (2021-present), Metachromatic leukodystrophy of Shire/Takeda (2020–2021), Krabbe (2021–2023) and GM1 gene therapy trials of Passage Bio (2021-present), GM1 natural history study from the University of Pennsylvania sponsored by Passage Bio (2021-present) and Adrenoleukodystrophy/Hematopoietic stem cell transplantation natural history study of Bluebird Bio (2019), a site sub-investigator for the MPS II gene therapy trial of Regenxbio (2021-present) and the MPS II clinical trial of Denali (2022-present). She has received an unrestricted educational grant from Takeda (2021–2022). Orchard Therapeutics: V. Calbi works as consultant for Orchard Therapeutics. F. Fumagalli is investigator of gene therapy clinical trials for MLD sponsored by Orchard Therapeutics, the licence holder of investigational medicinal product arsa-cel. Dr. Fumagalli has acted as ad-hoc consultants for Orchard Therapeutics advisory boards. The MLD gene therapy was licensed to GlaxoSmithKline in 2014, and then to Orchard Therapeutics in 2018. Telethon and Ospedale San Raffaele are entitled to receive milestone payments and royalties for such a therapy. M. Langeveld is involved in a premarketing studies with Sanofi-Genzyme, Protalix/Chiesi and Idorsia. Financial arrangements were made through AMC Research BV. No fees, travel support or grants were obtained from Pharmaceutical Industry. F. Mochel has participated in advisory boards arranged by Minoryx Therapeutics and Vigil Neuroscience. Her research work is funded by the French Ministry of Health (PHRC), the French Ministry of Research (ANR), the Paris Brain Institute and Minoryx Therapeutics. L. Schöls is a consultant to Vico Therapeutics and a site principal investigator for trials of Vigil Neuroscience, Stealth Biotherapeutics and PTC Therapeutics. C. Sevin is PI of the Takeda clinical trial and consultant for Orchard Therapeutics. A. Zerem is a site sub-investigator for the Takeda clinical trial and local PI for the Ionis clinical trial. Institutional research support from Shire plc and Orchard. Advisor and coinvestigator for trials in MLD (Shire/Takeda, Orchard) without personal payments. N. I. Wolf is researcher at the MLD initiative, which is a publicly funded academic registry and collaborative platform for metachromatic leukodystrophy and local PI for several multicenter trials for leukodystrophies (Takeda, Ionis, VigilNeuro). She does consultancies for Takeda, Ionis, VigilNeuro, Eli Lilly, PassageBio, Sana Biotech, Sanofi, without personal payments.
(© 2024 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)