MRI brain lesions in asymptomatic boys with X-linked adrenoleukodystrophy
Open accessAbstract
Objective To describe the brain MRI findings in asymptomatic patients with childhood cerebral adrenoleukodystrophy (CCALD). Methods We retrospectively reviewed a series of biochemically or genetically confirmed cases of adrenoleukodystrophy followed at our institution between 2001 and 2015. We identified and analyzed 219 brain MRIs from 47 asymptomatic boys (median age 6.0 years). Patient age, MRI scan, and brain lesion characteristics (e.g., contrast enhancement, volume, and Loes score) were recorded. The rate of lesion growth was estimated using a linear mixed effect model. Results Sixty percent of patients (28/47) showed brain lesions (median Loes score of 3.0 points; range 0.5–11). Seventy-nine percent of patients with CCALD (22/28) had contrast enhancement on first lesional or subsequent MRI. Lesion progression (Loes increase of ≥0.5 point) was seen in 50% of patients (14/28). The rate of lesion growth (mL/mo) was faster in younger patients (r = −0.745; p < 0.0001). Older patients (median age 14.4 y/o) tended to undergo spontaneous arrest of disease. Early lesions grew 46× faster when still limited to the splenium, genu of the corpus callosum, or the brainstem (p = 0.001). Conclusion We provide a description of CCALD lesion development in a cohort of asymptomatic boys. Understanding the early stages of CCALD is crucial to optimize treatments for children diagnosed by newborn screening.
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If an early-stage cerebral lesion is identified in a boy with neurologically asymptomatic ALD, he will be referred for hematopoietic stem cell transplantation or gene therapy, if applicable.
“If an early-stage cerebral lesion is identified in a boy with neurologically asymptomatic ALD [61], he will be referred for hematopoietic stem cell transplantation or gene therapy, if applicable.”
From Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy (2022) · cites this paper as [61]
MRI can detect early demyelinating lesions in X-ALD generally localized in the splenium of the corpus callosum, which progress to involve adjacent parieto-occipital white matter.
“During the follow-up of a patient’s brother with elevated VLCFAs or a child found positive at neonatal screening, MRI is able to detect early demyelinating lesions generally localized in the splenium of the corpus callosum (a region with a very high density of OLs), which progress to involve the adjacent parieto-occipital white matter [14,31,90,91,92].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [91]
The risk of developing cerebral disease is highest in childhood but remains present throughout life.
“The risk of developing cerebral disease is highest in childhood but remains present throughout life.1,29,33-39”
From International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy (2022) · cites this paper as [39]
Cites
Shapiro, E., Krivit, W., Lockman, L., Jambaqué, I., Peters, C., Cowan, M., Harris, R., Blanche, S., Bordigoni, P., Loes, D., et al. (2000) · The Lancet · doi:10.1016/s0140-6736(00)02629-5 · Cited by 329 · see citing works
Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy
Loes, D. J., Fatemi, A., Melhem, E. R., Gupte, N., Bezman, L., Moser, H. W., & Raymond, G. V. (2003) · Neurology · doi:10.1212/01.wnl.0000079050.91337.83 · Cited by 268 · see citing works
Moser, H. W., Loes, D. J., Melhem, E. R., Raymond, G. V., Bezman, L., Cox, C. S., & Lu, S.-E. (2000) · Neuropediatrics · doi:10.1055/s-2000-9236 · Cited by 210 · see citing works
Brain endothelial dysfunction in cerebral adrenoleukodystrophy
Musolino, P. L., Gong, Y., Snyder, J. M. T., Jimenez, S., Lok, J., Lo, E. H., Moser, A. B., Grabowski, E. F., Frosch, M. P., & Eichler, F. S. (2015) · Brain · doi:10.1093/brain/awv250 · Cited by 92 · see citing works
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International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy
Engelen, M., van Ballegoij, W. J. C., Mallack, E. J., Van Haren, K. P., Köhler, W., Salsano, E., van Trotsenburg, A. S. P., Mochel, F., Sevin, C., Regelmann, M. O., et al. (2022) · Neurology · doi:10.1212/wnl.0000000000201374 · Cited by 156 · see citing works
Self-citationMallack, E. J., Gao, K., Engelen, M., & Kemp, S. (2022) · Cells · doi:10.3390/cells11020283 · Cited by 60 · see citing works
“If an early-stage cerebral lesion is identified in a boy with neurologically asymptomatic ALD [61], he will be referred for hematopoietic stem cell transplantation or gene therapy, if applicable.”
BackgroundSelf-citationNeurocognitive benchmarks following transplant for emerging cerebral adrenoleukodystrophy
Pierpont, E. I., Nascene, D. R., Shanley, R., Kenney-Jung, D. L., Ziegler, R. S., Miller, W. P., Gupta, A. O., Lund, T. C., Orchard, P. J., & Eisengart, J. B. (2020) · Neurology · doi:10.1212/wnl.0000000000009929 · Cited by 21 · see citing works
Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy
Bougnères, P., & Le Stunff, C. (2025) · Genes · doi:10.3390/genes16050590 · Cited by 11 · see citing works
- Authors
- Liberato, A. P., Mallack, E. J., Aziz-Bose, R., Hayden, D., Lauer, A., Caruso, P. A., Musolino, P. L., & Eichler, F. S.
- Affiliations
- From the Department of Radiology, Division of Neuroradiology (A.P.L., P.A.C.), Department of Neurology (E.J.M., R.A.-B., A.L., P.L.M., F.S.E.), and Department of Biostatistics (D.H.), Harvard Medical School, Massachusetts General Hospital, Boston; and Department of Pediatrics, Division of Child Neurology (E.J.M.), Weill Cornell Medical College, New York–Presbyterian Hospital, New York.
- NewYork–Presbyterian Hospital (US)
- Venue
- Neurology
- Published
- 2019-04-09
- Volume
- 92
- Issue
- 15
- Pages
- e1698-e1708
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC6511088
- OpenAlex
- W2935904135
- Cited by
- 69
- References
- 4
- Citations by year
- 2026: 11 · 2025: 9 · 2024: 7 · 2023: 5 · 2022: 12 · 2021: 11 · 2020: 9 · 2019: 5
- FWCI
- 6.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5k12ns066274-10)
- National Institute of Neurological Disorders and Stroke (K08NS094683, K12-NS066274, R01NS117575)
- 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 › Neurology › Neurological diseases and metabolism
- Keywords
- X-linked adrenoleukodystrophy, childhood cerebral adrenoleukodystrophy, brain MRI lesions, lesion progression, lesion growth rate, contrast enhancement, corpus callosum, brainstem, newborn screening
- MeSH terms
- Adolescent, Adrenoleukodystrophy, Aging, Brain, Brain Stem, Child, Child, Preschool, Corpus Callosum, Humans, Image Enhancement, Infant, Infant, Newborn, Magnetic Resonance Imaging, Male, Retrospective Studies, Cohort Studies, Neonatal Screening, Disease Progression
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