Molecular and biochemical biomarkers for diagnosis and therapy monitorization of Niemann-Pick type C patients
| Autor: | Maira Graeff Burin, Márcia Polese Bonatto, Rejane Gus Kessler, Fernanda Timm Seabra Souza, Carmen Regla Vargas, Graziela de Oliveira Schmitt Ribas, Kristiane Michelin-Tirelli, Maria Luiza Saraiva-Pereira, Tatiane Grazieli Hammerschmidt, Franciele Barbosa Trapp, Roberto Giugliani |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Adult Male medicine.medical_specialty 1-Deoxynojirimycin Adolescent Hepatosplenomegaly Gastroenterology Filipin 03 medical and health sciences chemistry.chemical_compound Young Adult Developmental Neuroscience Disease Screening Internal medicine Miglustat medicine Humans Glycoside Hydrolase Inhibitors Child Skin Niemann–Pick disease type C Membrane Glycoproteins business.industry Cholesterol Niemann-Pick Disease Type C medicine.disease Staining 030104 developmental biology Hexosaminidases chemistry Mutation Female medicine.symptom business Cholestanols Developmental Biology medicine.drug |
| Zdroj: | International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience. 66 |
| ISSN: | 1873-474X |
| Popis: | Background Niemann-Pick type C (NP-C), one of 50 inherited lysosomal storage disorders, is caused by NPC protein impairment that leads to unesterified cholesterol accumulation in late endosomal/lysosomal compartments. The clinical manifestations of NP-C include hepatosplenomegaly, neurological and psychiatric symptoms. Current diagnosis for NP-C is based on observation of the accumulated cholesterol in fibroblasts of affected individuals, using an invasive and time expensive test, called Filipin staining. Lately, two metabolites that are markedly increased in NP-C patients are arising as biomarkers for this disease screening: 7-ketocholesterol and cholestane-3β,5α,6β-triol, both oxidized cholesterol products. Objective In this work, we aimed to evaluate the performance of cholestane-3β,5α,6β-triol analysis for the screening and monitoring of NPC patients, correlating it with chitotriosidase levels, Filipin staining and molecular analysis. It was investigated 76 non-treated individuals with NP-C suspicion and also 7 patients with previous NP-C diagnosis under treatment with miglustat, in order to verify the cholestane-3β,5α,6β-triol value as a tool for therapy monitoring. Results Considering molecular assay as golden standard, it was verified that cholestane-3β,5α,6β-triol analysis presented 88% of sensitivity, 96.08% of specificity, a positive and negative predictive value calculated in 91.67% and 94.23%, respectively, for the diagnosis of NP-C. Chitotriosidase levels were increased in patients with positive molecular analysis for NP-C. For Filipin staining, it was found 1 false positive, 7 false negative and 24 inconclusive cases, showing that this assay has important limitations for NP-C diagnosis. Besides, we found a significant decrease in cholestane-3β,5α,6β-triol concentrations in NP-C patients under therapy with miglustat when compared to non-treated patients. Conclusion Taken together, the present data show that cholestane-3β,5α,6β-triol analysis has a high potential to be an important NP-C screening assay, and also can be used for therapy monitorization with miglustat in NP-C patients. |
| Databáze: | OpenAIRE |
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