Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, National Institutes of Health (NIH), Bethesda, MD, USA.
Mol Genet Metab. 2024 Sep-Oct;143(1-2):108570. doi: 10.1016/j.ymgme.2024.108570. Epub 2024 Aug 30.
Smith-Lemli-Opitz syndrome (SLOS) is a rare, multiple malformation/intellectual disability disorder caused by pathogenic variants of DHCR7. DHCR7 catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol in the final step of cholesterol biosynthesis. This results in accumulation of 7DHC and a cholesterol deficiency. Although the biochemical defect is well delineated and multiple mechanisms underlying developmental defects have been explored, the post developmental neuropathological consequences of altered central nervous system sterol composition have not been studied. Preclinical studies suggest that astroglial activation may occur in SLOS. To determine if astroglial activation is present in individuals with SLOS, we quantified cerebrospinal fluid (CSF) glial fibrillary acidic protein using a Quanterix Simoa® GFAP Discovery Kit for SR-X™. Relative to an age-appropriate comparison group, we found that CSF GFAP levels were elevated 3.9-fold in SLOS (3980 ± 3732 versus 1010 ± 577 pg/ml, p = 0.0184). Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, has previously been shown to increase expression of hypomorphic DHCR7 alleles and in a placebo-controlled trial improved serum sterol levels and decreased irritability. Using archived CSF samples from that prior study, we observed a significant decrease (p = 0.0119) in CSF GFAP levels in response to treatment with simvastatin. Although further work needs to be done to understand the potential contribution of neuroinflammation to SLOS neuropathology and cognitive dysfunction, these data confirm astroglial activation in SLOS and suggest that CSF GFAP may be a useful biomarker to monitor therapeutic responses.
史密斯-莱姆利-奥皮茨综合征（SLOS）是一种罕见的多发性畸形/智力障碍疾病，由 DHCR7 的致病性变异引起。DHCR7 在胆固醇生物合成的最后一步催化 7-脱氢胆固醇（7DHC）还原为胆固醇。这导致 7DHC 积累和胆固醇缺乏。尽管生化缺陷已得到很好的描述，并且已经探索了多种导致发育缺陷的机制，但中枢神经系统固醇组成改变的发育后神经病理学后果尚未研究。临床前研究表明星形胶质细胞激活可能发生在 SLOS 中。为了确定 SLOS 个体是否存在星形胶质细胞激活，我们使用 Quanterix Simoa® GFAP Discovery Kit for SR-X™ 定量测定了脑脊液（CSF）神经胶质纤维酸性蛋白。与年龄相匹配的对照组相比，我们发现 SLOS 患者的 CSF GFAP 水平升高了 3.9 倍（3980±3732 与 1010±577 pg/ml，p=0.0184）。辛伐他汀是一种 3-羟基-3-甲基戊二酰辅酶 A 还原酶抑制剂，先前已被证明可以增加低功能态 DHCR7 等位基因的表达，并且在安慰剂对照试验中改善了血清固醇水平并降低了易激惹性。利用先前研究中的存档 CSF 样本，我们观察到辛伐他汀治疗后 CSF GFAP 水平显著降低（p=0.0119）。尽管需要进一步研究来了解神经炎症对 SLOS 神经病理学和认知功能障碍的潜在贡献，但这些数据证实了 SLOS 中的星形胶质细胞激活，并表明 CSF GFAP 可能是监测治疗反应的有用生物标志物。
