Cawley Niamh X, Zhou Ruyu, Mylvara Avani, Padilla Cameron J, Alexander Derek, Farhat Nicole, Alvarez Carolina, Cougnoux Antony, Berry-Kravis Elizabeth, Cologna Stephanie M, Liu Fang, Porter Forbes D
Section on Molecular Dysmorphology, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
Applied and Computational Mathematics and Statistics, University of Notre Dame, South Bend, IN.
Genet Med Open. 2025 Jul 7;3:103443. doi: 10.1016/j.gimo.2025.103443. eCollection 2025.
Niemann-Pick disease, type C1 (NPC1) is a fatal, neurodegenerative disease caused by pathological variants in . Analysis of serum neurofilament light (NfL), a marker of neuronal damage, could be useful as a biomarker for patient monitoring and clinical trial design.
We measured NfL levels in serum samples from 118 well-characterized individuals with NPC1 and analyzed them with respect to clinical measures and treatment status.
The results show a 6.1-fold increase in serum NfL in individuals with NPC1 compared with age-appropriate controls. Moreover, serum NfL levels showed a significant positive correlation with age of neurological symptom onset and the annual severity increment score. Serum NfL levels were also positively correlated with the 17- and 5-domain NPC Neurological Severity Scores. Longitudinal analyses reveal a 26% reduction in serum NfL levels in individuals on miglustat, a therapeutic drug used off-label for the treatment of NPC1 in the United States of America. Effectiveness of intrathecal hydroxypropyl-β-cyclodextrin treatment may be more beneficial in younger individuals. To help inform clinical trial design, our modeling predicts that a measurable reduction of serum NfL levels might be observed after 8 months of treatment with a potential drug exhibiting 10% to 20% efficacy.
Our data suggest that NfL may be a useful serum biomarker for NPC1.
1型尼曼-匹克病（NPC1）是一种由[相关基因]的病理变异引起的致命性神经退行性疾病。血清神经丝轻链（NfL）是神经元损伤的标志物，分析其水平可能有助于作为患者监测和临床试验设计的生物标志物。
我们测量了118例特征明确的NPC1患者血清样本中的NfL水平，并根据临床指标和治疗状态进行分析。
结果显示，与年龄匹配的对照组相比，NPC1患者血清NfL升高了6.1倍。此外，血清NfL水平与神经症状出现的年龄以及年度严重程度增加评分呈显著正相关。血清NfL水平也与17域和5域NPC神经严重程度评分呈正相关。纵向分析显示，在美国用于治疗NPC1的非标签治疗药物米格鲁司他治疗的患者中，血清NfL水平降低了26%。鞘内注射羟丙基-β-环糊精治疗可能对年轻个体更有益。为帮助指导临床试验设计，我们的模型预测，使用疗效为10%至20%的潜在药物治疗8个月后，可能会观察到血清NfL水平有可测量的降低。
我们的数据表明，NfL可能是NPC1一种有用的血清生物标志物。
