Niemann-Pick disease type C (NPC) is a neurodegenerative disease in which mutation of NPC1 or NPC2 gene leads to lysosomal accumulation of unesterified cholesterol and sphingolipids. Diagnosis of NPC disease is challenging due to non-specific early symptoms. Biomarker and genetic tests are used as first-line diagnostic tests for NPC. In this study, we developed a plasma test based on N-(3β,5α,6β-trihydroxy-cholan-24-oyl)glycine (TCG) that was markedly increased in the plasma of human NPC1 subjects. The test showed sensitivity of 0.9945 and specificity of 0.9982 to differentiate individuals with NPC1 from NPC1 carriers and controls. Compared to other commonly used biomarkers, cholestane-3β,5α,6β-triol (C-triol) and N-palmitoyl-O-phosphocholine (PPCS, also referred to as lysoSM-509), TCG was equally sensitive for identifying NPC1 but more specific. Unlike C-triol and PPCS, TCG showed excellent stability and no spurious generation of marker in the sample preparation or aging of samples. TCG was also elevated in lysosomal acid lipase deficiency (LALD) and acid sphingomyelinase deficiency (ASMD). Plasma TCG was significantly reduced after intravenous (IV) 2-hydroxypropyl-β-cyclodextrin (HPβCD) treatment. These results demonstrate that plasma TCG was superior to C-triol and PPCS as NPC1 diagnostic biomarker and was able to evaluate the peripheral treatment efficacy of IV HPβCD treatment.

尼曼-匹克病 C 型 (NPC) 是一种神经退行性疾病，其中NPC1或NPC2基因导致未酯化胆固醇和鞘脂的溶酶体积累。由于非特异性早期症状，NPC 疾病的诊断具有挑战性。生物标志物和基因检测被用作 NPC 的一线诊断检测。在本研究中，我们开发了一种基于 N-(3β,5α,6β-trihydroxy-cholan-24-oyl)glycine (TCG) 的血浆测试，其在人类 NPC1 受试者的血浆中显着增加。该测试显示出 0.9945 的灵敏度和 0.9982 的特异性，可将 NPC1 个体与 NPC1 携带者和对照区分开来。与其他常用的生物标志物 cholestane-3β,5α,6β-triol (C-triol) 和 N-palmitoyl-O-phosphocholine (PPCS, 也称为 lysoSM-509) 相比，TCG 对 NPC1 的识别同样敏感，但更多具体的。与 C-三醇和 PPCS 不同，TCG 表现出优异的稳定性，在样品制备或样品老化过程中不会产生伪标记物。TCG 在溶酶体酸性脂肪酶缺乏症 (LALD) 和酸性鞘磷脂酶缺乏症 (ASMD) 中也升高。静脉注射 (IV) 2-羟丙基-β-环糊精 (HPβCD) 治疗后，血浆 TCG 显着降低。这些结果表明，血浆 TCG 作为 NPC1 诊断生物标志物优于 C-三醇和 PPCS，并且能够评估 IV HPβCD 治疗的外周治疗效果。