Treatment of leukodystrophies: Advances and challenges.
Open accessAbstract
Leukodystrophies, a group of genetic disorders primarily affecting brain white matter, were once considered untreatable. Advances in MRI and genetic diagnostics now allow most patients to receive a genetic diagnosis, and emerging treatments are shifting the field from therapeutic nihilism to cautious optimism. Allogenic haematopoietic stem cell transplantation (HSCT), used since the 1980s, has shown efficacy in specific leukodystrophies, such as adrenoleukodystrophy and metachromatic leukodystrophy, when administered early. Gene therapy has become a viable option, with ex vivo approaches like atidarsagene autotemcel providing promising outcomes for early-onset MLD. Trials for gene replacement and antisense oligonucleotide therapies are ongoing for several leukodystrophies, including Canavan disease and Alexander disease. Certain treatments, such as guanabenz for Vanishing White Matter, target disease-specific dysregulated molecular pathways. Despite these advances, challenges remain, including the ultrarare nature of most leukodystrophies, limited natural history data, high treatment costs, and barriers to accessibility. Future developments, including newborn screening and close international collaboration, aim to enhance early diagnosis, refine treatment timing, and expand access to innovative therapies.
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For cerebral ALD, hematopoietic cell transplantation has been successful, but to be effective should be performed before or at the beginning of the development of pathologic symptoms.
“For cerebral ALD, hematopoietic cell transplantation has been successful, however, to be effective should be performed before or at the beginning of the development of pathologic symptoms (Wolf et al., 2025).”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Wolf et al., 2025
Section 2 (page unavailable) says HSCT can have a good outcome in cerebral ALD only when performed early, defined by a low brain-MRI lesion load. It does not define the treatment window as before or at the onset of symptoms; that symptom-based timing is more specific than the source supports. (LLM, conf=0.83)
Experimental — accuracy not yet measuredCurrent advances in treatment options for leukodystrophies may also benefit the treatment of ACBD5 patients.
“Although its relevance to ACBD5 deficiency remains to be established, current advances in the treatment options for leukodystrophies may also benefit the treatment of ACBD5 patients (Metovic et al., 2024; Wolf et al., 2025).”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Wolf et al., 2025
The Introduction and Gene therapy section describe current and emerging treatments for several leukodystrophies. The paper does not discuss ACBD5 deficiency or suggest that these advances may benefit ACBD5 patients; that possibility is the citing authors’ extrapolation, which they appropriately qualify as unestablished. (LLM, conf=0.84)
Experimental — accuracy not yet measured
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Cites
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The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models
Dawes, M. L., Haberlander, J. P., Islinger, M., & Schrader, M. (2025) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2025.1602343 · Cited by 7 · see citing works
- Authors
- Wolf, N. I., van der Knaap, M. S., & Engelen, M.
- Affiliations
- Emma Kinderziekenhuis (NL)
- Corresponding author
- Wolf, Nicole I.
- Venue
- European Journal of Paediatric Neurology
- Publisher
- Elsevier BV
- Published
- 2025-05
- Volume
- 56
- Pages
- 46-50
- ISSN
- 1090-3798 (ISSN-L)
- OpenAlex
- W4409452159
- Cited by
- 11
- References
- 7
- Citations by year
- 2026: 9 · 2025: 2
- FWCI
- 1.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- European Journal of Paediatric Neurology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (submittedVersion, cc-by)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- leukodystrophy, adrenoleukodystrophy, metachromatic leukodystrophy, Canavan disease, Alexander disease, vanishing white matter disease, allogeneic hematopoietic stem cell transplantation, gene therapy, antisense therapy, guanabenz, newborn screening, genetic diagnosis, treatment access, treatment costs
- MeSH terms
- Humans, Genetic Therapy, Hematopoietic Stem Cell Transplantation, Hereditary Central Nervous System Demyelinating Diseases, Leukoencephalopathies
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