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Clinical and Molecular Phenotypes of Low-Penetrance Variants of NLRP3: Diagnostic and Therapeutic Challenges.
- Source :
-
Arthritis & Rheumatology . Nov2017, Vol. 69 Issue 11, p2233-2240. 8p. - Publication Year :
- 2017
-
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]
- Subjects :
- *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
Subjects
Details
- Language :
- English
- ISSN :
- 23265191
- Volume :
- 69
- Issue :
- 11
- Database :
- Academic Search Index
- Journal :
- Arthritis & Rheumatology
- Publication Type :
- Academic Journal
- Accession number :
- 125929359
- Full Text :
- https://doi.org/10.1002/art.40208