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MRI surveillance of boys with X‐linked adrenoleukodystrophy identified by newborn screening: Meta‐analysis and consensus guidelines

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Mallack, Eric J., Turk, Bela R., Yan, Helena, Price, Carrie, Demetres, Michelle, Moser, Ann B., Becker, Catherine, Hollandsworth, Kim +15 more·2021·Journal of Inherited Metabolic Disease
DOI 10.1002/jimd.12356PMC PMC8113077
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Abstract

BACKGROUND: Among boys with X-Linked adrenoleukodystrophy, a subset will develop childhood cerebral adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic adrenoleukodystrophy. METHODS: To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus. RESULTS: One hundred twenty-three studies met inclusion criteria yielding 1285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0-9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (a) Obtain an MRI between 12 and 18 months old. (b) Obtain a second MRI 1 year after baseline. (c) Between 3 and 12 years old, obtain a contrast-enhanced MRI every 6 months. (d) After 12 years, obtain an annual MRI. CONCLUSION: Boys with adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD.

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  • 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 [90]

    The Introduction says lesions most often begin in the splenium of the corpus callosum and spread into adjacent white matter, and the Results describe early lesions detectable on MRI. Our copy does not specify that the adjacent white matter is parieto-occipital or support the parenthetical claim about oligodendrocyte density. No page numbers were provided for these passages. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • 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 [29]

    The Results (Surveillance guidelines; page unavailable) say the risk peaks at ages 3–12 and declines during the teenage years. The Methods exclude studies focused solely on adults, so this paper does not establish that the risk remains present throughout life. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • The accurate genetic diagnosis of ALD obligates the patient to rigorous monitoring protocols for adrenal insufficiency and cerebral ALD by MRI, requiring multiple medical subspecialty evaluations early in life.

    “The accurate genetic diagnosis of ALD obligates the patient to rigorous monitoring protocols for adrenal insufficiency [57] and cerebral ALD by MRI [58], requiring multiple medical subspecialty evaluations early in life.”

    From Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy (2022) · cites this paper as [58]

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Authors
Mallack, E. J., Turk, B. R., Yan, H., Price, C., Demetres, M., Moser, A. B., Becker, C., Hollandsworth, K., Adang, L., Vanderver, A., Van Haren, K., Ruzhnikov, M., Kurtzberg, J., Maegawa, G., Orchard, P. J., Lund, T. C., Raymond, G. V., Regelmann, M., Orsini, J. J., Seeger, E., Kemp, S., Eichler, F., & Fatemi, A.
Affiliations
  • NewYork–Presbyterian Hospital (US)
  • Kennedy Krieger Institute (US)
  • Harvard University (US)
  • Children's Hospital of Philadelphia (US)
  • Department of Neurology, Stanford University School of Medicine Lucile Packard Children's Hospital Stanford California USA
  • Lucile Packard Children's Hospital (US)
  • Duke University (US)
  • UF Health Shands Hospital (US)
  • University of Minnesota Children's Hospital (US)
  • Children's Hospital at Montefiore (US)
  • New York State Department of Health (US)
  • Aidan Jack Seeger Foundation Brooklyn New York USA
  • Emma Kinderziekenhuis (NL)
Corresponding author
Fatemi, Ali
ORCID
Venue
Journal of Inherited Metabolic Disease
Publisher
Wiley
Published
2021-01-09
Volume
44
Issue
3
Pages
728-739
ISSN
  • 0141-8955 (ISSN-L)
  • 1573-2665
DOI
10.1002/jimd.12356
PMC
PMC8113077
OpenAlex
W3117410688
Cited by
79
References
7
Citations by year
2026: 10 · 2025: 17 · 2024: 13 · 2023: 10 · 2022: 18 · 2021: 11
FWCI
6.46
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Journal of Inherited Metabolic Disease (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • Hunter's Hope Foundation
  • National Institutes of Health (5k12ns066274-10)
  • National Institute of Neurological Disorders and Stroke (K12-NS066274, U54NS115052)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD103538, U54HD079123)
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, neuroimaging surveillance, magnetic resonance imaging, newborn screening, boys, age at diagnosis, contrast-enhanced MRI, T2-weighted MRI, hematopoietic stem cell transplantation, surveillance guidelines
MeSH terms
Adrenoleukodystrophy, Child, Child, Preschool, Consensus Development Conferences as Topic, Consensus Statements as Topic, Humans, Infant, Infant, Newborn, Magnetic Resonance Imaging, Male, Neonatal Screening

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