Evaluation of X-Linked Adrenoleukodystrophy Newborn Screening in North Carolina
Open accessAbstract
Importance: X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal genetic disorder in which an accumulation of very long-chain fatty acids leads to inflammatory demyelination in the central nervous system and to adrenal cortex atrophy. In 2016, X-ALD was added to the US Recommended Uniform Screening Panel. Objective: To evaluate the performance of a single-tier newborn screening assay for X-ALD in North Carolina. Design, Setting, and Participants: This diagnostic screening study was of all newborn dried blood spot specimens received in the North Carolina State Laboratory of Public Health between January 2 and June 1, 2018, excluding specimens of insufficient quantity or quality. A total of 52 301 specimens were screened for X-ALD using negative ionization high-performance liquid chromatography tandem mass spectrometry to measure C24:0- and C26:0-lysophosphatidylcholine concentrations. Sanger sequencing of the adenosine triphosphate-binding cassette subfamily D member 1 (ABCD1) gene was performed on screen-positive specimens. Exposures: A medical and family history, newborn physical examination, sequencing of ABCD1 on dried blood spot samples, and plasma analysis of very long-chain fatty acids were obtained for all infants with screen-positive results. Main Outcomes and Measures: The prevalence of X-ALD in North Carolina and the positive predictive value and false-positive rate for the first-tier assay were determined. Results: Of 52 301 infants tested (47.8% female, 50.6% male, and 1.7% other or unknown sex), 12 received screen-positive results. Of these 12 infants, 8 were confirmed with a genetic disorder: 3 male infants with X-ALD, 3 X-ALD-heterozygous female infants, 1 female infant with a peroxisome biogenesis disorder, and 1 female infant with Aicardi-Goutières syndrome. Four infants were initially classified as having false-positives results, including 3 female infants who were deemed unaffected and 1 male infant with indeterminate results on confirmatory testing. The positive predictive value for X-ALD or other genetic disorders for the first-tier assay was 67%, with a false-positive rate of 0.0057%. Conclusions and Relevance: This newborn screening pilot study reported results on 2 lysophosphatidylcholine analytes, identifying 3 male infants with X-ALD, 3 X-ALD-heterozygous female infants, and 3 infants with other disorders associated with increased very long-chain fatty acids. These results showed successful implementation in a public health program with minimal risk to the population. The findings will support other state laboratories planning to implement newborn screening for X-ALD and related disorders.
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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 [54]
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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
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- Authors
- Lee, S., Clinard, K., Young, S. P., Rehder, C. W., Fan, Z., Calikoglu, A. S., Bali, D. S., Bailey, D. B., Gehtland, L. M., Millington, D. S., Patel, H. S., Beckloff, S. E., Zimmerman, S. J., Powell, C. M., & Taylor, J. L.
- Affiliations
- RTI International (US)
- University of North Carolina at Chapel Hill (US)
- Duke University (US)
- North Carolina State Laboratory of Public Health, Raleigh
- Corresponding author
- Taylor, Jennifer L.
- ORCID
- Venue
- JAMA Network Open
- Publisher
- American Medical Association (AMA)
- Published
- 2020-01-31
- Volume
- 3
- Issue
- 1
- Pages
- e1920356
- ISSN
- 2574-3805 (ISSN-L)
- PMC
- PMC7042889
- OpenAlex
- W3003384135
- Cited by
- 67
- References
- 7
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 9 · 2023: 10 · 2022: 19 · 2021: 11 · 2020: 5
- FWCI
- 7.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- JAMA Network Open (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health and Human Services
- National Institutes of Health
- University of North Carolina at Chapel Hill
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HHSN275201500010I)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- newborn screening, lysophosphatidylcholine, ABCD1 gene, peroxisomal disorders, very long chain fatty acids, false positive rate, positive predictive value, peroxisome biogenesis disorders, Aicardi-Goutières syndrome, dried blood spots, North Carolina
- MeSH terms
- Adrenoleukodystrophy, Female, Humans, Infant, Newborn, Lysophosphatidylcholines, Male, North Carolina, Pilot Projects, Neonatal Screening
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