Consensus-Based Expert Recommendations for Diagnosis and Clinical Management of Vanishing White Matter

Vanishing white matter (VWM) is a rare disorder, characterized by degeneration of CNS white matter, clinically often exacerbated by stressors such as fever and minor head trauma. VWM is caused by biallelic pathogenic variants in the <i>EIF2B1-5</i> genes, causing reduced activity of eukaryotic initiation of translation factor 2B, resulting in dysregulation of the integrated stress response (ISR). New scientific insights and increased clinical trials in experimental therapies highlight the need for clinical guidelines to improve and standardize care for patients with VWM worldwide. Standardized care is important for therapy development, as it lessens clinical variability of trial participants at study entry, enabling more sensitive evaluation of treatment outcomes. The aim of this study was to develop expert consensus-based recommendations for diagnosis and management of VWM. A real-time Delphi process with a multidisciplinary expert panel was conducted to formulate consensus-based recommendations. A literature review was performed to determine the strength of available evidence supporting each recommendation. The consensus yielded 43 recommendations on diagnosis, including genetic and MRI criteria, and on clinical management concerning disease progression, acute and long-term care, and preventive strategies. All known pathogenic and likely pathogenic <i>EIF2B1-5</i> variants were identified from the literature and Amsterdam Leukodystrophy Center laboratory. An overview of these <i>EIF2B1-5</i> variants was composed to facilitate diagnosis. Clinically used drugs may activate the ISR, posing a risk in VWM, or have no effect on or suppress the ISR, being probably safe in VWM. A second literature search explored the effects of clinically frequently used drugs on the ISR. Drugs were categorized into those likely to activate the ISR, suppress it, and have no likely effects on the ISR. Final judgment was achieved in a consensus meeting of experts. A patient management card was developed with input from clinical experts and patient advocates to provide information on these consensus-based recommendations in lay language and bridge the gap between scientific evidence and expert opinion on one side and the practical needs of clinicians and families on the other side. This study contributes to improving and standardizing VWM care based on scientific and expert insights, while highlighting key areas for future research.

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Journal
Neurology
Published
2025-11-13
DOI
https://doi.org/10.1212/wnl.0000000000214320
Citations
1
Primary Topic
RNA regulation and disease
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article
Field-Weighted Citation Impact
0.81
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article

Consensus-Based Expert Recommendations for Diagnosis and Clinical Management of Vanishing White Matter

Anne Marie Sbrocchi, Corrie Timmer, Geneviève Bernard, Adeline Vanderver et al.
1 citations
Neurology
RNA regulation and disease
0.81
article

Consensus-Based Expert Recommendations for Diagnosis and Clinical Management of Vanishing White Matter

Anne Marie Sbrocchi, Corrie Timmer, Geneviève Bernard, Adeline Vanderver, Jochen Meyburg, Marc van Heerde, Isabelle Thiffault, Nicole I. Wolf, Susan G. Campbell, Ali Fatemi, Paulo Victor Sgobbi de Souza, Bernard Brais, Davide Tonduti, Sabine E Hannema, Prisca S. Leferink, Allyson Buck, Donna Skwirut, Hanka Dekker, Caroline Sevin, Enrico Bertini, Jennifer Orthmann‐Murphy, Katherine Hayes, Samuel Groeschel, Marjo S. van der Knaap, Joshua L. Bonkowsky, Nicole Jaffe, Ingeborg Krägeloh‐Mann, Ludger J. Schöls, Daphne H. Schoenmakers, Ettore Salsano, Truus E. M. Abbink, Kasper W. ter Horst, Romy J. van Voorst, Ron Chapleau, Geesje H Hofsteenge, Carolina Sudmeier-Broek, Bret Hollberg
article en
1 citations

Abstract

Vanishing white matter (VWM) is a rare disorder, characterized by degeneration of CNS white matter, clinically often exacerbated by stressors such as fever and minor head trauma. VWM is caused by biallelic pathogenic variants in the <i>EIF2B1-5</i> genes, causing reduced activity of eukaryotic initiation of translation factor 2B, resulting in dysregulation of the integrated stress response (ISR). New scientific insights and increased clinical trials in experimental therapies highlight the need for clinical guidelines to improve and standardize care for patients with VWM worldwide. Standardized care is important for therapy development, as it lessens clinical variability of trial participants at study entry, enabling more sensitive evaluation of treatment outcomes. The aim of this study was to develop expert consensus-based recommendations for diagnosis and management of VWM. A real-time Delphi process with a multidisciplinary expert panel was conducted to formulate consensus-based recommendations. A literature review was performed to determine the strength of available evidence supporting each recommendation. The consensus yielded 43 recommendations on diagnosis, including genetic and MRI criteria, and on clinical management concerning disease progression, acute and long-term care, and preventive strategies. All known pathogenic and likely pathogenic <i>EIF2B1-5</i> variants were identified from the literature and Amsterdam Leukodystrophy Center laboratory. An overview of these <i>EIF2B1-5</i> variants was composed to facilitate diagnosis. Clinically used drugs may activate the ISR, posing a risk in VWM, or have no effect on or suppress the ISR, being probably safe in VWM. A second literature search explored the effects of clinically frequently used drugs on the ISR. Drugs were categorized into those likely to activate the ISR, suppress it, and have no likely effects on the ISR. Final judgment was achieved in a consensus meeting of experts. A patient management card was developed with input from clinical experts and patient advocates to provide information on these consensus-based recommendations in lay language and bridge the gap between scientific evidence and expert opinion on one side and the practical needs of clinicians and families on the other side. This study contributes to improving and standardizing VWM care based on scientific and expert insights, while highlighting key areas for future research.

NeurologyVol. 105(11)
Intermountain Healthcare (US), Montreal Neurological Institute and Hospital (CA), Kennedy Krieger Institute (US), Muscular Dystrophy Association (US), Primary Children's Hospital (US), Children's Mercy Hospital (US), Children's Hospital of Philadelphia (US), Johns Hopkins University (US), University of Milan (IT), University of Utah (US), Montreal Children's Hospital (CA), Families USA (US), German Center for Neurodegenerative Diseases (DE), McGill University Health Centre (CA), Academy of Nutrition and Dietetics (US), University of Utah Hospital (US), Emma Kinderziekenhuis (NL), Centro Paulista de Investigação Clinica (BR), Amsterdam Neuroscience (NL), Bambino Gesù Children's Hospital (IT), University Children's Hospital Tübingen (DE), Ospedale dei Bambini Vittore Buzzi (IT), Hertie Institute for Clinical Brain Research (DE), Klinikum Ludwigsburg (DE), Amsterdam University Medical Centers (NL), Bicêtre Hospital (FR), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), Center for Human Reproduction (US), Stichting tot Steun VCVGZ (NL), McGill University (CA), Sheffield Hallam University (GB), University of Missouri–Kansas City (US), University of Pennsylvania (US), Vrije Universiteit Amsterdam (NL), Universidade Federal de São Paulo (BR), University of Amsterdam (NL), Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
Openalex Percentile: Top 22%
RNA regulation and disease
0.81
DOIOpen Access PDFOpenAlex
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