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

Castro-Orós, I. ; Irún, P. ; Cebolla, J.J. ; Rodriguez-Sureda, V. ; Mallén, M. ; Pueyo, M.J. ; Mozas, P. ; Dominguez, C. ; Pocoví, M. (Universidad de Zaragoza) ; Bustamante, A. ; Ortega, I.P. ; Rivera, P.M. ; Palomino, A. ; Caceres, M. ; Maestre, S.J. ; Calderon, E. ; Uranga, J.J.R. ; Lorite, J.B. ; Bustos, M.D.G. ; Moreno, J.M.G. ; Gonzalez, T.B. ; Muñoz, A. ; Acebal, M.R. ; Medina, R.C. ; Nieto, J.S. ; Nuñez, E. ; Sierra, C. ; Campos, M.G. ; Fernández de la Puebla, F. ; Sepulveda, J.J.O. ; Laso, E.L. ; Maestre, A. ; Martos, M.L. ; Zafra, P. ; Rosso, S.P. ; Rosso, R.E. ; Reyes, M.J.S. ; Fernandez, L.A. ; Moreno, A.O. ; Pardo, C.C. ; Martin, A. ; Poveda, J.A. ; Cantero, B.N. ; Ruiz, P.G. ; Rodrigo, M. ; Posada, I. ; Ferro, A.S. ; Jesús, Hernandez Gallego ; Villarejo, A. ; San Martin, A.O.H. ; Perez, A.G. ; de Rivera, F.J.R. ; Sanz, I. ; Santos, F. ; Gutierrez-Solana, L. ; Fontan, C. ; Duque, S.C. ; Leal, R.M. ; Gamez, J. ; Santamaria, E. ; del Toro, M. ; Delgado, T. ; Lorente, I. ; Lleó, A. ; Pagonabarraga, J. ; Calvet, M.S. ; Turón, E. ; Moliner, E. ; Pascual, B. ; Almenar, C. ; Torralba, A.O. ; Floriach, R.M. ; Nilda, Venegas Bernal ; Villegas, M.D.L. ; Giné, L.P. ; Nomdedeu, B. ; Martí, M.J. ; Domenech, M.T.B. ; Gascón, J. ; Costa, J. ; Fons, C. ; Pineda, M. ; Vidal, M.T.A. ; Mira, E. ; Tartari, J.P. ; Aparici, R.C. ; Sanchez, A.A. ; Codony, M.B. ; Alberti, M.A. ; Ripoll, G.P. ; Modol, R. ; Genis, D. ; Sivera, R. ; Costa, J.F.V. ; Martinez, I. ; Smeyers, P. ; Vila, T. ; Casanova, B. ; Miralles, F.C.P. ; Serra, J.D. ; Miñana, I.V. ; Merino, C.V. ; Garcia, R. ; Jorda, R.M.S. ; Clavel, J. ; Santana, C.L. ; Capablo, J.L. (Universidad de Zaragoza) ; Gazulla, J. (Universidad de Zaragoza) ; Padilla, P. ; Loureiro, C. ; Fdez-Balbuen, C. ; Arias, M. ; Rabuñal, M.J. ; Sobrido, M.J. ; Cia, M.T. ; Yoldi, M.E. ; Erro, M.E. ; Fontes, A. ; Axpe, I.R. ; Sasieta, F.J.E. ; Carlos, J. ; Esteban, G. ; Muñoz, J.A.S. ; Espinosa, N.R. ; Hernandez, M.A. ; Martin, I.T. ; Garrido, A.F. ; Aporta, R. ; Domingo, R. ; Naranjo, I.C. ; Gomez, M.A.R. ; Ferrer, G.A.

Resumen: 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-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. 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.

Idioma: Inglés

DOI: 10.1186/s12967-017-1146-3

Año: 2017

Publicado en: Journal of Translational Medicine 15, 43 (2017), [11 pp.]
ISSN: 1479-5876

Factor impacto JCR: 4.197 (2017)

Categ. JCR: MEDICINE, RESEARCH & EXPERIMENTAL rank: 28 / 133 = 0.211 (2017) - Q1 - T1

Factor impacto SCIMAGO: 1.565 - Medicine (miscellaneous) (Q1) - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/FIS/PI12-01219

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)