X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism
Abstract
X-linked adrenoleukodystrophy (X-ALD) is a progressive peroxisomal disorder affecting adrenal glands, testes and myelin stability that is caused by mutations in the ABCD1 (NM_000033) gene. Males with X-ALD may be diagnosed by the demonstration of elevated very long chain fatty acid (VLCFA) levels in plasma. In contrast, only 80% of female carriers have elevated plasma VLCFA; therefore targeted mutation analysis is the most effective means for carrier detection. Amongst 489 X-ALD families tested at Kennedy Krieger Institute, we identified 20 cases in which the ABCD1 mutation was de novo in the index case, indicating that the mutation arose in the maternal germ line and supporting a new mutation rate of at least 4.1% for this group. In addition, we identified 10 cases in which a de novo mutation arose in the mother or the grandmother of the index case. In two of these cases studies indicated that the mothers were low level gonosomal mosaics. In a third case biochemical, molecular and pedigree analysis indicated the mother was a gonadal mosaic. To the best of our knowledge mosaicism has not been previously reported in X-ALD. In addition, we identified one pedigree in which the maternal grandfather was mosaic for the familial ABCD1 mutation. Less than 1% of our patient population had evidence of gonadal or gonosomal mosaicism, suggesting it is a rare occurrence for this gene and its associated disorders. However, the residual maternal risk for having additional ovum carrying the mutant allele identified in an index case that appears to have a de novo mutation is at least 13%.
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The mutation c.1816 T > C, p.S606P is shown to be pathogenic in at least seven patients according to the ALD mutation database.
“Two of the three cases which were not recognized by a cutoff ≥ 0.02 for the ratio of C26:0/C22:0 presented with the mutation c.1816 T > C, p.S606P (both females), shown to be pathogenic in at least seven patients according to the ALD mutation database (http://adrenoleukodystrophy.info18–21.”
From Defining diagnostic cutoffs in neurological patients for serum very long chain fatty acids (VLCFA) in genetically confirmed X-Adrenoleukodystrophy (2020) · cites this paper as [18]
The de novo mutation rate in X-ALD ranges from 4 to 19%.
“The de novo mutation rate ranged from 4 to 19% [32,101].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [101]
A comprehensive study based on molecular characterization of 489 families found only 4.1% of index cases to carry de novo mutations in ABCD1.
“Similarly, a comprehensive study based on molecular characterization of 489 families found only 4.1% of index cases to carry de novo mutations in the ABCD1 gene.11”
From The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis (2015) · cites this paper as [11]
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Self-citationAdrenoleukodystrophy: Incidence, new mutation rate, and results of extended family screening
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Symptoms in carriers of adrenoleukodystrophy relate to skewed X inactivation
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Cerebral X‐linked adrenoleukodystrophy in a girl with Xq27‐Ter deletion
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X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects
Kemp, S., Berger, J., & Aubourg, P. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2012.03.012 · Cited by 283 · see citing works
Adrenoleukodystrophy—Neuroendocrine pathogenesis and redefinition of natural history
Kemp, S., Huffnagel, I. C., Linthorst, G. E., Wanders, R. J., & Engelen, M. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.90 · Cited by 275 · see citing works
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Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy
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- Authors
- Wang, Y., Busin, R., Reeves, C., Bezman, L., Raymond, G., Toomer, C. J., Watkins, P. A., Snowden, A., Moser, A., Naidu, S., Bibat, G., Hewson, S., Tam, K., Clarke, J. T. R., Charnas, L., Stetten, G., Karczeski, B., Cutting, G., & Steinberg, S.
- Affiliations
- Johns Hopkins University (US)
- Kennedy Krieger Institute (US)
- Hospital for Sick Children (CA)
- University of Minnesota (US)
- Corresponding author
- Steinberg, Steven
- ORCID
- Venue
- Molecular Genetics and Metabolism
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 104
- Issue
- 1-2
- Pages
- 160-166
- ISSN
- 1096-7192 (ISSN-L)
- OpenAlex
- W2606781181
- Cited by
- 58
- References
- 7
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 3 · 2023: 1 · 2022: 6 · 2021: 7 · 2020: 2 · 2019: 5 · 2018: 3 · 2017: 1 · 2016: 5 · 2015: 1 · 2014: 2 · 2013: 7 · 2012: 6
- FWCI
- 2.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Genetics and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- 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 › Genetic and rare skin diseases.
- Keywords
- X-linked adrenoleukodystrophy, ABCD1 gene, de novo mutations, gonadal mosaicism, gonosomal mosaicism, peroxisomal disorders, very long chain fatty acids, carrier detection, carrier risk, pedigree analysis
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenoleukodystrophy, Base Sequence, Child, Child, Preschool, DNA Mutational Analysis, Exons, Family, Female, Gonads, Heterozygote, Humans, Male, Molecular Sequence Data, Mosaicism, Mutation, Fatal Outcome, ATP-Binding Cassette Transporters
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