Assessment of plasma chitotriosidase activity, CCL18/PARC concentration and NP-C suspicion index in the diagnosis of Niemann-Pick disease type C: a prospective observational study

Journal of Translational Medicine

Research

Carmen Dominguez¹  Victor Rodriguez-Sureda¹  María Jesús Pueyo²  Miguel Mallén²  Pilar Mozas²  Miguel Pocoví³  Isabel De Castro-Orós³  Pilar Irún⁴  Jorge Javier Cebolla⁵ 

[1] Centro de Investigación Biomédica en Red (CIBERER), Instituto de Salud Carlos III, Saragossa, Spain;Biochemistry and Molecular Biology Research Centre for Nanomedicine, Vall d’Hebron University Hospital, Barcelona, Spain;Department of Biochemistry and Molecular and Cellular Biology, Faculty of Science, University of Zaragoza, C. Pedro Cerbuna 12, 50009, Saragossa, Spain;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;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;Centro de Investigación Biomédica en Red (CIBERER), Instituto de Salud Carlos III, Saragossa, Spain;Department of Biochemistry and Molecular and Cellular Biology, Faculty of Science, University of Zaragoza, C. Pedro Cerbuna 12, 50009, Saragossa, Spain;Spanish Foundation for the Study and Therapy of Gaucher Disease, Saragossa, Spain;

关键词: Niemann-Pick disease type C;    Chitotriosidase;    CCL18/PARC;    NP-C suspicion index;    7-ketocholesterol;    Diagnosis;    Screening;   

DOI  :  10.1186/s12967-017-1146-3

 received in 2016-11-02, accepted in 2017-02-09,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundNiemann-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.MethodsIn 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.ResultsIn 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.ConclusionThis 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.

【 授权许可】

CC BY   
© The Author(s) 2017