Contiguous deletion of the X‐linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders
Open accessAbstract
X-linked adrenoleukodystrophy (X-ALD) results from mutations in ABCD1. ABCD1 resides on Xq28 and encodes an integral peroxisomal membrane protein (ALD protein [ALDP]) that is of unknown function and that belongs to the ATP-binding cassette-transporter superfamily. Individuals with ABCD1 mutations accumulate very-long-chain fatty acids (VLCFA) (carbon length >22). Childhood cerebral X-ALD is the most devastating form of the disease. These children have the earliest onset (age 7.2 +/- 1.7 years) among the clinical phenotypes for ABCD1 mutations, but onset does not occur at <3 years of age. Individuals with either peroxisomal biogenesis disorders (PBD) or single-enzyme deficiencies (SED) in the peroxisomal beta-oxidation pathway--disorders such as acyl CoA oxidase deficiency and bifunctional protein deficiency--also accumulate VLCFA, but they present during the neonatal period. Until now, it has been possible to distinguish unequivocally between individuals with these autosomal recessively inherited syndromes and individuals with ABCD1 mutations, on the basis of the clinical presentation and measurement of other biochemical markers. We have identified three newborn boys who had clinical symptoms and initial biochemical results consistent with PBD or SED. In further study, however, we showed that they lacked ALDP, and we identified deletions that extended into the promoter region of ABCD1 and the neighboring gene, DXS1357E. Mutations in DXS1357E and the ABCD1 promoter region have not been described previously. We propose that the term "contiguous ABCD1 DXS1357E deletion syndrome" (CADDS) be used to identify this new contiguous-gene syndrome. The three patients with CADDS who are described here have important implications for genetic counseling, because individuals with CADDS may previously have been misdiagnosed as having an autosomal recessive PBD or SED
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Raised VLCFA in CADDS is like that seen in isolated ABCD1 defects.
“As in DDCH, severe developmental delay, dystonia, deafness, and white matter abnormalities are commonly reported, while the presence of raised VLCFA is like that seen in isolated ABCD1 defects.”
From Interstitial lung disease and pancreatic exocrine insufficiency in <scp>CADDS</scp>: Phenotypic expansion and literature review (2023) · cites this paper as [5]
In CADDS, severe developmental delay, dystonia, deafness, and white matter abnormalities are commonly reported.
“As in DDCH, severe developmental delay, dystonia, deafness, and white matter abnormalities are commonly reported, while the presence of raised VLCFA is like that seen in isolated ABCD1 defects.”
From Interstitial lung disease and pancreatic exocrine insufficiency in <scp>CADDS</scp>: Phenotypic expansion and literature review (2023) · cites this paper as [5]
Unlike DDCH or X-ALD, CADDS affected males have persistent cholestatic liver disease.
“However, unlike either DDCH or X‐ALD, CADDS affected males have persistent cholestatic liver disease and commonly die in infancy. 5 , 6 , 7 , 8 , 9”
From Interstitial lung disease and pancreatic exocrine insufficiency in <scp>CADDS</scp>: Phenotypic expansion and literature review (2023) · cites this paper as [5]
Most CADDS individuals presented in early infancy with hepatic cholestasis, severe growth failure, profound hypotonia, developmental delay and elevated VLCFAs.
“most individuals presented in early infancy with hepatic cholestasis, severe growth failure, profound hypotonia, developmental delay and elevated VLCFAs (Table 2).”
From Interstitial lung disease and pancreatic exocrine insufficiency in <scp>CADDS</scp>: Phenotypic expansion and literature review (2023) · cites this paper as [5]
CADDS affected males commonly die in infancy.
“However, unlike either DDCH or X‐ALD, CADDS affected males have persistent cholestatic liver disease and commonly die in infancy. 5 , 6 , 7 , 8 , 9”
From Interstitial lung disease and pancreatic exocrine insufficiency in <scp>CADDS</scp>: Phenotypic expansion and literature review (2023) · cites this paper as [5]
RNA analyses and immunocytochemical studies on cultured fibroblasts from affected CADDS patients have previously confirmed the absence of BCAP31 transcripts and ALDP, respectively, in keeping with a loss-of-function effect.
“RNA analyses and immunocytochemical studies on cultured fibroblasts from affected CADDS patients have previously confirmed the absence of BCAP31 transcripts and ALDP (the protein encoded by ABCD1), respectively, in keeping with a loss‐of‐function effect.”
From Interstitial lung disease and pancreatic exocrine insufficiency in <scp>CADDS</scp>: Phenotypic expansion and literature review (2023) · cites this paper as [5]
Death from respiratory causes is reported in 50% of males with CADDS.
“overall, death from respiratory causes is reported in 50% of males with CADDS. 5 , 6”
From Interstitial lung disease and pancreatic exocrine insufficiency in <scp>CADDS</scp>: Phenotypic expansion and literature review (2023) · cites this paper as [5]
Previous studies have reported normal plasmalogen levels in blood and cultured fibroblasts, with normal peroxisomal size, number and assembly demonstrated in liver tissue by electron microscopy and immunochemistry.
“Previous studies, have reported normal plasmalogen levels in blood and cultured fibroblasts, with normal peroxisomal size, number and assembly demonstrated in liver tissue by electron microscopy and immunochemistry. 5 , 6”
From Interstitial lung disease and pancreatic exocrine insufficiency in <scp>CADDS</scp>: Phenotypic expansion and literature review (2023) · cites this paper as [5]
Cites
Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters
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Self-citationMoser, H. W., Mahmood, A., & Raymond, G. V. (2007) · Nature Clinical Practice Neurology · doi:10.1038/ncpneuro0421 · Cited by 663 · see citing works
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Self-citationAdrenoleukodystrophy: Incidence, new mutation rate, and results of extended family screening
Bezman, L., Moser, A. B., Raymond, G. V., Rinaldo, P., Watkins, P. A., Smith, K. D., Kass, N. E., & Moser, H. W. (2001) · Annals of Neurology · doi:10.1002/ana.101 · Cited by 324 · see citing works
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Genomic organization of the adrenoleukodystrophy gene
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Mallack, E. J., Gao, K., Engelen, M., & Kemp, S. (2022) · Cells · doi:10.3390/cells11020283 · Cited by 60 · see citing works
“CADDS is characterized by severe intrauterine growth retardation, neonatal hypotonia, failure to thrive, severe global developmental delay, and liver dysfunction, leading to early death [33].”
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Heath, O., Pandithan, D., Pitt, J., Savva, E., Raiti, L., Bracken, J., Vandeleur, M., Delatycki, M. B., Yaplito‐Lee, J., Hardikar, W., et al. (2023) · JIMD Reports · doi:10.1002/jmd2.12390 · Cited by 2 · see citing works
- Authors
- Corzo, D., Gibson, W., Johnson, K., Mitchell, G., LePage, G., Cox, G. F., Casey, R., Zeiss, C., Tyson, H., Cutting, G. R., Raymond, G. V., Smith, K. D., Watkins, P. A., Moser, A. B., Moser, H. W., & Steinberg, S. J.
- Affiliations
- Boston Children's Hospital (US)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Kennedy Krieger Institute (US)
- University of Calgary (CA)
- Yale University (US)
- Corresponding author
- Steinberg, Steven J.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2002-06
- Volume
- 70
- Issue
- 6
- Pages
- 1520-1531
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC419992
- OpenAlex
- W2003109429
- Cited by
- 85
- References
- 6
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 5 · 2019: 2 · 2018: 6 · 2017: 4 · 2016: 4 · 2015: 1 · 2014: 6 · 2013: 1 · 2012: 10
- FWCI
- 1.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service
- National Center for Research Resources (RR 000 52, M01RR000052)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-10981, P01HD010981)
- 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, contiguous gene deletion, neonatal phenotype, peroxisome biogenesis disorders, very long chain fatty acids, ALDP, genetic counseling, misdiagnosis, neonates
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenoleukodystrophy, Child, Child, Preschool, Exons, Female, Fibroblasts, Genetic Complementation Test, Heterozygote, Humans, Infant, Infant, Newborn, Infant, Newborn, Diseases, Male, Membrane Proteins, Phenotype, Prenatal Diagnosis, Promoter Regions, Genetic, Proteins, Syndrome, X Chromosome, Sequence Deletion, Age of Onset, ATP-Binding Cassette Transporters, Peroxisomal Disorders, Chemokines, CC, Peroxisomes, Chemokine CCL22
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