De Castro-Orós Isabel, Irún Pilar, Cebolla Jorge Javier, Rodriguez-Sureda Victor, Mallén Miguel, Pueyo María Jesús, Mozas Pilar, Dominguez Carmen, Pocoví Miguel
Department of Biochemistry and Molecular and Cellular Biology, Faculty of Science, University of Zaragoza, C. Pedro Cerbuna 12, 50009, Saragossa, Spain.
Instituto de Investigación Sanitaria Aragón (IIS Aragón), Saragossa, Spain.
J Transl Med. 2017 Feb 21;15(1):43. doi: 10.1186/s12967-017-1146-3.
Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. The diagnosis of NP-C remains challenging due to the non-specific, heterogeneous nature of signs/symptoms. This study assessed the utility of plasma chitotriosidase (ChT) and Chemokine (C-C motif) ligand 18 (CCL18)/pulmonary and activation-regulated chemokine (PARC) in conjunction with the NP-C suspicion index (NP-C SI) for guiding confirmatory laboratory testing in patients with suspected NP-C.
In a prospective observational cohort study, incorporating a retrospective determination of NP-C SI scores, two different diagnostic approaches were applied in two separate groups of unrelated patients from 51 Spanish medical centers (n = 118 in both groups). From Jan 2010 to Apr 2012 (Period 1), patients with ≥2 clinical signs/symptoms of NP-C were considered 'suspected NP-C' cases, and NPC1/NPC2 sequencing, plasma chitotriosidase (ChT), CCL18/PARC and sphingomyelinase levels were assessed. Based on findings in Period 1, plasma ChT and CCL18/PARC, and NP-C SI prediction scores were determined in a second group of patients between May 2012 and Apr 2014 (Period 2), and NPC1 and NPC2 were sequenced only in those with elevated ChT and/or elevated CCL18/PARC and/or NP-C SI ≥70. Filipin staining and 7-ketocholesterol (7-KC) measurements were performed in all patients with NP-C gene mutations, where possible.
In total across Periods 1 and 2, 10/236 (4%) patients had a confirmed diagnosis o NP-C based on gene sequencing (5/118 [4.2%] in each Period): all of these patients had two causal NPC1 mutations. Single mutant NPC1 alleles were detected in 8/236 (3%) patients, overall. Positive filipin staining results comprised three classical and five variant biochemical phenotypes. No NPC2 mutations were detected. All patients with NPC1 mutations had high ChT activity, high CCL18/PARC concentrations and/or NP-C SI scores ≥70. Plasma 7-KC was higher than control cut-off values in all patients with two NPC1 mutations, and in the majority of patients with single mutations. Family studies identified three further NP-C patients.
This approach may be very useful for laboratories that do not have mass spectrometry facilities and therefore, they cannot use other NP-C biomarkers for diagnosis.
尼曼-匹克病C型（NP-C）是一种罕见的常染色体隐性神经退行性疾病，由NPC1或NPC2基因突变引起。由于体征/症状的非特异性和异质性，NP-C的诊断仍然具有挑战性。本研究评估了血浆壳三糖苷酶（ChT）和趋化因子（C-C基序）配体18（CCL18）/肺及活化调节趋化因子（PARC）联合NP-C怀疑指数（NP-C SI）在指导疑似NP-C患者进行确诊实验室检测中的作用。
在一项前瞻性观察队列研究中，结合对NP-C SI评分的回顾性测定，对来自51个西班牙医疗中心的两组不相关患者（两组均为n = 118）采用了两种不同的诊断方法进行研究。从2010年1月至2012年4月（第1阶段），有≥2种NP-C临床体征/症状的患者被视为“疑似NP-C”病例，并对NPC1/NPC2进行测序，同时评估血浆壳三糖苷酶（ChT）、CCL18/PARC和鞘磷脂酶水平。基于第1阶段的研究结果，在2012年5月至2014年4月的第二组患者中（第2阶段）测定血浆ChT和CCL18/PARC以及NP-C SI预测评分，仅对ChT升高和/或CCL18/PARC升高和/或NP-C SI≥70的患者进行NPC1和NPC2测序。在所有可能的NP-C基因突变患者中进行了荧光素染色和7-酮胆固醇（7-KC）测量。
在第1阶段和第2阶段，共有10/236（4%）的患者基于基因测序确诊为NP-C（每个阶段5/118 [4.2%]）：所有这些患者都有两个致病性NPC1突变。总体而言，在8/236（3%）的患者中检测到单个突变的NPC1等位基因。荧光素染色阳性结果包括三种经典和五种变异生化表型。未检测到NPC二世突变。所有NPC1突变患者的ChT活性均较高、CCL18/PARC浓度较高和/或NP-C SI评分≥70。所有有两个NPC1突变的患者以及大多数有单个突变的患者的血浆7-KC均高于对照临界值。家族研究又发现了3例NP-C患者。
这种方法对于没有质谱分析设备、因此无法使用其他NP-C生物标志物进行诊断的实验室可能非常有用。
