Late-onset Niemann-Pick type C (NP-C) is a rare, underdiagnosed lysosomal disease with neurological manifestations. A specific treatment, miglustat, can stabilize the disease if given early. Recently, three plasma screening biomarkers (PSBs) were developed [cholestane3β,5α,6βtriol (C-triol), 7-ketocholesterol (7-KC), and lysosphingomyelin-509 (LSM-509)], allowing a simpler and quite robust screening of patients suitable for genetic testing. The objective of our study was to evaluate practical utility and feasibility of large-scale PSB screening for NP-C in selected adult patients. Patients were prospectively enrolled if they showed, starting from 12 years of age, at least one of the three initial neuro-psychiatric manifestations described in NP-C: (1) gait disorder (cerebellar and/or dystonic); (2) cognitive decline with frontal lobe syndrome; (3) atypical psychosis. PSBs were measured in plasma of all patients and, if positive (LSM-509 and/or C-triol + 7-KC elevated), sequencing of NPC1 and NPC2 genes was performed. A total of 251 patients [136 males, 115 females; median age 42.1 (range 12.2–85.6) years] were screened. Six patients had positive PSBs. Two were confirmed to have NP-C (0.8% diagnostic yield, both with all three PSBs highly increased, especially LSM-509). False-positive rate was 1.2%, which was identical if only considering LSM-509. By contrast, false-positive rates were 8.1% and 5.7% for 7-KC and C-triol, respectively. We showed that selecting patients with neurologic and/or psychiatric symptoms consistent with NP-C for large-scale PSB screening is a simple and valid strategy to identify new adult NP-C patients, and would probably lead to earlier diagnosis and treatment administration if widely applied.

迟发性尼曼-匹克C型（NP-C）是一种罕见的，诊断不足的溶酶体病，具有神经系统表现。如果尽早给予特定的治疗，米格司他，可以使疾病稳定。最近，开发了三种血浆筛选生物标记物（胆甾烷3β，5α，6β三醇（C-三醇），7-酮胆固醇（7-KC）和溶血鞘磷脂-509（LSM-509）]，从而可以进行更简单，更可靠的筛选适合基因测试的患者。我们研究的目的是评估在选定的成年患者中进行大规模PSB筛查NP-C的实用性和可行性。如果患者从12岁开始表现出NP-C中描述的三种最初的神经精神病学表现中的至少一种，则前瞻性入组：（1）步态障碍（小脑和/或肌张力障碍）；（2）额叶综合征伴认知功能减退；（3）非典型精神病。测量所有患者血浆中的PSB，如果阳性（LSM-509和/或C-triol + 7-KC升高），则对进行了NPC1和NPC2基因。总计251位患者[136例男性，115例女性；筛选年龄中位数为42.1岁（范围为12.2-85.6）]。6名患者PSB阳性。证实其中两个具有NP-C（诊断产率为0.8％，所有三个PSB均高度升高，尤其是LSM-509）。假阳性率为1.2％，如果仅考虑LSM-509，则为假阳性。相比之下，7-KC和C-三醇的假阳性率分别为8.1％和5.7％。我们表明，选择具有与NP-C一致的神经系统和/或精神病学症状的患者进行大规模PSB筛查是识别新的成年NP-C患者的简单有效的策略，如果广泛使用，可能会导致早期诊断和治疗应用。