Cerebral adrenoleukodystrophy (ALD) is a rare neuroinflammatory disorder characterized by progressive demyelination. Mutations within the ABCD1 gene result in very long-chain fatty acid (VLCFA) accumulation within the peroxisome, particularly in the brain. While this VLCFA accumulation is known to be the driving cause of the disease, oxidative stress can be a contributing factor. For patients with early cerebral disease, allogeneic hematopoietic stem cell transplantation (HSCT) is the standard of care, and this can be supported by antioxidants. To evaluate the involvement of fatty acid oxidation in the disease, F 2-isoprostanes (F 2-IsoPs), F 2-dihomo-isoprostanes (F 2-dihomo-IsoPs) and F 4-neuroprostanes (F 4-NeuroPs)-which are oxygenated metabolites of arachidonic (ARA), adrenic (AdA) and docosahexaenoic (DHA) acids, respectively-in plasma samples from ALD subjects ( n = 20)-with various phenotypes of the disease-were measured. Three ALD groups were classified according to patients with: (1) confirmed diagnosis of ALD but without cerebral disease; (2) cerebral disease in early period post-HSCT (<100 days post-HSCT) and on intravenous N-acetyl-L-cysteine (NAC) treatment; (3) cerebral disease in late period post-HSCT (beyond 100 days post-HSCT) and off NAC therapy. In our observation, when compared to healthy subjects ( n = 29), in ALD (i), F 2-IsoPs levels were significantly ( p < 0.01) increased in all patients, with the single exception of the early ALD and on NAC subjects; (ii) significant elevated ( p < 0.0001) amounts of F 2-dihomo-IsoPs were detected, with the exception of patients with a lack of cerebral disease; (iii), a significant increase ( p < 0.003) in F 4-NeuroP plasma levels was detected in all ALD patients. Moreover, F 2-IsoPs plasma levels were significantly higher ( p = 0.038) in early ALD in comparison to late ALD stage, and F 4-NeuroPs were significantly lower ( p = 0.012) in ALD subjects with a lack of cerebral disease in comparison to the late disease stage. Remarkably, plasma amounts of all investigated isoprostanoids were shown to discriminate ALD patients vs. healthy subjects. Altogether, isoprostanoids are relevant to the phenotype of X-ALD and may be helpful in predicting the presence of cerebral disease and establishing the risk of progression.
|Original language||English (US)|
|State||Published - Feb 2022|
Bibliographical noteFunding Information:
Funding: The present work was partly funded by the Tuscan Region, Bando Salute 2009: “?ntioxi-omega-3 polyunsaturated Fatty Acids, lipoic acid—supplementation in Rett syndrome: A novel approach novel approach to therapy”, RT No. 142; 2009–2014, and by the Toscana Life Sciences “Ruolo dello stress ossidativo e di molecole antiossidanti nella sindrome di Rett”; 2015–2018. S.L. was a recipient of research fellowship funded by the Child Neuropsichiatry Unit, Azienda Ospedaliera Universi-taria Senese (Siena, Italy). Institutional Review Board Statement: The study was conducted according to the guidelines of the Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki, according to the University of Minnesota Blood and Marrow Transplant
The presentworkwas partly funded by the Tuscan Region, Bando Salute 2009: “Antioxidants— omega-3 polyunsaturated FattyAcids, lipoic acid—supplementation in Rett syndrome: Anovel approach to therapy”, RT No. 142; 2009–2014, and by the Toscana Life Sciences “Ruolo dello stress ossidativo e di molecole antiossidanti nella sindrome di Rett”; 2015–2018. S.L. was a recipient of research fellowship funded by the Child Neuropsichiatry Unit, Azienda Ospedaliera Universitaria Senese (Siena, Italy).
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
- Cerebral adrenoleukodystrophy
- Fatty acids
- Hematopoietic stem cell transplantation
PubMed: MeSH publication types
- Journal Article