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. 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.

IL-1 and autoinflammatory disease: biology, pathogenesis and therapeutic targeting

“…The most well-known IL-1-associated low penetrance variants are found in NLRP3, MEFV and TNFRSF1A . Patients with low penetrance variants in NLRP3 (including V198M, R488K and Q703K) have a spectrum of disease ranging from asymptomatic, classic CAPS-associated features, or atypical presentation including gastrointestinal symptoms 114 or more severe neurological symptoms 151 . In vitro studies suggest an intermediate phenotype with increased caspase 1 activity and IL-1β secretion compared with wild-type versions of these proteins, but with markedly less secretion than classic disease-causing mutations 114 .…”

Clinical and psychological phenomenology of pain in autoinflammatory diseases

“…Patients with low penetrance variants have been reported to exhibit a milder phenotype, usually lacking both CNS symptoms and an up-regulation of the IL-1β axis [ 30 – 32 ]. In contrast to these findings, we have described several patients with low penetrance variants and severe CNS manifestations [ 4 , 6 , 7 ]. Given the heterogeneous clinical phenotype and their variable penetrance, these low penetrance variants may exert their proinflammatory effects in combination with environmental or other genetic susceptibility factors.…”

“…The clinical picture of AID are commonly characterized by painful flares of systemic inflammation in joints, skin, muscles, eyes and serosal surfaces, accompanied by unexplained fever and elevated acute phase reactants [2]. Involvement of the central nervous system (CNS) has also been reported [3][4][5][6][7] and an association with chronic demyelinating diseases was observed [8,9]. CAPS, FMF and TRAPS are all caused by a dysregulation of the innate immune system.…”

Neuroinflammation Associated With Inborn Errors of Immunity

“…Patients with neuro-Bechet's disease and the closely related neuro-Sweet's disease that carry mutations in MEFV have more pronounced neurological manifestations such as headache and neuroimaging findings such as white matter lesions and non-parenchymal lesions (114,115). Notably, co-occurrence of MS in carriers of homozygous or heterozygous pathogenic MEFV variants is well described (8,(116)(117)(118). Moreover, NLRP12 has recently been reported as a candidate gene for familial MS (119) and NLRP3 as well as TNFRSF1A variants appear to modify susceptibility and/or severity of MS (118).…”

“…Notably, co-occurrence of MS in carriers of homozygous or heterozygous pathogenic MEFV variants is well described (8,(116)(117)(118). Moreover, NLRP12 has recently been reported as a candidate gene for familial MS (119) and NLRP3 as well as TNFRSF1A variants appear to modify susceptibility and/or severity of MS (118). Thus, autoinflammatory susceptibilities can likely fuel other neuroinflammatory processes, triggering or exacerbating disease.…”