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Multi-Omic Approach to Identify Phenotypic Modifiers Underlying Cerebral Demyelination in X-Linked Adrenoleukodystrophy

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Richmond, Phillip A., van der Kloet, Frans, Vaz, Frederic M., Lin, David, Uzozie, Anuli, Graham, Emma, Kobor, Michael, Mostafavi, Sara +7 more·2020·Frontiers in Cell and Developmental Biology
DOI 10.3389/fcell.2020.00520PMC PMC7330173

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Abstract

gene, and is characterized by the accumulation of very long-chain fatty acids in plasma and tissues. Disease-causing mutations are 'loss of function' mutations, with no prognostic value with respect to the clinical outcome of an individual. All male patients with ALD develop spinal cord disease and a peripheral neuropathy in adulthood, although age of onset is highly variable. However, the lifetime prevalence to develop progressive white matter lesions, termed cerebral ALD (CALD), is only about 60%. Early identification of transition to CALD is critical since it can be halted by allogeneic hematopoietic stem cell therapy only in an early stage. The primary goal of this study is to identify molecular markers which may be prognostic of cerebral demyelination from a simple blood sample, with the hope that blood-based assays can replace the current protocols for diagnosis. We collected six well-characterized brother pairs affected by ALD and discordant for the presence of CALD and performed multi-omic profiling of blood samples including genome, epigenome, transcriptome, metabolome/lipidome, and proteome profiling. In our analysis we identify discordant genomic alleles present across all families as well as differentially abundant molecular features across the omics technologies. The analysis was focused on univariate modeling to discriminate the two phenotypic groups, but was unable to identify statistically significant candidate molecular markers. Our study highlights the issues caused by a large amount of inter-individual variation, and supports the emerging hypothesis that cerebral demyelination is a complex mix of environmental factors and/or heterogeneous genomic alleles. We confirm previous observations about the role of immune response, specifically auto-immunity and the potential role of PFN1 protein overabundance in CALD in a subset of the families. We envision our methodology as well as dataset has utility to the field for reproducing previous or enabling future modifier investigations.

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  • Attempts to identify a modifier variant among 16 candidate genes, including some involved in inflammatory processes, had no success.

    “Although a large segregation analysis suggested the presence of a single “major” autosomal modifier locus [111], attempts to identify a modifier variant among 16 candidate genes, including some involved in inflammatory processes, had no success [15,112,113,114,115,116], as reviewed in [15].”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [112]

    The Introduction says candidate-gene modifier studies had little success, and the Results report that previously proposed variants did not segregate with the phenotype in this cohort. But the paper does not specify 16 candidate genes or say that some of those genes were selected for inflammatory roles. It also reports identification of one modifier gene, CYP4F2, with limited prognostic power, so “no success” overstates its account. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In six ABCD1-mutated brother pairs discordant for the presence of cALD, multi-omic profiling of blood samples including genome, epigenome, transcriptome, metabolome/lipidome, and proteome profiling was unable to identify statistically significant candidate molecular markers able to differentiate AMN and cALD patients.

    “In six ABCD1-mutated brother pairs discordant for the presence of cALD, the multi-omic profiling of blood samples including genome, epigenome, transcriptome, metabolome/lipidome, and proteome profiling was unable to identify statistically significant candidate molecular markers able to differentiate AMN and cALD patients [112].”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [112]

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Authors
Richmond, P. A., van der Kloet, F., Vaz, F. M., Lin, D., Uzozie, A., Graham, E., Kobor, M., Mostafavi, S., Moerland, P. D., Lange, P. F., van Kampen, A. H. C., Wasserman, W. W., Engelen, M., Kemp, S., & van Karnebeek, C. D. M.
Affiliations
  • University of British Columbia (CA)
  • Amsterdam Public Health (NL)
  • Emma Kinderziekenhuis (NL)
Corresponding author
  • Engelen, Marc
  • Kemp, Stephan
ORCID
Venue
Frontiers in Cell and Developmental Biology
Publisher
Frontiers Media SA
Published
2020-06-25
Volume
8
Pages
520-520
ISSN
2296-634X (ISSN-L)
DOI
10.3389/fcell.2020.00520
PMC
PMC7330173
OpenAlex
W3037668580
Cited by
29
References
8
Citations by year
2026: 6 · 2025: 3 · 2024: 6 · 2023: 1 · 2022: 4 · 2021: 6 · 2020: 3
FWCI
2.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cell and Developmental Biology (publishedVersion, cc-by)
  • medRxiv (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • BC Children's Hospital
  • Stichting Metakids
  • ZonMw (016.196.310)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (016196310)
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 › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
X-linked adrenoleukodystrophy, cerebral adrenoleukodystrophy, brain demyelination, multi-omics profiling, blood-based biomarkers, very long chain fatty acids, autoimmunity, profilin-1, hematopoietic stem cell therapy, disease progression prediction, interindividual variability

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