Signorini Cinzia, De Felice Claudio, Durand Thierry, Galano Jean-Marie, Oger Camille, Leoncini Silvia, Hayek Joussef, Lee Jetty Chung-Yung, Lund Troy C, Orchard Paul J
Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
Neonatal Intensive Care Unit, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy.
Life (Basel). 2022 Jan 20;12(2):146. doi: 10.3390/life12020146.
Cerebral adrenoleukodystrophy (ALD) is a rare neuroinflammatory disorder characterized by progressive demyelination. Mutations within the 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-isoprostanes (F-IsoPs), Fdihomo-isoprostanes (F-dihomo-IsoPs) and F-neuroprostanes (F-NeuroPs)-which are oxygenated metabolites of arachidonic (ARA), adrenic (AdA) and docosahexaenoic (DHA) acids, respectively-in plasma samples from ALD subjects ( = 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 ( = 29), in ALD (i), F-IsoPs levels were significantly ( < 0.01) increased in all patients, with the single exception of the early ALD and on NAC subjects; (ii) significant elevated ( < 0.0001) amounts of F-dihomo-IsoPs were detected, with the exception of patients with a lack of cerebral disease; (iii), a significant increase ( < 0.003) in F-NeuroP plasma levels was detected in all ALD patients. Moreover, F-IsoPs plasma levels were significantly higher ( = 0.038) in early ALD in comparison to late ALD stage, and F-NeuroPs were significantly lower ( = 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.
脑型肾上腺脑白质营养不良（ALD）是一种罕见的神经炎症性疾病，其特征为进行性脱髓鞘。该基因内的突变导致过氧化物酶体中极长链脂肪酸（VLCFA）蓄积，尤其是在大脑中。虽然已知这种VLCFA蓄积是该疾病的驱动原因，但氧化应激可能是一个促成因素。对于患有早期脑部疾病的患者，异基因造血干细胞移植（HSCT）是标准治疗方法，并且这可以由抗氧化剂提供支持。为了评估脂肪酸氧化在该疾病中的作用，我们检测了来自20例患有不同疾病表型的ALD受试者血浆样本中的F - 异前列腺素（F - IsoPs）、F - 二高异前列腺素（F - dihomo - IsoPs）和F - 神经前列腺素（F - NeuroPs），它们分别是花生四烯酸（ARA）、肾上腺酸（AdA）和二十二碳六烯酸（DHA）的氧化代谢产物。根据患者情况将ALD患者分为三组：（1）确诊为ALD但无脑部疾病；（2）HSCT后早期（HSCT后<100天）且正在接受静脉注射N - 乙酰 - L - 半胱氨酸（NAC）治疗的脑部疾病患者；（3）HSCT后晚期（HSCT后超过100天）且停止NAC治疗的脑部疾病患者。在我们的观察中，与健康受试者（n = 29）相比，在ALD患者中：（i）除早期ALD且正在接受NAC治疗的受试者外，所有患者的F - IsoPs水平均显著升高（P < 0.01）；（ii）检测到F - 二高异前列腺素的量显著升高（P < 0.0001），无脑部疾病的患者除外；（iii）所有ALD患者的血浆F - NeuroP水平均显著升高（P < 0.003）。此外，早期ALD患者的血浆F - IsoPs水平显著高于晚期ALD阶段（P = 0.038），无脑部疾病的ALD受试者的血浆F - NeuroPs水平显著低于疾病晚期（P = 0.012）。值得注意的是，所有研究的异前列腺素的血浆量均显示可区分ALD患者与健康受试者。总之，异前列腺素与X - ALD的表型相关，可能有助于预测脑部疾病的存在并确定疾病进展风险。
