Laroui Asma, Rojas Daniela, Bouhour Sophie, Proteau-Lemieux Mélodie, Galarneau Luc, Benachenhou Sérine, Abolghasemi Armita, Plantefeve Rosalie, Mallet Pierre-Luc, Corbin François, Lepage Jean-François, Çaku Artuela
Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Department of Psychology, University of Montreal, Montreal, Quebec, Canada.
J Lipid Res. 2025 Mar 27;66(5):100787. doi: 10.1016/j.jlr.2025.100787.
Fragile X syndrome (FXS) is caused by mutations in the fragile X mental retardation 1 gene, characterized by low plasma cholesterol levels. Considering the essential role of brain cholesterol in signaling and synaptogenesis, it is important to screen for brain cholesterol abnormalities in FXS and explore their link with neuropsychological profiles. Brain cholesterol is synthesized in situ, and the excess is primarily converted to 24(S)-hydroxycholesterol (24(S)-OHC). 27-hydroxycholesterol (27-OHC) is the major cholesterol oxidation metabolite that crosses the blood-brain barrier from peripheral circulation into the brain. Plasma levels of 24(S)-OHC and 27-OHC were quantified in FXS and control individuals. The FXS group underwent transcranial magnetic stimulation to evaluate corticospinal excitability and inhibition. The clinical profile was assessed using questionnaires evaluating specific symptoms related to autism, aberrant behaviors, and anxiety. Study results show a significant decrease in plasma levels of 24(S)-OHC in FXS as compared to controls (78.48 nM ± 20.90 vs. 99.53 nM ± 32.30; P = 0.006). Moreover, a negative correlation was observed between plasma levels of 24(S)-OHC and motor evoked potential (r = -0.57; P = 0.05) in FXS. Similarly, a negative correlation was also found between plasma levels of 24(S)-OHC and the total score of the Social Communication Questionnaire (r = -0.72; P = 0.002) and the Anxiety Depression and Mood Scale (r = -0.61; P = 0.02). The 24(S)-OHC is associated with specific neurophysiological and behavioral characteristics in individuals with FXS. Larger studies are warranted to confirm the potential of 24(S)-OHC as a reliable biomarker for FXS.
脆性X综合征（FXS）由脆性X智力低下1基因的突变引起，其特征为血浆胆固醇水平较低。鉴于脑胆固醇在信号传导和突触形成中的重要作用，筛查FXS患者的脑胆固醇异常并探索其与神经心理学特征的联系具有重要意义。脑胆固醇在原位合成，多余的主要转化为24(S)-羟基胆固醇（24(S)-OHC）。27-羟基胆固醇（27-OHC）是主要的胆固醇氧化代谢产物，可从外周循环穿过血脑屏障进入大脑。对FXS患者和对照个体的血浆24(S)-OHC和27-OHC水平进行了定量分析。FXS组接受经颅磁刺激以评估皮质脊髓兴奋性和抑制。使用评估与自闭症、异常行为和焦虑相关的特定症状的问卷对临床特征进行评估。研究结果显示，与对照组相比，FXS患者血浆24(S)-OHC水平显著降低（78.48 nM ± 20.90 vs. 99.53 nM ± 32.30；P = 0.006）。此外，在FXS患者中，观察到血浆24(S)-OHC水平与运动诱发电位之间存在负相关（r = -0.57；P = 0.05）。同样，在血浆24(S)-OHC水平与社交沟通问卷总分（r = -0.72；P = 0.002）以及焦虑抑郁和情绪量表（r = -0.61；P = 0.02）之间也发现了负相关。24(S)-OHC与FXS患者的特定神经生理和行为特征相关。需要进行更大规模的研究来证实24(S)-OHC作为FXS可靠生物标志物的潜力。
