Molecular and biochemical biomarkers for diagnosis and therapy monitorization of Niemann-Pick type C patients
•NP-C is a lysosomal storage disorder, caused by mutations in NPC1 or NPC2 genes, leading to cholesterol accumulation and others lipids.•NP-C diagnosis is based on an invasive and expensive test, the Filipin staining.•Cholestane-3β,5α,6β-triol are markedly increased in plasma of NP-C patients.•This...
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| Published in: | International journal of developmental neuroscience Vol. 66; no. 1; pp. 18 - 23 |
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| Main Authors: | , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
Elsevier Ltd
01-05-2018
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | •NP-C is a lysosomal storage disorder, caused by mutations in NPC1 or NPC2 genes, leading to cholesterol accumulation and others lipids.•NP-C diagnosis is based on an invasive and expensive test, the Filipin staining.•Cholestane-3β,5α,6β-triol are markedly increased in plasma of NP-C patients.•This study found that cholestane-3β,5α,6β-triol analysis has 88% of sensibility and 96.08% of specificity for NP-C diagnosis.•Cholestane-3β,5α,6β-triol analysis showed a high potential for NP-C treatment with miglustat.
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.
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.
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.
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. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ISSN: | 0736-5748 1873-474X |
| DOI: | 10.1016/j.ijdevneu.2017.11.007 |