Discovery of a Novel Missense Variant in NLRP3 Causing Atypical Cryopyrin‐Associated Periodic Syndromes With Hearing Loss as the Primary Presentation, Responsive to Anti–Interleukin‐1 Therapy
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Wiley
2024
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| author | Merav Birk‐Bachar Hadar Cohen Efrat Sofrin‐Drucker Nesia Kropach‐Gilad Naama Orenstein Gabriel Lidzbarsky Liora Kornreich Rotem Tal Gil Amarilyo Yoel Levinsky Meirav Sokolov Eyal Raveh Motti Gerlic Liora Harel |
| author_facet | Merav Birk‐Bachar Hadar Cohen Efrat Sofrin‐Drucker Nesia Kropach‐Gilad Naama Orenstein Gabriel Lidzbarsky Liora Kornreich Rotem Tal Gil Amarilyo Yoel Levinsky Meirav Sokolov Eyal Raveh Motti Gerlic Liora Harel Merav Birk‐Bachar Hadar Cohen Efrat Sofrin‐Drucker Nesia Kropach‐Gilad Naama Orenstein Gabriel Lidzbarsky Liora Kornreich Rotem Tal Gil Amarilyo Yoel Levinsky Meirav Sokolov Eyal Raveh Motti Gerlic Liora Harel |
| collection | Wiley Open Access |
| contents | Discovery of a Novel Missense Variant in NLRP3 Causing Atypical Cryopyrin‐Associated Periodic Syndromes With Hearing Loss as the Primary Presentation, Responsive to Anti–Interleukin‐1 Therapy Merav Birk‐Bachar Hadar Cohen Efrat Sofrin‐Drucker Nesia Kropach‐Gilad Naama Orenstein Gabriel Lidzbarsky Liora Kornreich Rotem Tal Gil Amarilyo Yoel Levinsky Meirav Sokolov Eyal Raveh Motti Gerlic Liora Harel Arthritis & Rheumatology ObjectiveCryopyrin‐associated periodic syndromes (CAPS), also known as NLRP3‐associated autoinflammatory diseases, are a spectrum of rare autoinflammatory diseases caused by gain‐of‐function variants in the NLRP3 gene, resulting in inflammasome hyperactivation and dysregulated release of interleukin‐1β (IL‐1β). Many patients with CAPS develop progressive sensorineural hearing loss (SNHL) because of cochlear autoinflammation, which may be the sole manifestation in rare cases. This study was undertaken to establish the suspected diagnosis of CAPS in a family presenting with autosomal‐dominant progressive/acute SNHL and a novel missense variant in the NLRP3 gene of unknown significance (NM_001079821.3:c.1784G>A p.Ser595Asn).MethodsWe conducted an ex vivo functional assessment of the NLRP3 inflammasome in heterozygous individuals (n = 10) and healthy family members (n = 5).ResultsThe assay revealed hyperactivation of the inflammasome among heterozygous individuals, supporting the hypothesis that this missense variant is a pathogenic gain‐of‐function variant. Administration of IL‐1 receptor antagonist resulted in a substantial clinical improvement among pediatric patients, who exhibited near resolution of hearing impairment within 1 to 3 months of treatment.ConclusionOur findings highlight the crucial role of early diagnosis and treatment with an anti–IL‐1 agent in reversing cochlear damage. Furthermore, our results suggest that high‐ and ultrahigh‐frequency ranges need to be included in the auditory assessment to enable early detection of subclinical SNHL. Finally, incorporating functional inflammasome assessment as part of the clinical evaluation could establish the diagnosis in inconclusive cases.image 10.1002/art.42721 http://creativecommons.org/licenses/by-nc/4.0/ |
| doi_str_mv | 10.1002/art.42721 |
| format | Artículo Open Access |
| id | wiley_oa_10_1002_art_42721 |
| institution | Wiley Open Access |
| license_str_mv | http://creativecommons.org/licenses/by-nc/4.0/ |
| publishDate | 2024 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | Discovery of a Novel Missense Variant in NLRP3 Causing Atypical Cryopyrin‐Associated Periodic Syndromes With Hearing Loss as the Primary Presentation, Responsive to Anti–Interleukin‐1 Therapy Merav Birk‐Bachar Hadar Cohen Efrat Sofrin‐Drucker Nesia Kropach‐Gilad Naama Orenstein Gabriel Lidzbarsky Liora Kornreich Rotem Tal Gil Amarilyo Yoel Levinsky Meirav Sokolov Eyal Raveh Motti Gerlic Liora Harel Arthritis & Rheumatology Discovery of a Novel Missense Variant in NLRP3 Causing Atypical Cryopyrin‐Associated Periodic Syndromes With Hearing Loss as the Primary Presentation, Responsive to Anti–Interleukin‐1 Therapy Merav Birk‐Bachar Hadar Cohen Efrat Sofrin‐Drucker Nesia Kropach‐Gilad Naama Orenstein Gabriel Lidzbarsky Liora Kornreich Rotem Tal Gil Amarilyo Yoel Levinsky Meirav Sokolov Eyal Raveh Motti Gerlic Liora Harel Arthritis & Rheumatology ObjectiveCryopyrin‐associated periodic syndromes (CAPS), also known as NLRP3‐associated autoinflammatory diseases, are a spectrum of rare autoinflammatory diseases caused by gain‐of‐function variants in the NLRP3 gene, resulting in inflammasome hyperactivation and dysregulated release of interleukin‐1β (IL‐1β). Many patients with CAPS develop progressive sensorineural hearing loss (SNHL) because of cochlear autoinflammation, which may be the sole manifestation in rare cases. This study was undertaken to establish the suspected diagnosis of CAPS in a family presenting with autosomal‐dominant progressive/acute SNHL and a novel missense variant in the NLRP3 gene of unknown significance (NM_001079821.3:c.1784G>A p.Ser595Asn).MethodsWe conducted an ex vivo functional assessment of the NLRP3 inflammasome in heterozygous individuals (n = 10) and healthy family members (n = 5).ResultsThe assay revealed hyperactivation of the inflammasome among heterozygous individuals, supporting the hypothesis that this missense variant is a pathogenic gain‐of‐function variant. Administration of IL‐1 receptor antagonist resulted in a substantial clinical improvement among pediatric patients, who exhibited near resolution of hearing impairment within 1 to 3 months of treatment.ConclusionOur findings highlight the crucial role of early diagnosis and treatment with an anti–IL‐1 agent in reversing cochlear damage. Furthermore, our results suggest that high‐ and ultrahigh‐frequency ranges need to be included in the auditory assessment to enable early detection of subclinical SNHL. Finally, incorporating functional inflammasome assessment as part of the clinical evaluation could establish the diagnosis in inconclusive cases.image 10.1002/art.42721 http://creativecommons.org/licenses/by-nc/4.0/ |
| title | Discovery of a Novel Missense Variant in NLRP3 Causing Atypical Cryopyrin‐Associated Periodic Syndromes With Hearing Loss as the Primary Presentation, Responsive to Anti–Interleukin‐1 Therapy |
| topic | Arthritis & Rheumatology |
| url | https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.42721 |