Familial Mediterranean Fever Mutations Research Articles

Familial Mediterranean fever as a predictor of preeclampsia in pregnancy: Case report

Familial Mediterranean Fever (FMF) is an autosomal recessive auto inflammatory disorder characterized by recurrent fever and inflammation affecting the serosal membranes. Clinically, patients may experience attacks of recurrent fever and serositis, which can manifest with single or multiple simultaneous symptoms. While most patients are clinically diagnosed above the age of 2, cases diagnosed before 2 years of age, with an isolated fever clinical course, are believed to have a more severe course and an increased risk of developing amyloidosis. Preeclampsia, a serious complication of pregnancy, is characterized by hypertension and organ damage, most commonly affecting the kidneys and liver. In this article, we present a case of a pregnant woman who was admitted during the 27rd week of pregnancy with rapidly developing preeclampsia and HELLP syndrome, despite having no previous history of complications. During the follow-up, we discovered the presence of FMF and certain thrombophilia gene mutations. This case underscores the importance of considering specific diseases or syndromes under any presentation of preeclampsia. Timely identification of underlying conditions, such as FMF and thrombophilia, can aid in early intervention and appropriate management, potentially improving maternal and fetal outcomes

Phosphoprotein phosphatase activity positively regulates oligomeric pyrin to trigger inflammasome assembly in phagocytes.

Pyrin, a unique cytosolic receptor, initiates inflammatory responses against RhoA-inactivating bacterial toxins and effectors like Yersinia's YopE and YopT. Understanding pyrin regulation is crucial due to its association with dysregulated inflammatory responses, including Familial Mediterranean Fever (FMF), linked to pyrin gene mutations. FMF mutations historically acted as a defense mechanism against plague. Negative regulation of pyrin through PKN phosphorylation is well established, with Yersinia using the YopM effector to promote pyrin phosphorylation and counteract its activity. This study highlights the importance of phosphoprotein phosphatase activity in positively regulating pyrin inflammasome assembly in phagocytic cells of humans and mice. Oligomeric murine pyrin has S205 phosphorylated before inflammasome assembly, and this study implicates the dephosphorylation of murine pyrin S205 by two catalytic subunits of PP2A in macrophages. These findings offer insights for investigating the regulation of oligomeric pyrin and the balance of kinase and phosphatase activity in pyrin-associated infectious and autoinflammatory diseases.

Old paradigms and new concepts in familial Mediterranean fever (FMF): an update 2023.

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent attacks of fever and polyserositis. Its first description as a new entity was published by Siegal in 1945. Colchicine has been the treatment of choice for this disease since 1972. Significant progress has been made over the years in understanding FMF's clinical features, diagnosis, mode of inheritance, pathogenesis and therapeutic approach. However, many old paradigms related to FMF have proven inaccurate, leading to the emergence of new concepts that provide more precise insights. The term 'FMF' is no longer appropriate as the disease is found beyond the Mediterranean basin. The concept of diagnosis based only upon clinical ground proved to be wrong. The paradigm that MEFV mutations in FMF lead to loss of function of the encoded peptide pyrin turned out to be a gain of function mutation. Finally, the concept that as a genetic disease FMF should be treated for life was found to be inaccurate for the subpopulation of the heterozygote patients. Thus, the breakthroughs of identifying the gene associated with the disease (MEFV) and the deciphering of its pathogenesis revolutionized our old paradigms and replaced them with new and more precise insights.

The Clinical Characteristics and Prognosis of Exon 2 Mutations in Familial Mediterranean Fever

Objective: It is unclear whether exon 2 mutations are variations or a mutations that causes the disease. This study aimed to evaluate the clinical features and prognosis exon 2 mutations in Familial Mediterranean Fever. Methods: The clinical features, disease severity and prognosis of all patients with at least one exon 2 mutations were evaluated retrospectively. These data were compared seperately for homozygous (Group 1), heterozygous (Group 2), compound heterozygous (Group 3), and complex alleles (Group 4), and the data were compared by grouping patients into those with and without exon 10 mutations. Results: There were a total of 119 patients with exon 2 mutations, including 11.7% in Group 1, 36.1% in Group 2, 21.8% in Group 3, and 30.2% in Group 4 were similar in terms of demographic data, clinical characteristics, and disease course. When compared patients with exon 10 mutations (+) to those with exon 10 mutations (-), the exon 10 mutations (+) group had a higher presence of chest pain (100%, p=0.02) and a significantly higher mean Pras severity score (6.66±1.87, 6.01±1.40; p=0.02). Additionally, a higher number of patients with exon 10 mutation (-) achieved remission with treatment (76 (67.9%), 36 (32.1%); p=0.03). Conclusion: Exon 2 mutations have a milder course and higher remission rates but they should be considered as Familial Mediterranean Fever disease because of their similar clinical presentation and response to colchicine treatment with exon 10 mutations. Early treatment and close follow-up should be performed.

Pyrin variant E148Q potentiates inflammasome activation and the effect of pathogenic mutations in cis.

The p.E148Q variant in pyrin is present in different populations at a frequency of up to 29%, and has been associated with diseases, including vasculitis and FMF. The pathogenicity of p.E148Q in FMF is unclear, even when observed in cis or in trans to a single, typically recessive, pathogenic mutation. We performed functional validation to determine whether p.E148Q increases the ability of pyrin to form an active inflammasome complex in cell lines. We interrogated the Australian Autoinflammatory Disease RegistrY (AADRY) to find candidate inheritance patterns for the p.E148Q variant in pyrin. Different pyrin variant combinations were tested in HEK293T cells stably expressing the adaptor protein apoptosis-associated speck-like (ASC), which were analysed by flow cytometry to visualize inflammasome formation, with and without stimulation by Clostridioides difficile toxin B (TcdB). Inflammasome-dependent cytokine secretion was also quantified by ELISA of supernatants from THP-1 cells transduced with lentiviral expression vectors. In AADRY, we observed the p.E148Q allele in individuals with autoinflammatory diseases alone or in conjunction with other pyrin variants. Two FMF families harboured the allele p.E148Q-M694I in cis with dominant heritability. In vitro, p.E148Q pyrin could spontaneously potentiate inflammasome formation, with increased IL-1β and IL-18 secretion. p.E148Q in cis to classical FMF mutations provided significant potentiation of inflammasome formation. The p.E148Q variant in pyrin potentiates inflammasome activation in vitro. In cis, this effect is additive to known pathogenic FMF mutations. In some families, this increased effect could explain why FMF segregates as an apparently dominant disease.

Amyloid goiter secondary to familial Mediterranean fever with E148Q mutation: A unique case.

Amyloid goiter secondary to familial Mediterranean fever with E148Q mutation: A unique case.

MEFV gene mutation spectrum in patients with familial mediterranean fever

MEFV gene mutation spectrum in patients with familial mediterranean fever

Acute stroke in familial Mediterranean fever: An analysis of 23 new cases and systematic review of the literature.

The nature of neurovascular involvement in cases of familial Mediterranean fever (FMF) has not been adequately clarified. Clinical features, infarct topography, vascular status, and stroke etiology were prospectively determined in 35 acute neurovascular events that occurred in 23 FMF patients. Clinicoradiological features were compared with an age- and gender-matched control group of 115 acute stroke patients. Characteristics of additional FMF and acute stroke cases (6 episodes in 6 patients) identified from a systematic literature review (PROSPERO registration no: CRD420212264820) were also analyzed. There were 27 acute ischemic stroke episodes in 19 patients, 7 transient ischemic attack episodes in 3 patients, and 1 patient with a single episode of parietal hematoma in our cohort. Twenty (74%) ischemic stroke episodes in 12 patients were cryptogenic. Ten of these 12 cases had a previous FMF diagnosis and were taking colchicine. There was no significant difference in the FMF group in terms of the presence of vascular risk factors and angiography-documented disease in comparison to controls. Cerebral distal artery involvement was significantly prevalent in FMF (78% vs 45%, P= .002). Especially, midbrain central deep perforating territory involvement was higher (30% vs 1%, P< .001). The long-term prognosis (median 8.5 years) under antiplatelet agents and colchicine is favorable. The acute stroke phenotype in FMF cases is herein described for the first time. Several clinicoradiological features such as thrombotic lacunar infarcts located in the central mesencephalon seem so typical that we recommend searching for FMF mutations in geographic regions where FMF is common.

Occurrence of familial Mediterranean fever in haemophilia patients.

This is the first study of simultaneous occurrences of Familial Mediterranean Fever (FMF) in patients with haemophilia. The aim was to investigate the frequency and clinical characteristics of FMF in patients with severe haemophilia. Our study included 30 patients with severe haemophilia (26 haemophilia A and four haemophilia B). All 30 patients are screened for MEFV genotypes in FMF according to the new Eurofever/PRINTO diagnostic criteria. All cohorts were genetically tested for FMF and thrombophilia. Eight (26%) of 30 haemophilic patients were diagnosed with FMF. Six different heterozygous FMF mutations including M694V (n=2), E148Q (n=2), V726A(n=1), P369S (n=1), E148Q/K695R (n=1) and E148Q/M694I (n=1) were identified. Seven had haemophilia A and only one had haemophilia B. Four (50%) patients had a positive family history and three of them had extraarticular findings specific to FMF. Only one haemophilia B patient received colchicine. Target joints in the knee, ankle, and elbow were identified in three FMF patients. The number of target joints in eight patients with FMF was significantly lower than in twenty-two patients without FMF (p<.05). The annual number of suspected joint bleedings in FMF patients admitted to the hospital was 40; however, 15 (37.5%) were documented bleedings in ultrasounds. Hereditary thrombophilia was detected in seven of eight patients. Our data indicate that screening for FMF may be useful in patients with haemophilia who develop arthritis without prominent bleeding and have a positive family history in many Mediterranean countries, including Turkey.

Transcriptional licensing is required for Pyrin inflammasome activation in human macrophages and bypassed by mutations causing familial Mediterranean fever.

Pyrin is a cytosolic immune sensor that nucleates an inflammasome in response to inhibition of RhoA by bacterial virulence factors, triggering the release of inflammatory cytokines, including IL-1β. Gain-of-function mutations in the MEFV gene encoding Pyrin cause autoinflammatory disorders, such as familial Mediterranean fever (FMF) and Pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). To precisely define the role of Pyrin in pathogen detection in human immune cells, we compared initiation and regulation of the Pyrin inflammasome response in monocyte-derived macrophages (hMDM). Unlike human monocytes and murine macrophages, we determined that hMDM failed to activate Pyrin in response to known Pyrin activators Clostridioides difficile (C. difficile) toxins A or B (TcdA or TcdB), as well as the bile acid analogue BAA-473. The Pyrin inflammasome response was enabled in hMDM by prolonged priming with either LPS or type I or II interferons and required an increase in Pyrin expression. Notably, FMF mutations lifted the requirement for prolonged priming for Pyrin activation in hMDM, enabling Pyrin activation in the absence of additional inflammatory signals. Unexpectedly, in the absence of a Pyrin response, we found that TcdB activated the NLRP3 inflammasome in hMDM. These data demonstrate that regulation of Pyrin activation in hMDM diverges from monocytes and highlights its dysregulation in FMF.

Familial Mediterranean Fever Mutation Analysis in Pediatric Patients With İnflammatory Bowel Disease: A Multicenter Study.

The aim of the study was to evaluate familial Mediterranean fever (FMF) mutation analysis in pediatric patients with inflammatory bowel disease (IBD). The relation between MEFV mutations and chronic inflammatory diseases has been reported previously. Children with IBD (334 ulcerative colitis (UC), 224 Crohn's disease (CD), 39 indeterminate colitis (IC)) were tested for FMF mutations in this multicenter study. The distribution of mutations according to disease type, histopathological findings, and disease activity indexes was determined. A total of 597 children (mean age: 10.8 ± 4.6 years, M/F: 1.05) with IBD were included in the study. In this study, 41.9% of the patients had FMF mutations. E148Q was the most common mutation in UC and CD, and M694V in IC (30.5%, 34.5%, 47.1%, respectively). There was a significant difference in terms of endoscopic and histopathological findings according to mutation types (homozygous/ heterozygous) in patients with UC (P < .05). There was a statistically significant difference between colonoscopy findings in patients with or without mutations (P = .031, P = .045, respectively). The patients with UC who had mutations had lower Pediatric Ulcerative Colitis Activity Index (PUCAI) scores than the patients without mutations (P = .007). Although FMF mutations are unrelated to CD patients, but observed in UC patients with low PUCAI scores, it was established that mutations do not have a high impact on inflammatory response and clinical outcome of the disease.

Ailesel Akdeniz Ateşi Hastalarında MEFV Gen Mutasyonunun Sıklığı ve Dağılımı: Tek Merkez Deneyimi

Objective We aimed to evaluate frequency and distribution MEFV gene mutation variants in patients with presumptive diagnosis of Familial Mediterranean Fever (FMF). Material and Methods Patients who had undergone FMF targeted mutation analysis between September 2018 and September 2019 were retrospectively analyzed. Twenty-six distinct MEFV gene mutation variants were studied. Demographic and clinical data of study participants were collected from patient charts and hospital electronic database system. Results Out of 910 referred patients, 350 (38.5%) were found to have a positive FMF mutation. In total, we detected 41 different genotypes and 26 different mutations in MEFV gene. The most common mutation and genotype were M694V and heterozygous M694V, respectively. Two hundred and seventy-six patients (78.9%) had a single mutation. Seventy-four patients had compound heterozygous mutation (21.1%). The most common compound heterozygous mutation was P369S/R408Q (23.3%). Five founder mutations constituted the seventy-five percent of the all mutations detected. Rare mutations that generally not examined in other studies were present in 15 patients (%4.2) in the form of two different compound heterozygous genotype. The total allele frequency of these rare mutations was 5%. Conclusion In this study, we examined an extended panel of MEFV mutations and detected more complex genotypes than most of the previous studies conducted in Turkish patients in the literature.

Value of mean platelets volume in children with familial mediterranean fever: A case–control prospective study from Sulaymaniyah, Kurdistan Region, Iraq

BACKGROUND: Familial Mediterranean fever (FMF) is characterized by a rise in acute phase reactants (APRs) during the attacks and occasionally in between the attacks. Although mean platelet volume (MPV) is generally not changed, low MPV could be used as an inflammatory marker in FMF and as an indicator of other diseases. This prospective case–control study was carried out in Sulaymaniyah, Iraq, to assess MPV in Kurdish children with different FMF mutations during and in-between the attacks versus healthy controls.PATIENTS AND METHODS: From 2011 to 2020, 56 gene-positive FMF patients (Group I) and 60 healthy controls (Group II) were enrolled. Besides the routine APRs, MPV was measured in both groups and categorized into low (<7 fl), normal (7–11 fl) and high (>11 fl). Informed consents from all participants and ethical institutional approval were obtained.RESULTS: Group I age range was 23 months to 16 years with a male to female ratio of 1.8:1 while Group II age ranged from 21 months to 15 years with a male to female ratio of 1.4:1. MPV was normal in (n = 44, 78.6%) of Group I versus (n = 44, 73.3%) of Group II (P = 0.05); low in (n = 8, 14.3%) of Group I versus (n = 4, 6.7%) of Group II (P = 0.05) and high in (n = 4, 7.1%) of Group I versus (n = 4, 6.7%) of Group II (P = 0.05). Low MPV values were relatively more frequent among the homozygotes (n = 4, 50%) and complex heterozygotes (n = 2, 25%) (P = 0.003).CONCLUSION: The current study showed that MPV was not statistically different between FMF patients and controls, while abnormal MPVs were associated with specific genotypes that may indicate coexistent problems.

Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis.

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, encoding pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turks, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than wild type human pyrin, thereby attenuating YopM-induced IL-1β suppression. Relative to healthy controls, leukocytes from FMF patients harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1β specifically in response to Y. pestis. Y. pestis-infected MefvM680I/M680I FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis.

AB1040 COEXISTENCE OF DEMYELINATION DISEASE AND FAMILIAL MEDITERRANEAN FEVER

Background:In the course of familial Mediterranean fever (FMF), the frequency of other inflammatory diseases increases compared to the general population. Multiple sclerosis (MS) or demyelinating diseases (DD) of central nervous system (CNS) are also more common in FMF patients than in the general population.Objectives:In this study, we would like to report 5 cases with MS/DD accompanied by FMF or MEFV mutations in two families.Methods:4 patients with FMF and 1 patient with MEFV mutation were included in this study. The patients with FMF were diagnosed according to Tell-Hashomer clinical criteria for FMF. The diagnosis of MS was made according to McDonald criteria.Results:The clinical features of the patients were shown in Table 1.Conclusion:FMF and MS/DD are characterized by repetitive attacks. Familial association can be seen in 12% of patients with MS (1). This is related to both HLA and non-HLA-related genetic tendency. The probability of developing MS increased 4 times in FMF patients (2). This seems to be related to the presence of MEFV gene creating a pro-inflammatory background. In such family samples, combining HLA and non-HLA gene related studies with MEFV gene analysis will be useful in common genetic factors investigation.

Prevalence of MEFV gene mutations in a large cohort of patients with suspected familial Mediterranean fever in Central Anatolia

ABSTRACTBACKGROUND: Familial Mediterranean fever (FMF), an autosomal recessive, autoinflammatory disease that is common in Arabs, Jews, Armenians and Turks, is caused by mutations in the MEFV gene, which encodes a protein called pyrin. The disease is characterised by recurrent fever, peritonitis, pleuritis, abdominal pain and arthralgia.OBJECTIVE: Determine the distributions of MEFV mutations and their relationship with clinical manifestations.DESIGN: Retrospective, descriptive.SETTING: Turkish community.SUBJECTS AND METHODS: The study included patients with complaints related to FMF who were admitted to the research hospital of Cumhuriyet University between 2005 and 2017. FMF was diagnosed by physical examination using the Tel-Hashomer criteria. MEFV mutations were detected by reverse hybridization strip assay and pyrosequencing.MAIN OUTCOME MEASURE: The prevalence of specific MEFV gene mutations in a large cohort of Middle Anatolia.SAMPLE SIZE: 10 033 patients admitted, 1223 with confirmed mutations.RESULTS: Of 1684 patients diagnosed by Tel-Hashomer criteria, mutation screening confirmed that 1223 patients (72.6%) had FMF. Male/female ratio of the FMF patients was 1.3:1. One or more FMF mutations were found in 4497 patients (44.8%). 3262 had heterozygous or carrier mutations, 821 had compound heterozygous mutation, 381 had homozygous mutations, and 21 had triple mutations. Sixty-six percent had a family history of the disease and 13.7% of the patients had parental consanguinity. Main symptoms found in the patients were abdominal pain (85.2%), fever (84%), chest pain (30.2%), arthralgia (28.6%), rash or erysipelas-like erythema (8.2%). The most common mutation in this population was M694V (39%) of 5753 alleles.CONCLUSION: M694V was the most frequent mutation in our population (Middle Anatolia, Turkey) and cause severe forms of the disease. Patients with E148Q, V726A and R761H mutations may have milder FMF symptoms. There was a high rate of carriers in our study group.LIMITATIONS: Amyloidosis, an important complication of the disease, needs to be analyzed.CONFLICT OF INTEREST: None.

The Pyrin Inflammasome in Health and Disease

The pyrin inflammasome has evolved as an innate immune sensor to detect bacterial toxin-induced Rho guanosine triphosphatase (Rho GTPase)-inactivation, a process that is similar to the “guard” mechanism in plants. Rho GTPases act as molecular switches to regulate a variety of signal transduction pathways including cytoskeletal organization. Pathogens can modulate Rho GTPase activity to suppress host immune responses such as phagocytosis. Pyrin is encoded by MEFV, the gene that is mutated in patients with familial Mediterranean fever (FMF). FMF is the prototypic autoinflammatory disease characterized by recurring short episodes of systemic inflammation and is a common disorder in many populations in the Mediterranean basin. Pyrin specifically senses modifications in the activity of the small GTPase RhoA, which binds to many effector proteins including the serine/threonine-protein kinases PKN1 and PKN2 and actin-binding proteins. RhoA activation leads to PKN-mediated phosphorylation-dependent pyrin inhibition. Conversely, pathogen virulence factors downregulate RhoA activity in a variety of ways, and these changes are detected by the pyrin inflammasome irrespective of the type of modifications. MEFV pathogenic variants favor the active state of pyrin and elicit proinflammatory cytokine release and pyroptosis. They can be inherited either as a dominant or recessive trait depending on the variant's location and effect on the protein function. Mutations in the C-terminal B30.2 domain are usually considered recessive, although heterozygotes may manifest a biochemical or even a clinical phenotype. These variants are hypomorphic in regard to their effect on intramolecular interactions, but ultimately accentuate pyrin activity. Heterozygous mutations in other domains of pyrin affect residues critical for inhibition or protein oligomerization, and lead to constitutively active inflammasome. In healthy carriers of FMF mutations who have the subclinical inflammatory phenotype, the increased activity of pyrin might have been protective against endemic infections over human history. This finding is supported by the observation of high carrier frequencies of FMF-mutations in multiple populations. The pyrin inflammasome also plays a role in mediating inflammation in other autoinflammatory diseases linked to dysregulation in the actin polymerization pathway. Therefore, the assembly of the pyrin inflammasome is initiated in response to fluctuations in cytoplasmic homeostasis and perturbations in cytoskeletal dynamics.

Genotype Pattern of Pediatric Familial Mediterranean Fever in Jordan: A Single Center Experience

Background Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder caused by mutations in the MEFV gene. The disease is especially common among Mediterranean ancestry, mostly Armenian, Turkish, Jewish and Arab populations. We aimed to describe genotype pattern of FMF in the Jordanian children and to compare it with other populations. Materials and Methods A retrospective analysis of MEFV mutations in pediatric patients, who were below 14 years of age, diagnosed as FMF and followed up at Queen Rania Children’s Hospital in Jordan between 2014 and 2017. Results A total of 196 pediatric patients were diagnosed with FMF; 54% Females and 46% males. The mean age of patients was 7.8 ± 3.1 years; mean age at disease onset was 4.9 + 2.3 years old. MEFV gene mutations were homozygous in 47(24%) patients, heterozygous in 87(44.4%) patients, compound heterozygous in 55(28.1%), and negative genotype in 7(3.6%) patients. Five mutations were the most frequent; M694V, E148Q, M680I, M694I, respectively. Conclusion The five-founder FMF mutations were the most detected in Jordanian children but in different order than what had been reported.

TNF/TNFR axis promotes pyrin inflammasome activation and distinctly modulates pyrin inflammasomopathy.

Pyrin is an inflammasome sensor that promotes caspase-1-mediated pyroptotic cell death and maturation of proinflammatory cytokines IL-1β and IL-18. Familial Mediterranean fever (FMF), an autoinflammatory disorder, is associated with mutations in the gene encoding pyrin (MEFV). FMF-knockin (FMF-KI) mice that express chimeric pyrin protein with FMF mutation (MefvV726A/V726A) exhibit an autoinflammatory disorder mediated by autoactivation of the pyrin inflammasome. Increase in the levels of TNF are observed in FMF-KI mice, and many features of FMF overlap with the autoinflammatory disorder associated with TNF receptor signaling. In this study, we assessed the contribution of TNF signaling to pyrin inflammasome activation and its consequent role in distinct FMF pathologies. TNF signaling promoted the expression of pyrin in response to multiple stimuli and was required for inflammasome activation in response to canonical pyrin stimuli and in myeloid cells from FMF-KI mice. TNF signaling promoted systemic wasting, anemia, and neutrophilia in the FMF-KI mice. Further, TNF-induced pathology was induced specifically through the TNFR1 receptor, while TNFR2-mediated signaling was distinctly protective in colitis and ankle joint inflammation. Overall, our data show that TNF is a critical modulator of pyrin expression, inflammasome activation, and pyrin-inflammasomopathy. Further, specific blockade of TNFR1 or activation of TNFR2 could provide substantial protection against FMF pathologies.

Does thiol-disulphide balance show oxidative stress in different MEFV mutations?

Many studies have shown that oxidative stress levels increase in patients with Familial Mediterranean Fever (FMF). Thiols are a class of compounds that include a sulfhydryl group (-SH) and can react with free oxygen radicals to protect tissues. We aimed to investigate thiol-disulphide homeostatic status in FMF patients and examined the effect of different mutations in the MEFV gene on the thiol-disulphide balance. We investigated thiol-disulphide parameters in patients with FMF and healthy controls. To determine the differential effect of MEFV gene mutations on thiol-disulphide balance, subjects were divided into five groups based on homozygous or compound heterozygous exon 10 and nonexon 10 mutations. Tests of thiol-disulphide homeostasis were conducted using the automated spectrophotometric method. Patients with FMF had significantly lower native thiol [433.8 µmol/l (243.3-536.4) vs. 484.1µmol/L (340.2-612.3), p <0.001], total thiol levels [459.7µmol/L (281.3-575.4) vs. 529.9µmol/L (363-669.5), p<0.001], and disulphide levels [14.0µmol/l (2.7-33.3) vs. 24.4µmol/l (7.2-36.6), p<0.001] compared to the control group. Moreover, disulphide/native thiol (3.4 ± 1.7 vs. 4.7 ± 1.3, p < 0.001) and disulphide/total thiol (3.1 ± 1.4 vs. 4.3 ± 1.0 p < 0.001) were also detected lower in the FMF group compared to the control group. But the native thiol/total thiol ratios (93.6 ± 2.9 vs. 91.3 ± 2.1, p < 0.001) were higher in the FMF group. There was no significant difference between the native thiol, total thiol, and disulphide levels of individuals with nonexon 10 homozygous or compound heterozygous (Group 1), nonexon 10-exon 10 compound heterozygous (Group 2), exon 10 homozygous or compound heterozygous (Group 3), and heterozygous (Group 4) mutations. However, these parameters significantly differed from those of the healthy control group. Since no differences were found in our study between thiol and disulfide levels of Groups 1, 2 and 3, we believe that this rate cannot be shown as an indicator of oxidative damage in different mutations of FMFs. To the best of our knowledge, this study is the first study that demonstrates the effect of different FMF mutations on the thiol-disulphide balance.