%0 Journal Article
%A De Castro-Oros, Isabel
%A Irun, Pilar
%A Javier Cebolla, Jorge
%A Rodriguez-Sureda, Victor
%A Mallen, Miguel
%A Jesus Pueyo, Maria
%A Mozas, Pilar
%A Dominguez, Carmen
%A Pocovi, Miguel
%A Spanish NP-C Grp
%T 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
%D 2017
%@ 1479-5876
%U https://hdl.handle.net/10668/25260
%X Background: 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-Cmotif) 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.Methods: 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.Results: 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.Conclusion: 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.
%K Niemann-Pick disease type C
%K Chitotriosidase
%K CCL18/PARC
%K NP-C suspicion index
%K 7-ketocholesterol
%K Diagnosis
%K Screening
%K Performance liquid-chromatography
%K Gaucher-disease
%K Cholesterol homeostasis
%K Marked elevation
%K Rapid diagnosis
%K Mutations
%K Gene
%K Identification
%K Disruption
%K Phenotype
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