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Cited by 24Metabolism and Genetic DisordersLysosomal Storage Disorders ResearchHereditary Neurological Disorders

Deciphering the modifiers for phenotypic variability of X-linked adrenoleukodystrophy

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Palakuzhiyil, Shruti V, Christopher, Rita, Chandra, Sadanandavalli Retnaswami·2020·World Journal of Biological Chemistry
DOI 10.4331/wjbc.v11.i3.99PMC PMC7672940
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Abstract

1 mutation and the clinical phenotypes, and the molecular basis of phenotypic variability in X-ALD is yet to be resolved. Various genetic, epigenetic, and environmental influences are speculated to modify the disease onset and severity. In this review, we summarize the observations made in various studies investigating the potential modifying factors regulating the clinical manifestation of X-ALD, which could help understand the pathogenesis of the disease and develop suitable therapeutic strategies.

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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 [116]

    The “Modifier genes” section (page unavailable) says studies investigated candidate genes in inflammatory and other pathways, and Table 1 reports many variants with no significant association. The copy does not specify a set of 16 candidate genes, and the table also reports some positive associations, so it does not support an unqualified claim that all attempts had no success. (LLM, conf=0.84)

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Research works printed but not linked: 45

  1. [2]Kemp S Wanders R Biochemical aspects of X-linked adrenoleukodystrophy Brain Pathol 2010 20 831 837 20626744 PMC8094824
  2. [3]Berger J Forss-Petter S Eichler FS Pathophysiology of X-linked adrenoleukodystrophy Biochimie 2014 98 135 142 24316281 PMC3988840
  3. [5]Parisi LR Sowlati-Hashjin S Berhane IA Galster SL Carter KA Lovell JF Chemler SR Karttunen M Atilla-Gokcumen GE Membrane Disruption by Very Long Chain Fatty Acids during Necroptosis ACS Chem Biol 2019 14 2286 2294 31490656 PMC6800604
  4. [6]Khan M Singh J Gilg AG Uto T Singh I Very long-chain fatty acid accumulation causes lipotoxic response via 5-lipoxygenase in cerebral adrenoleukodystrophy J Lipid Res 2010 51 1685 1695 20173212 PMC2882744
  5. [7]van de Beek MC Ofman R Dijkstra I Wijburg F Engelen M Wanders R Kemp S Lipid-induced endoplasmic reticulum stress in X-linked adrenoleukodystrophy Biochim Biophys Acta Mol Basis Dis 2017 1863 2255 2265 28666219
  6. [8]Launay N Ruiz M Fourcade S Schlüter A Guilera C Ferrer I Knecht E Pujol A Oxidative stress regulates the ubiquitin-proteasome system and immunoproteasome functioning in a mouse model of X-adrenoleukodystrophy Brain 2013 136 891 904 23436506
  7. [9]Powers JM DeCiero DP Ito M Moser AB Moser HW Adrenomyeloneuropathy: a neuropathologic review featuring its noninflammatory myelopathy J Neuropathol Exp Neurol 2000 59 89 102 10749098
  8. [10]van Geel BM Assies J Wanders RJ Barth PG X linked adrenoleukodystrophy: clinical presentation, diagnosis, and therapy J Neurol Neurosurg Psychiatry 1997 63 4 14 9221959 PMC2169642
  9. [11]Jangouk P Zackowski KM Naidu S Raymond GV Adrenoleukodystrophy in female heterozygotes: underrecognized and undertreated Mol Genet Metab 2012 105 180 185 22112817
  10. [13]Chen X Chen Z Huang D Liu X Gui Q Yu S Adult cerebral adrenoleukodystrophy and Addison's disease in a female carrier Gene 2014 544 248 251 24768737
  11. [15]Wang Z Yan A Lin Y Xie H Zhou C Lan F Familial skewed x chromosome inactivation in adrenoleukodystrophy manifesting heterozygotes from a Chinese pedigree PLoS One 2013 8 e57977 23469258 PMC3585930
  12. [16]Moser HW Moser AB Smith KD Bergin A Borel J Shankroff J Stine OC Merette C Ott J Krivit W Adrenoleukodystrophy: phenotypic variability and implications for therapy J Inherit Metab Dis 1992 15 645 664 1528023
  13. [17]Simpson RH Rodda J Reinecke CJ Adrenoleukodystrophy in a mother and son J Neurol Neurosurg Psychiatry 1987 50 1165 1172 2822858 PMC1032350
  14. [18]Elrington GM Bateman DE Jeffrey MJ Lawton NF Adrenoleukodystrophy: heterogeneity in two brothers J Neurol Neurosurg Psychiatry 1989 52 310 313 2538572 PMC1032401
  15. [19]Korenke GC Fuchs S Krasemann E Doerr HG Wilichowski E Hunneman DH Hanefeld F Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype Ann Neurol 1996 40 254 257 8773611
  16. [20]Gosalakkal J Balky AP Intra familial phenotypical variations in adrenoleukodystrophy Neurol India 2010 58 109 111 20228476
  17. [21]Soardi FC Esquiaveto-Aun AM Guerra-Júnior G Lemos-Marini SH Mello MP Phenotypic variability in a family with x-linked adrenoleukodystrophy caused by the p.Trp132Ter mutation Arq Bras Endocrinol Metabol 2010 54 738 743 21340162
  18. [22]Kallabi F Ellouz E Tabebi M Ben Salah G Kaabechi N Keskes L Triki C Kamoun H Phenotypic variability in a Tunisian family with X-linked adrenoleukodystrophy caused by the p.Gln316Pro novel mutation Clin Chim Acta 2016 453 141 146 26686776
  19. [23]van Geel BM Assies J Weverling GJ Barth PG Predominance of the adrenomyeloneuropathy phenotype of X-linked adrenoleukodystrophy in The Netherlands: a survey of 30 kindreds Neurology 1994 44 2343 2346 7991123
  20. [26]Kok F Neumann S Sarde CO Zheng S Wu KH Wei HM Bergin J Watkins PA Gould S Sack G Mutational analysis of patients with X-linked adrenoleukodystrophy Hum Mutat 1995 6 104 115 7581394
  21. [27]Mosser J Douar AM Sarde CO Kioschis P Feil R Moser H Poustka AM Mandel JL Aubourg P Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters Nature 1993 361 726 730 8441467
  22. [28]Gallati S Disease-modifying genes and monogenic disorders: experience in cystic fibrosis Appl Clin Genet 2014 7 133 146 25053892 PMC4104546
  23. [29]Nadeau JH Modifier genes in mice and humans Nat Rev Genet 2001 2 165 174 11256068
  24. [32]Smith KD Kemp S Braiterman LT Lu JF Wei HM Geraghty M Stetten G Bergin JS Pevsner J Watkins PA X-linked adrenoleukodystrophy: genes, mutations, and phenotypes Neurochem Res 1999 24 521 535 10227685
  25. [35]Matsukawa T Asheuer M Takahashi Y Goto J Suzuki Y Shimozawa N Takano H Onodera O Nishizawa M Aubourg P Tsuji S Identification of novel SNPs of ABCD1, ABCD2, ABCD3, and ABCD4 genes in patients with X-linked adrenoleukodystrophy (ALD) based on comprehensive resequencing and association studies with ALD phenotypes Neurogenetics 2011 12 41 50 20661612 PMC3029816
  26. [36]Kemp S Valianpour F Denis S Ofman R Sanders RJ Mooyer P Barth PG Wanders RJ Elongation of very long-chain fatty acids is enhanced in X-linked adrenoleukodystrophy Mol Genet Metab 2005 84 144 151 15670720
  27. [39]Moser HW Smith KD Watkins PA Powers J MA X-linked adrenoleukodystrophy. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease (Vol. 4). New York: McGraw Hill, 2001: 3257-3301
  28. [42]Gomez-Lira M Marzari MG Uziel G Pignatti P Rizzuto N Salviati A Myelin oligodendrocyte glycoprotein (MOG) polymorphisms and adrenoleukodystrophy J Neuroimmunol 2000 111 245 247 11063846
  29. [43]Huang CJ Nazarian R Lee J Zhao PM Espinosa-Jeffrey A de Vellis J Tumor necrosis factor modulates transcription of myelin basic protein gene through nuclear factor kappa B in a human oligodendroglioma cell line Int J Dev Neurosci 2002 20 289 296 12175864
  30. [44]Barbier M Sabbagh A Kasper E Asheuer M Ahouansou O Pribill I Forss-Petter S Vidaud M Berger J Aubourg P CD1 gene polymorphisms and phenotypic variability in X-linked adrenoleukodystrophy PLoS One 2012 7 e29872 22253809 PMC3257241
  31. [45]Linnebank M Kemp S Wanders RJ Kleijer WJ van der Sterre ML Gärtner J Fliessbach K Semmler A Sokolowski P Köhler W Schlegel U Schmidt S Klockgether T Wüllner U Methionine metabolism and phenotypic variability in X-linked adrenoleukodystrophy Neurology 2006 66 442 443 16476952
  32. [46]Linnebank M Semmler A Kleijer WJ van der Sterre ML Gärtner J Fliessbach K Sokolowski P Köhler W Schlegel U Klockgether T Wanders RJ Schmidt S Wüllner U Kemp S The cystathionine beta-synthase variant c.844_845ins68 protects against CNS demyelination in X-linked adrenoleukodystrophy Hum Mutat 2006 27 1063 1064 16941496
  33. [47]Cao GN Bao XH Xiong H Wu Y Wu XR [Association of genetic polymorphisms in methionine metabolism genes with X-linked adrenoleukodystrophy] Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2011 28 279 282 21644223
  34. [48]Semmler A Bao X Cao G Köhler W Weller M Aubourg P Linnebank M Genetic variants of methionine metabolism and X-ALD phenotype generation: results of a new study sample J Neurol 2009 256 1277 1280 19353223
  35. [49]Brose RD Avramopoulos D Smith KD SOD2 as a potential modifier of X-linked adrenoleukodystrophy clinical phenotypes J Neurol 2012 259 1440 1447 22218650
  36. [50]Płatek T Orso E Zapała B Polus A Kieć-Wilk B Piwowar M Chojnacka M Ciałowicz U Malczewska-Malec M Schmitz G Solnica B Dembińska-Kieć A Case report of dysregulation of primary bile acid synthesis in a family with X-linked adrenoleukodystrophy Medicine (Baltimore) 2018 97 e13353 30544401 PMC6310492
  37. [52]Orchard PJ Markowski TW Higgins L Raymond GV Nascene DR Miller WP Pierpont EI Lund TC Association between APOE4 and biomarkers in cerebral adrenoleukodystrophy Sci Rep 2019 9 7858 31133696 PMC6536544
  38. [54]Schlüter A Sandoval J Fourcade S Díaz-Lagares A Ruiz M Casaccia P Esteller M Pujol A Epigenomic signature of adrenoleukodystrophy predicts compromised oligodendrocyte differentiation Brain Pathol 2018 28 902 919 29476661 PMC6857458
  39. [55]Shah N Singh I MicroRNA Profiling Identifies miR-196a as Differentially Expressed in Childhood Adrenoleukodystrophy and Adult Adrenomyeloneuropathy Mol Neurobiol 2017 54 1392 1403 26843114 PMC4972693
  40. [56]Ranea-Robles P Launay N Ruiz M Calingasan NY Dumont M Naudí A Portero-Otín M Pamplona R Ferrer I Beal MF Fourcade S Pujol A Aberrant regulation of the GSK-3β/NRF2 axis unveils a novel therapy for adrenoleukodystrophy EMBO Mol Med 2018 10 e8604 29997171 PMC6079538
  41. [57]Nury T Zarrouk A Ragot K Debbabi M Riedinger JM Vejux A Aubourg P Lizard G 7-Ketocholesterol is increased in the plasma of X-ALD patients and induces peroxisomal modifications in microglial cells: Potential roles of 7-ketocholesterol in the pathophysiology of X-ALD J Steroid Biochem Mol Biol 2017 169 123 136 27041118
  42. [58]Jang J Park S Jin Hur H Cho HJ Hwang I Pyo Kang Y Im I Lee H Lee E Yang W Kang HC Won Kwon S Yu JW Kim DW 25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome Nat Commun 2016 7 13129 27779191 PMC5093305
  43. [59]Yang Y Wang H Kouadir M Song H Shi F Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors Cell Death Dis 2019 10 128 30755589 PMC6372664
  44. [60]Vejux A Lizard G Cytotoxic effects of oxysterols associated with human diseases: Induction of cell death (apoptosis and/or oncosis), oxidative and inflammatory activities, and phospholipidosis Mol Aspects Med 2009 30 153 170 19248805
  45. [64]McGuinness MC Griffin DE Raymond GV Washington CA Moser HW Smith KD Tumor necrosis factor-alpha and X-linked adrenoleukodystrophy J Neuroimmunol 1995 61 161 169 7593551

Cited by

Sorted by citations

Authors
Palakuzhiyil, S. V., Christopher, R., & Chandra, S. R.
Affiliations
National Institute of Mental Health and Neurosciences (IN)
ORCID
Venue
World Journal of Biological Chemistry
Publisher
Baishideng Publishing Group Inc.
Published
2020-11-27
Volume
11
Issue
3
Pages
99-111
ISSN
1949-8454 (ISSN-L)
DOI
10.4331/wjbc.v11.i3.99
PMC
PMC7672940
OpenAlex
W3100006004
Cited by
24
References
18
Citations by year
2026: 2 · 2025: 6 · 2024: 5 · 2023: 4 · 2022: 5 · 2021: 2
FWCI
0.35
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • World Journal of Biological Chemistry (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • 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 › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
X-linked adrenoleukodystrophy, phenotypic variability, disease modifiers, genetic modifiers, epigenetic factors, environmental factors, pathogenesis, ABCD1 mutations

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