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, USA.
Applied and Computational Mathematics and Statistics, University of Notre Dame, South Bend, IN, USA.
Mol Genet Metab. 2023 Nov;140(3):107656. doi: 10.1016/j.ymgme.2023.107656. Epub 2023 Jul 23.
Niemann-Pick disease, type C1 (NPC1) is an ultrarare, recessive disorder due to pathological variants of NPC1. The NPC1 phenotype is characterized by progressive cerebellar ataxia and cognitive impairment. Although classically a childhood/adolescent disease, NPC1 is heterogeneous with respect to the age of onset of neurological signs and symptoms. While miglustat has shown to be clinically effective, there are currently no FDA approved drugs to treat NPC1. Identification and characterization of biomarkers may provide tools to facilitate therapeutic trials. Ubiquitin C-terminal hydrolase-L1 (UCHL1) is a protein which is highly expressed by neurons and is a biomarker of neuronal damage. We thus measured cerebrospinal fluid (CSF) levels of UCHL1 in individuals with NPC1.
CSF levels of UCHL1 were measured using a Quanterix Neuroplex 4 assay in 94 individuals with NPC1 and 35 age-appropriate comparison samples. Cross-sectional and longitudinal CSF UCHL1 levels were then evaluated for correlation with phenotypic measures and treatment status.
CSF UCHL1 levels were markedly elevated (3.3-fold) in individuals with NPC1 relative to comparison samples. The CSF UCHL1 levels showed statistically significant (adj p < 0.0001), moderate, positive correlations with both the 17- and 5-domain NPC Neurological Severity Scores and the Annual Severity Increment Scores. Miglustat treatment significantly decreased (adj p < 0.0001) CSF UCHL1 levels by 30% (95% CI 17-40%).
CSF UCHL1 levels are elevated in NPC1, increase with increasing clinical severity and decrease in response to therapy with miglustat. Based on these data, UCHL1 may be a useful biomarker to monitor disease progression and therapeutic response in individuals with NPC1.
尼曼-匹克病 C1 型（NPC1）是一种由 NPC1 病理性变异引起的超罕见隐性疾病。NPC1 表型的特征是进行性小脑共济失调和认知障碍。虽然 NPC1 经典地表现为儿童/青少年疾病，但在神经系统体征和症状的发病年龄方面存在异质性。尽管米格列醇已显示出临床疗效，但目前尚无 FDA 批准的药物可治疗 NPC1。生物标志物的鉴定和特征描述可能为治疗试验提供工具。泛素 C 端水解酶-L1（UCHL1）是一种在神经元中高度表达的蛋白质，是神经元损伤的生物标志物。因此，我们测量了 NPC1 个体的脑脊液（CSF）UCHL1 水平。
使用 Quanterix Neuroplex 4 测定法测量了 94 名 NPC1 个体和 35 名年龄匹配的对照样本的 CSF UCHL1 水平。然后评估了 CSF UCHL1 水平与表型测量和治疗状况的横断面和纵向相关性。
与对照样本相比，NPC1 个体的 CSF UCHL1 水平明显升高（升高 3.3 倍）。CSF UCHL1 水平与 17 域和 5 域 NPC 神经严重程度评分以及年度严重程度递增评分均呈统计学显著（调整后 p<0.0001）、中度、正相关。米格列醇治疗可使 CSF UCHL1 水平显著降低（调整后 p<0.0001）30%（95%CI 17-40%）。
NPC1 中 CSF UCHL1 水平升高，与临床严重程度增加呈正相关，且对米格列醇治疗的反应降低。基于这些数据，UCHL1 可能是监测 NPC1 个体疾病进展和治疗反应的有用生物标志物。
