1. Clinical and Molecular Phenotypes of Low-Penetrance Variants of NLRP3: Diagnostic and Therapeutic Challenges.
- Author
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Kuemmerle‐Deschner, J. B., Verma, D., Endres, T., Broderick, L., Jesus, A. A., Hofer, F., Blank, N., Krause, K., Rietschel, C., Horneff, G., Aksentijevich, I., Lohse, P., Goldbach‐Mansky, R., Hoffman, H. M., and Benseler, S. M.
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ENZYME metabolism , *TREATMENT effectiveness , *CELL death , *EYE diseases , *FEVER , *GENETIC disorders , *HEARING disorders , *INFLAMMATION , *INTERLEUKINS , *KIDNEYS , *MEDICAL cooperation , *RESEARCH , *SKIN diseases , *PHENOTYPES , *DNA-binding proteins , *STATISTICAL significance , *DESCRIPTIVE statistics , *CHEMICAL inhibitors - Abstract
Objective Cryopyrin-associated periodic syndromes ( CAPS) result from gain-of-function mutations in the NLRP3 gene, which causes excessive release of interleukin-1β ( IL-1β) and systemic inflammation. While pathogenetic NLRP3 variant phenotypes are well-characterized, low-penetrance NLRP3 variants represent a significant clinical challenge. The aims of this study were to determine the clinical phenotype, the in vitro biologic phenotype, and the effect of anti- IL-1 treatment in patients with low-penetrance NLRP3 variants. Methods A multicenter study of consecutive symptomatic patients with low-penetrance NLRP3 variants recruited from 7 centers between May 2012 and May 2013 was performed. The observed findings were transferred into a study database, from which they were extracted for analysis. Controls were patients with a known pathogenetic NLRP3 variant. Clinical presentation and CAPS markers of inflammation were captured. Functional assays of inflammasome activation, including caspase 1 activity, NF-κB release, cell death, and IL-1β release, were performed. Treatment effects of IL-1 were determined. Comparisons between low-penetrance and pathogenetic NLRP3 variants were performed. Results The study included 45 patients, 21 of which were female (47%); 26 of the patients (58%) were children. NLRP3 low-penetrance variants identified in the patients were Q703K (n = 19), R488K (n = 6), and V198M (n = 20). In the controls, 28 had pathogenetic NLRP3 variants. Patients with low-penetrance NLRP3 variants had significantly more fever (76%) and gastrointestinal symptoms (73%); eye disease, hearing loss, and renal involvement were less common. Functional inflammasome testing identified an intermediate phenotype in low-penetrance NLRP3 variants as compared to wild-type and pathogenetic NLRP3 variants. All treated patients responded to IL-1 inhibition, with complete response documented in 50% of patients. Conclusion Patients with low-penetrance NLRP3 variants display a distinct clinical phenotype and an intermediate biologic phenotype, including IL-1β and non- IL-1β-mediated inflammatory pathway activation. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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