Abstract
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(s) = -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(s) = -0.72; P = 0.002) and the Anxiety Depression and Mood Scale (r(s) = -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.