Adrenoleukodystrophy Newborn Screening in the Netherlands (SCAN Study): The X-Factor
Open accessAbstract
X-linked adrenoleukodystrophy (ALD) is a devastating metabolic disorder affecting the adrenal glands, brain and spinal cord. Males with ALD are at high risk for developing adrenal insufficiency or progressive cerebral white matter lesions (cerebral ALD) at an early age. If untreated, cerebral ALD is often fatal. Women with ALD are not at risk for adrenal insufficiency or cerebral ALD. Newborn screening for ALD in males enables prospective monitoring and timely therapeutic intervention, thereby preventing irreparable damage and saving lives. The Dutch Ministry of Health adopted the advice of the Dutch Health Council to add a boys-only screen for ALD to the newborn screening panel. The recommendation made by the Dutch Health Council to only screen boys, without gathering any unsolicited findings, posed a challenge. We were invited to set up a prospective pilot study that became known as the SCAN study (SCreening for ALD in the Netherlands). The objectives of the SCAN study are: (1) designing a boys-only screening algorithm that identifies males with ALD and without unsolicited findings; (2) integrating this algorithm into the structure of the Dutch newborn screening program without harming the current newborn screening; (3) assessing the practical and ethical implications of screening only boys for ALD; and (4) setting up a comprehensive follow-up that is both patient- and parent-friendly. We successfully developed and validated a screening algorithm that can be integrated into the Dutch newborn screening program. The core of this algorithm is the “X-counter.” The X-counter determines the number of X chromosomes without assessing the presence of a Y chromosome. The X-counter is integrated as second tier in our 4-tier screening algorithm. Furthermore, we ensured that our screening algorithm does not result in unsolicited findings. Finally, we developed a patient- and parent-friendly, multidisciplinary, centralized follow-up protocol. Our boys-only ALD screening algorithm offers a solution for countries that encounter similar ethical considerations, for ALD as well as for other X-linked diseases. For ALD, this alternative boys-only screening algorithm may result in a more rapid inclusion of ALD in newborn screening programs worldwide.
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The implementation of newborn screening for ALD in the United States and the Netherlands has provided the opportunity to identify patients at birth.
“The implementation of newborn screening for ALD in the United States and the Netherlands has provided the opportunity to identify patients at birth [7,51,52,53,54,55,56].”
From Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy (2022) · cites this paper as [52]
The Introduction (page not specified) says New York began ALD newborn screening and that 16 U.S. states had started by March 2020. It describes Dutch ALD screening as a planned pilot, not an already implemented program identifying patients at birth. The paper supports the U.S. portion and the potential for newborn identification, but not the claim of implementation in the Netherlands at that time. (LLM, conf=0.88)
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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
“, plasmalogens, phytanic acid, pristanic acid, and bile acid intermediates) should be analyzed to exclude related diseases such as Zellweger spectrum disorder, ACOX1 (or HSD1B4) deficiency, CADDS, ACBD5 deficiency, and Aicardi-Goutières syndrome.(24)”
BackgroundSelf-citationMallack, E. J., Gao, K., Engelen, M., & Kemp, S. (2022) · Cells · doi:10.3390/cells11020283 · Cited by 60 · see citing works
Self-citationRevisiting the Pathogenesis of X-Linked Adrenoleukodystrophy
Bougnères, P., & Le Stunff, C. (2025) · Genes · doi:10.3390/genes16050590 · Cited by 11 · see citing works
- Authors
- Barendsen, R. W., Dijkstra, I. M. E., Visser, W. F., Alders, M., Bliek, J., Boelen, A., Bouva, M. J., van der Crabben, S. N., Elsinghorst, E., van Gorp, A. G. M., Heijboer, A. C., Jansen, M., Jaspers, Y. R. J., van Lenthe, H., Metgod, I., Mooij, C. F., van der Sluijs, E. H. C., van Trotsenburg, A. S. P., Verschoof-Puite, R. K., Vaz, F. M., Waterham, H. R., Wijburg, F. A., Engelen, M., Dekkers, E., & Kemp, S.
- Affiliations
- Emma Kinderziekenhuis (NL)
- Amsterdam University Medical Centers (NL)
- National Institute for Public Health and the Environment (NL)
- Corresponding author
- Kemp, Stephan
- ORCID
- Venue
- Frontiers in Cell and Developmental Biology
- Publisher
- Frontiers Media SA
- Published
- 2020-06-17
- Volume
- 8
- Pages
- 499-499
- ISSN
- 2296-634X (ISSN-L)
- PMC
- PMC7311642
- OpenAlex
- W3036445007
- Cited by
- 65
- References
- 7
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 7 · 2023: 9 · 2022: 16 · 2021: 13 · 2020: 6
- FWCI
- 7.29
- Type
- journal article
- Language
- en
- Update notices
- corrigendum (2021-01-28)
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Cell and Developmental Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Rivm (National Institute for Public Health and the Environment) (submittedVersion)
- Rivm (National Institute for Public Health and the Environment) (submittedVersion, other-oa)
- Funders
- ZonMw (543002004)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- X-linked adrenoleukodystrophy, newborn screening, screening algorithm, X-linked disorders, ethics of screening, follow-up protocol, adrenal insufficiency, cerebral adrenoleukodystrophy
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