In recent years the oxysterol species cholestane-3β, 5α, 6β-triol (C-triol) has found application as a diagnostic biomarker for Niemann-Pick disease type C. Other studies have described increased C-triol in patients with Niemann-Pick disease type A/B and milder increases in lysosomal acid lipase deficiency (LALD), whereas they note normal C-triol levels in Smith-Lemli-Opitz syndrome (SLOS) and familial hypercholesterolaemia (FH) patients. Herein, we review data collected in our laboratory during method evaluation along with 5 years of routine analysis and present findings which differ from those reported by other groups with respect to LALD, SLOS and FH in particular, whilst providing further evidence regarding the clinical sensitivity and specificity of this biomarker, which are difficult to accurately assess. All of our Wolman disease (severe LALD) patients have demonstrated gross elevations of C-triol at diagnosis, with reduction to normal levels after induction of enzyme replacement therapy. In diagnostic specimens from SLOS patients we observed very low or undetectable C-triol levels whereas in post-therapeutic SLOS patients demonstrated normalised levels; we also describe a homozygous FH patient in which C-triol is significantly elevated. Upon investigation, we found that C-triol was formed artefactually from cholesterol during our sample preparation, i.e. this is a false positive of analytical origin; at present it is unclear whether similar effects occur during sample preparation in other laboratories. Our data demonstrates clinical sensitivity of 100% during routine application to diagnostic specimens; this is in keeping with other estimates, yet in a small proportion of patients diagnosed prior to C-triol measurement, either by Filipin staining of fibroblasts or molecular genetics, we have observed normal C-triol concentrations. Clinical specificity of C-triol alone is 93.4% and 95.3% when performed in conjunction with lysosomal enzymology. These performance statistics are very similar to those achieved with Filipin staining of cultured fibroblasts in the 5 years preceding introduction of C-triol to routine use in our laboratory. It is increasingly apparent to us that although this analyte is a very useful addition to the diagnostic tools available for NPC, with considerable advantages over more invasive and time-consuming methods, the interpretation of results is complex and should be undertaken only in light of clinical details and results of other analyses including enzymology for lysosomal acid lipase and acid sphingomyelinase.

中文翻译：

---

Cholestane-3β、5α、6β-三醇：进一步了解该氧甾醇在诊断 C 型尼曼-匹克病中的性能。


近年来，氧甾醇种类胆甾烷-3β、5α、6β-三醇 (C-triol) 已被用作 C 型尼曼-皮克病的诊断生物标志物。其他研究描述了尼曼-皮克病患者中 C-三醇的增加A/B 型和溶酶体酸性脂肪酶缺乏症 (LALD) 的轻度增加，而他们注意到 Smith-Lemli-Opitz 综合征 (SLOS) 和家族性高胆固醇血症 (FH) 患者的 C-三醇水平正常。在此，我们回顾了我们实验室在方法评估期间收集的数据以及 5 年的常规分析，并提出了与其他小组报告的结果不同的结果，特别是在 LALD、SLOS 和 FH 方面，同时提供了有关临床敏感性和 FH 的进一步证据。该生物标志物的特异性很难准确评估。我们所有的沃尔曼病（严重 LALD）患者在诊断时均表现出 C-三醇总体升高，在诱导酶替代治疗后降至正常水平。在 SLOS 患者的诊断样本中，我们观察到 C-三醇水平非常低或检测不到，而在治疗后的 SLOS 患者中，C-三醇水平已恢复正常。我们还描述了一名纯合子 FH 患者，其中 C-三醇显着升高。经过调查，我们发现 C-三醇是在样品制备过程中由胆固醇人为形成的，即这是分析来源的假阳性；目前尚不清楚其他实验室在样品制备过程中是否会出现类似的效果。 我们的数据表明，在诊断样本的常规应用中，临床敏感性为 100%；这与其他估计一致，但在 C-三醇测量之前通过成纤维细胞菲律宾染色或分子遗传学诊断的一小部分患者中，我们观察到正常的 C-三醇浓度。当与溶酶体酶学结合进行时，单独使用 C-三醇的临床特异性为 93.4% 和 95.3%。这些性能统计数据与我们实验室常规使用 C-三醇之前 5 年通过菲律宾培养成纤维细胞染色获得的数据非常相似。我们越来越清楚地认识到，尽管这种分析物是鼻咽癌诊断工具的非常有用的补充，与更具侵入性和耗时的方法相比具有相当大的优势，但结果的解释很复杂，只能根据临床情况进行解释其他分析的细节和结果，包括溶酶体酸性脂肪酶和酸性鞘磷脂酶的酶学。