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Cited by 148Metabolism and Genetic DisordersLysosomal Storage Disorders ResearchNeurological diseases and metabolism

Pathomechanisms underlying X-adrenoleukodystrophy: A three-hit hypothesis

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Singh, Inderjit, Pujol, Aurora·2010·Brain Pathology
DOI 10.1111/j.1750-3639.2010.00392.xPMC PMC3021280
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Abstract

X‐adrenoleukodystrophy (X‐ALD) is a complex disease where inactivation of ABCD1 gene results in clinically diverse phenotypes, the fatal disorder of cerebral ALD (cALD) or a milder disorder of adrenomyeloneuropathy (AMN). Loss of ABCD1 function results in defective beta oxidation of very long chain fatty acids (VLCFA) resulting in excessive accumulation of VLCFA, the biochemical “hall mark” of X‐ALD. At present, the ABCD1‐mediated mechanisms that determine the different phenotype of X‐ALD are not well understood. The studies reviewed here suggest for a “three‐hit hypothesis” for neuropathology of cALD. An improved understanding of the molecular mechanisms associated with these three phases of cALD disease should facilitate the development of effective pharmacological therapeutics for X‐ALD.

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  • Abcd1−/− mice, despite being congenic littermates living in the same cage, show variable motor deficits at different ages, supporting the importance of stochasticity for determining phenotypes.

    “Abcd1−/− mice, despite being congenic littermates living in the same cage, show variable motor deficits at different ages, thereby supporting the importance of stochasticity for determining phenotypes [136].”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [136]

    The Introduction (page unavailable) reports motor and locomotor deficits in ABCD1-null mice at around 20 months of age. It also suggests stochastic factors may affect outcomes in people with X-ALD, but does not report variable ages of motor deficits among congenic, same-cage mouse littermates or draw that inference from mice. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Experimental results from A. Pujol's laboratory demonstrated overproduction of redox free radicals altering mitochondrial functions in brain white matter or cultured cells.

    “Experimental results from A. Pujol’s laboratory demonstrated overproduction of redox free radicals altering mitochondrial functions in brain white matter or cultured cells [80,136,179,180,181,182,183,184,185,186,187,188,189].”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [136]

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Research works printed but not linked: 49

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Authors
Singh, I., & Pujol, A.
Affiliations
  • Medical University of South Carolina (US)
  • Institució Catalana de Recerca i Estudis Avançats (ES)
ORCID
Venue
Brain Pathology
Publisher
Wiley
Published
2010-06-07
Volume
20
Issue
4
Pages
838-844
ISSN
  • 1015-6305 (ISSN-L)
  • 1750-3639
DOI
10.1111/j.1750-3639.2010.00392.x
PMC
PMC3021280
OpenAlex
W1924236635
Cited by
148
References
16
Citations by year
2026: 2 · 2025: 10 · 2024: 11 · 2023: 8 · 2022: 8 · 2021: 11 · 2020: 5 · 2019: 5 · 2018: 3 · 2017: 10 · 2016: 10 · 2015: 12 · 2014: 14 · 2013: 14 · 2012: 13
FWCI
1.25
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Brain Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (acceptedVersion)
  • RECERCAT (Consorci de Serveis Universitaris de Catalunya) (submittedVersion, public-domain)
Funders
National Institute of Neurological Disorders and Stroke (NS-22576, NS 37766, R01NS037766, R01NS022576)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
Keywords
ABCD1 gene, very long chain fatty acids, very long chain fatty acid beta-oxidation, cerebral adrenoleukodystrophy, adrenomyeloneuropathy, pathogenesis, phenotypic variability, neuropathology
MeSH terms
ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenoleukodystrophy, Brain, Fatty Acids, Humans, Nerve Degeneration, Oxidative Stress, ATP-Binding Cassette Transporters

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