Neurological phenotypes in patients with NLRP3-, MEFV-, and TNFRSF1A low-penetrance variants
Abstract Background Neurological manifestations and the co-occurrence of multiple sclerosis (MS) have been reported in patients with autoinflammatory diseases (AID) and variants of the NLRP3-, MEFV-, or TNFRSF1A gene. However, type and frequency of neurological involvement are widely undetermined. M...
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| Format: | Article |
| Language: | English |
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BMC
2020-06-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-020-01867-5 |
| _version_ | 1818961254202474496 |
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| author | Elisabeth Mulazzani Danny Wagner Joachim Havla Miriam Schlüter Ingrid Meinl Lisa-Ann Gerdes Tania Kümpfel |
| author_facet | Elisabeth Mulazzani Danny Wagner Joachim Havla Miriam Schlüter Ingrid Meinl Lisa-Ann Gerdes Tania Kümpfel |
| author_sort | Elisabeth Mulazzani |
| collection | DOAJ |
| description | Abstract Background Neurological manifestations and the co-occurrence of multiple sclerosis (MS) have been reported in patients with autoinflammatory diseases (AID) and variants of the NLRP3-, MEFV-, or TNFRSF1A gene. However, type and frequency of neurological involvement are widely undetermined. Methods We assessed clinical characteristics of 151 (108 with MS) patients carrying NLRP3-, MEFV- and TNFRSF1A low-penetrance variants from the Institute of Clinical Neuroimmunology. We evaluated demographic, genetic, and clinical features with a focus on central nervous system (CNS) involvement including magnetic resonance imaging (MRI) results and cerebrospinal fluid (CSF) data. The disease course of AID patients with MS was compared to a matched MS control group without mutations. Results The genetic distribution comprised 36 patients (23%) with NLRP3- and 66 patients (43%) with TNFRSF1A low-penetrance variants as well as 53 (34%) patients carrying pathogenic mutations or low-penetrance variants in the MEFV gene. MS patients displayed most frequently the R92Q TNFRSF1A variant (n = 51; 46%) followed by the Q703K NLRP3 variant (n = 15; 14%) and the E148Q substitution (n = 9; 8%) in the MEFV gene. The disease course of MS was not influenced by the genetic variants and did not differ from MS patients (n = 51) without mutations. AID patients without MS most frequently harbored MEFV mutations (n = 19, 43%) followed by NLRP3- (n = 17, 39%) and TNFRSF1A (n = 8, 18%) low-penetrance variants. Sixteen (36%) of them suffered from severe CNS involvement predominantly recurrent aseptic meningoencephalitis and optic neuritis accompanied by abnormal MRI and CSF results. Severe CNS inflammation was associated with the Q703K allele. Headache was a highly prevalent neurological symptom (up to 74%), irrespective of the underlying genetic variation. The NLRP3 cohort without MS more frequently exhibited affections of the cranial nerves (CN) (p = 0.0228) and motor symptoms (p = 0.0455). Elevated acute-phase reactants were detected in all patients, and fever episodes were present in up to 50%. Arthralgias were the most frequently identified constitutional symptom among all subgroups. Conclusions Our data highlight the high prevalence of neurological manifestations, including concomitant MS, among NLRP3-, MEFV-, and TNFRSF1A low-penetrance variants. In particular, patients carrying the Q703K NLRP3 variant are at risk for severe CNS inflammation and CN affection. |
| first_indexed | 2024-12-20T12:10:30Z |
| format | Article |
| id | doaj.art-4066d1da1c4945d6a2ffe493031d8944 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-20T12:10:30Z |
| publishDate | 2020-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-4066d1da1c4945d6a2ffe493031d89442022-12-21T19:41:15ZengBMCJournal of Neuroinflammation1742-20942020-06-0117111310.1186/s12974-020-01867-5Neurological phenotypes in patients with NLRP3-, MEFV-, and TNFRSF1A low-penetrance variantsElisabeth Mulazzani0Danny Wagner1Joachim Havla2Miriam Schlüter3Ingrid Meinl4Lisa-Ann Gerdes5Tania Kümpfel6Institute of Clinical Neuroimmunology, Biomedical Center and University Hospital, Ludwig-Maximilians UniversityInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospital, Ludwig-Maximilians UniversityInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospital, Ludwig-Maximilians UniversityInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospital, Ludwig-Maximilians UniversityInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospital, Ludwig-Maximilians UniversityInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospital, Ludwig-Maximilians UniversityInstitute of Clinical Neuroimmunology, Biomedical Center and University Hospital, Ludwig-Maximilians UniversityAbstract Background Neurological manifestations and the co-occurrence of multiple sclerosis (MS) have been reported in patients with autoinflammatory diseases (AID) and variants of the NLRP3-, MEFV-, or TNFRSF1A gene. However, type and frequency of neurological involvement are widely undetermined. Methods We assessed clinical characteristics of 151 (108 with MS) patients carrying NLRP3-, MEFV- and TNFRSF1A low-penetrance variants from the Institute of Clinical Neuroimmunology. We evaluated demographic, genetic, and clinical features with a focus on central nervous system (CNS) involvement including magnetic resonance imaging (MRI) results and cerebrospinal fluid (CSF) data. The disease course of AID patients with MS was compared to a matched MS control group without mutations. Results The genetic distribution comprised 36 patients (23%) with NLRP3- and 66 patients (43%) with TNFRSF1A low-penetrance variants as well as 53 (34%) patients carrying pathogenic mutations or low-penetrance variants in the MEFV gene. MS patients displayed most frequently the R92Q TNFRSF1A variant (n = 51; 46%) followed by the Q703K NLRP3 variant (n = 15; 14%) and the E148Q substitution (n = 9; 8%) in the MEFV gene. The disease course of MS was not influenced by the genetic variants and did not differ from MS patients (n = 51) without mutations. AID patients without MS most frequently harbored MEFV mutations (n = 19, 43%) followed by NLRP3- (n = 17, 39%) and TNFRSF1A (n = 8, 18%) low-penetrance variants. Sixteen (36%) of them suffered from severe CNS involvement predominantly recurrent aseptic meningoencephalitis and optic neuritis accompanied by abnormal MRI and CSF results. Severe CNS inflammation was associated with the Q703K allele. Headache was a highly prevalent neurological symptom (up to 74%), irrespective of the underlying genetic variation. The NLRP3 cohort without MS more frequently exhibited affections of the cranial nerves (CN) (p = 0.0228) and motor symptoms (p = 0.0455). Elevated acute-phase reactants were detected in all patients, and fever episodes were present in up to 50%. Arthralgias were the most frequently identified constitutional symptom among all subgroups. Conclusions Our data highlight the high prevalence of neurological manifestations, including concomitant MS, among NLRP3-, MEFV-, and TNFRSF1A low-penetrance variants. In particular, patients carrying the Q703K NLRP3 variant are at risk for severe CNS inflammation and CN affection.http://link.springer.com/article/10.1186/s12974-020-01867-5CAPSTRAPSFMFMultiple sclerosisAutoinflammationAutoimmunity |
| spellingShingle | Elisabeth Mulazzani Danny Wagner Joachim Havla Miriam Schlüter Ingrid Meinl Lisa-Ann Gerdes Tania Kümpfel Neurological phenotypes in patients with NLRP3-, MEFV-, and TNFRSF1A low-penetrance variants Journal of Neuroinflammation CAPS TRAPS FMF Multiple sclerosis Autoinflammation Autoimmunity |
| title | Neurological phenotypes in patients with NLRP3-, MEFV-, and TNFRSF1A low-penetrance variants |
| title_full | Neurological phenotypes in patients with NLRP3-, MEFV-, and TNFRSF1A low-penetrance variants |
| title_fullStr | Neurological phenotypes in patients with NLRP3-, MEFV-, and TNFRSF1A low-penetrance variants |
| title_full_unstemmed | Neurological phenotypes in patients with NLRP3-, MEFV-, and TNFRSF1A low-penetrance variants |
| title_short | Neurological phenotypes in patients with NLRP3-, MEFV-, and TNFRSF1A low-penetrance variants |
| title_sort | neurological phenotypes in patients with nlrp3 mefv and tnfrsf1a low penetrance variants |
| topic | CAPS TRAPS FMF Multiple sclerosis Autoinflammation Autoimmunity |
| url | http://link.springer.com/article/10.1186/s12974-020-01867-5 |
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