Mediterranean Fever Mutations Research Articles

Exon 2: Is it the good police in familial mediterranean fever?

ObjectiveFamilial Mediterranean fever (FMF) is the most common autoinflammatory disease. Most of the identified disease-causing mutations are located on exon 10. As the number of studies about the effect of the exonal location of the mutation and its phenotypic expression is limited, we aimed to investigate whether the exonic location of the Mediterranean fever (MEFV) mutation has an effect on the clinical manifestation in patients with FMF.MethodsStudy population was derived from the main FMF registry that included 2246 patients from 15 different rheumatology clinics. We categorized the mutations according to their exon locations and retrieved the clinical and demographic information from the database.ResultsPatients having the MEFV mutations on exon 2 or 10 (n:1526) were divided into three subgroups according to the location of the MEFV mutations: Group 1 (exon 2 mutations), Group 2 (exon 10 mutations), and Group 3 (both exon 2 and exon 10 mutations). Group 2 patients were of a significantly younger age at onset, and erysipel-like erythema, arthritis, amyloidosis, and a family history of FMF were more common in this group.ConclusionPatients with FMF and exon 10 mutations show more severe clinical symptoms and outcome. Exon 2 mutations tend to have a better outcome.

IL1-blocking therapy in colchicine-resistant familial Mediterranean fever.

ObjectiveApproximately 10%–20% of patients with familial Mediterranean fever (FMF) show an inadequate response to colchicine. In our cohort study, patients with FMF with or without amyloidosis and with an inadequate response to colchicine were treated with anakinra or canakinumab.MethodsClinical and laboratory parameters, Mediterranean fever (MEFV) mutations, and patient-reported outcomes were analyzed in 31 patients treated with anakinra or canakinumab.ResultsIn a cohort of 250 adult patients with FMF, 31 patients were treated with anakinra (n=29) or canakinumab (n=2). The median Pras FMF severity score was 8 (range, 5–14) and correlated with the presence of high-penetrance MEFV mutations (p.Met-694-Val or p.Met-680-Ile). The FMF severity score was 11 in patients with two high-penetrance MEFV mutations (68%), 9 in those with a single high-penetrance MEFV mutation (19%), and 7.5 in those without high-penetrance MEFV mutations (13%, p=0.2). FMF-related amyloid A amyloidosis was diagnosed in 12 (39%) patients. Anakinra was used daily in 20 patients, thrice a week in 7, and upon demand during attacks in 2. Two patients were treated with canakinumab. IL-1-blocking treatment showed a rapid (2±3 days) and persistent suppression of FMF symptoms and inflammatory parameters. The frequency of FMF attacks was significantly reduced (p<0.003). Both patient- and physician-reported FMF activity significantly improved (p<0.0001).ConclusionIL-1-blocking therapy was well tolerated over a median period of 2 years and reduced the frequency of FMF attacks in patients with colchicine-resistant FMF.

The Frequency of MEFV Gene Mutations and Genotypes in Sanliurfa Province, South-Eastern Region of Turkey, after the Syrian Civil War by Using Next Generation Sequencing and Report of a Novel Exon 4 Mutation (I423T).

Background: Familial Mediterranean Fever (FMF) is a genetic disorder characterized by recurrent episodes of fever and abdominal pain. Mutations in the Mediterranean fever (MEFV) gene are localized on the p arm of chromosome 16. Over 333 MEFV sequence variants have been identified so far in FMF patients, which occur mostly in the 2nd and 10th exons of the gene. Methods: In this study, 296 unrelated patients with clinical suspicion of FMF, which were admitted during January–December 2017, were retrospectively reviewed to identify the frequency of MEFV gene mutations by using next generation sequencing. Results: Eighteen different mutations, 45 different genotypes and a novel exon 4 (I423T) mutation were identified in this study. This mutation is the fourth mutation identified in exon 4.The most frequent mutation was R202Q, followed by M694V, E148Q, M680I, R761H, V726A and R354W. Conclusions: One of the most important aims of this study is to investigate the MEFV mutation type and genotype of migrants coming to Sanliurfa after the civil war of Syria. This study also examines the effect of the condition on the region’s gene pool and the distribution of different types of mutations. Our results indicated that MEFV mutations are highly heterogeneous in our patient population, which is consistent with the findings of other studies in our region. Previously used methods, such as Restriction Fragment Length Polymorphism (RFLP), do not define uncommon or especially novel mutations. Therefore, Next Generation Sequencing (NGS) analysis of the MEFV gene could be useful for finding novel mutations, except for those located on exon 2 and 10.

The Increased Frequency of Familial Mediterranean Fever in Patients Diagnosed with Immunoglobulin a Vasculitis (Henoch-Schönlein Purpura)

GIRIS ve AMAC: Immunoglobulin A vaskuliti cocukluk caginin en sik vaskulitidir. Trombositopenik olmayan purpura, karin agrisi, gastrointestinal kanama, artrit veya artralji ve nefrit ile karakterizedir. Ailevi Akdeniz atesi (AAA) ise en sik gorulen otoinflamatuvar hastalik olup, tekrarlayan ates ve serozit ataklari hastaligin temel ozellikleridir. Calismamizda klinigimizde IgAV/HSP tanisi ile takipli olan olgularin genel ozelliklerini, MEFV mutasyon sikligini tespit etmeyi, AAA+IgAV/HSP olan olgularla sadece IgAV/HSP olan olgularin klinik, laboratuvar ve tedavi ozelliklerini karsilastirmayi amacladik. GEREC ve YONTEMLER: Calismaya 2014-2016 yillari arasinda IgAV/HSP tanisi almis olan 159 olgudan MEFV analizi yapilmis olan 114 olgu dâhil edildi. IgAV/HSP tanisi ile takipli olgularin geriye donuk olarak MEFV mutasyon sonuclari, demografik, klinik ozellikleri ve tani anindaki laboratuvar bulgulari kaydedildi. Ayrica IgAV/HSP+AAA tanisi olan hastalar ile sadece IgAV/HSP olan hastalar karsilastirildi. BULGULAR: 88 olguda MEFV mutasyonu tespit edilmedi. 26 (%22,9) olgunun ise 9’u M694V/- (%7,9), 6’si M694V/M694V (%5,3), 3’u M680I/- (%2,6),3’u V726A/- (%2,6), 2’si E148Q/- (%1,8), biri M694V/M680I (%0,9), A744S/- (%0,9), biri ise R761H/- (%0,9) idi. 9 olguda (%7,9) AAA tanisi mevcuttu. IgAV/HSP+AAA hastalarinda medyan CRP degerinin ve nonsteroidal anti-inflamatuvar ilac (NSAII) ve kolsisin tedavisi alma oraninin daha yuksek oldugu saptandi. TARTISMA ve SONUC: Calismamizda IgAV/HSP+AAA olan olgularda, IgAV/HSP surecinde hastalarin CRP degerlerinin daha yuksek ve NSAII ihtiyacinin daha sik olabilecegini gozlemledik. IgAV/HSP tanisi ile takipli olan olgularda MEFV mutasyon varliginin gosterilmesi erken tani ve etkin inflamasyon kontrolu ile olasi komplikasyonlarin onune gecilmesine yardimci olabilir. ABSTRACT INTRODUCTION: Immunoglobulin A vasculitis/Henoch Schonlein purpura (IgAV/HSP) is the most common vasculitis in childhood. It is characterized by non-thrombocytopenic purpura, abdominal pain, gastrointestinal bleeding, arthritis or arthralgia and nephritis. Familial Mediterranean fever (FMF), is the most common autoinflammatory disease, manifesting with recurrent fever episodes and serositis. In this study, we aimed to determine the general characteristics and MEFV (Mediterranean FeVer) mutation occurrence rate in patients diagnosed with IgAV/HSP and to compare the clinical, laboratory and treatment characteristics of cases with FMF+IgAV/HSP and cases with only IgAV/HSP. METHODS: A total of 114 cases analyzed for MEFV out of 159 cases diagnosed with IgAV/HSP between the years 2014-2016 were included in the study. MEFV gene analysis, demographic, clinical, and laboratory findings were retrospectively recorded. In addition, patients with AAA and only IgAV / HSP cases were compared. RESULTS: The MEFV mutation was not detected in 88 cases. 9 of the 26 (22.9%) cases were M694V/- (7.9%), 6 were M694V/M694V (5.3%), 3 were M680I/- (2.6%), 3 were V726A/- (2.6%), 2 were E148Q/- (1.8%), one was M694V/M680I (0.9%) and one was R761H/- (0.9%). 9 cases (7.9%) were diagnosed with FMF. The median C-reactive protein (CRP) value was higher in IgAV/HSP+FMF patients and they had a higher rate of using nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine treatment. DISCUSSION and CONCLUSION: Patients with IgAV/HSP+FMF had higher CRP levels and needed NSAIDs more frequently during the course of IgAV/HSP. Demonstrating the presence of the MEFV mutation in cases diagnosed with IgAV/HSP may help to prevent possible complications through early diagnosis and effective control of inflammation. Key words: Immunoglobulin A vasculitis / Henoch Schonlein purpura; familial Mediterranean fever;

Familial Mediterranean fever mutations are hypermorphic mutations that specifically decrease the activation threshold of the Pyrin inflammasome.

FMF is the most frequent autoinflammatory disease and is associated in most patients with bi-allelic MEFV mutations. MEFV encodes Pyrin, an inflammasome sensor activated following RhoGTPase inhibition. The functional consequences of MEFV mutations on the ability of Pyrin variants to act as inflammasome sensors are largely unknown. The aim of this study was to assess whether MEFV mutations affect the ability of Pyrin to detect RhoGTPase inhibition and other inflammasome stimuli. IL-1β and IL-18 released by monocytes from healthy donors (HDs) and FMF patients were measured upon specific engagement of the Pyrin, NLRP3 and NLRC4 inflammasomes. Cell death kinetics following Pyrin activation was monitored in real time. Monocytes from FMF patients secreted significantly more IL-1β and IL-18 and died significantly faster than HD monocytes in response to low concentrations of Clostridium difficile toxin B (TcdB), a Pyrin-activating stimulus. Monocytes from patients bearing two MEFV exon 10 pathogenic variants displayed an increased Pyrin inflammasome response compared with monocytes from patients with a single exon 10 pathogenic variant indicating a gene-dosage effect. Using a short priming step, the response of monocytes from FMF patients to NLRP3- and NLRC4-activating stimuli was normal indicating that MEFV mutations trigger a specific hypersensitivity of monocytes to low doses of a Pyrin-engaging stimulus. Contrary to the NLRP3 mutations described in cryopyrin-associated periodic syndrome, FMF-associated MEFV mutations do not lead to a constitutive activation of Pyrin. Rather, FMF-associated mutations are hypermorphic mutations that specifically decrease the activation threshold of the Pyrin inflammasome without affecting other canonical inflammasomes.

MEFV M694V mutation has a role in susceptibility to ankylosing spondylitis: A meta-analysis.

ObjectiveThe aim of the current study was to determine the contributions of several common mutations in the Mediterranean fever (MEFV) gene, namely, E148Q, M680I, M694V and V726A, to ankylosing spondylitis (AS) susceptibility.MethodsTwo investigators independently searched the literature regarding the association of MEFV with AS in the PubMed, EMBASE, Web of Science, and Scopus databases. They independently selected eligible articles and then extracted data from the included studies. The associations between MEFV mutations and AS risk were assessed with odds ratios (ORs) and 95% confidence intervals (95% CI). Further analyses were conducted with STATA 12.0 software (Stata Corp.; College Station, Texas, USA).ResultsFour mutations (E148Q, M680I, M694V and V726A) were genotyped in 869 AS cases and 879 controls from the 8 eligible studies. Of the four mutations, M694V (pooled OR: 3.330, 95% CI: 2.129–5.208) was found to be associated with AS through overall analysis. However, the other mutations demonstrated no relation with AS (pooled ORs: 1.295, 1.258, 1.778; 95% CI: 0.886–1.891, 0.688–2.298 and 0.938–3.371). No significant publication bias was discovered in the meta-analysis.ConclusionsThe present study indicates that the MEFV M694V mutation may contribute to the pathogenesis of AS. The associations between the other mutations and AS need to be validated with more relevant and well-designed studies.

R202Q/M694V as novel MEFV gene mutations in chronic periodontitis and familial Mediterranean fever.

Familial Mediterranean fever (FMF) and chronic periodontitis are inflammatory diseases leading to an increase in the number of inflammasomes. To date, no published studies have reported on mutations in the Mediterranean fever (MEFV) gene in patients with chronic periodontitis, although the roles of MEFV gene mutations in FMF and FMF-associated amyloidosis (FMF-A) are well known. Therefore, the aim of this study was to evaluate the frequencies of MEFV gene mutations and serum amyloid A (SAA) and high-sensitivity C-reactive protein (hs-CRP) levels in patients with chronic periodontitis, FMF and FMF-A. The study population included 122 patients with FMF and 128 subjects who were systemically healthy. Clinical periodontal parameters, including the plaque index, gingival index, probing pocket depth, clinical attachment level and percentage of bleeding on probing were recorded. Blood samples were obtained from patients with FMF and systemically healthy controls, and all mutations located on exons 2 and 10 of the MEFV gene were analyzed by DNA Sanger Sequencing, which is the gold standard. SAA and high-sensitive CRP levels were also assessed. Mean gingival index, percentage of bleeding on probing, probing pocket depth and clinical attachment level, and the levels of SAA and hs-CRP were higher in the FMF-A group than those in the FMF and control groups. The two most relevant mutations in patients with FMF were heterozygous M694V (46.2%), and heterozygous R202Q (32.7%). The frequencies of the homozygous M694V and R202Q mutations in the FMF-A group were 53.8% and 46.1%, respectively. The complex R202Q/M694V homozygous state led to an increased risk of chronic periodontitis (odds ratio: 3.6), and FMF-A (odds ratio: 7.6). This is the first study to report the R202Q mutation in patients with periodontitis. Furthermore, the MEFV gene-mediated inflammatory pathway increased serum acute phase reactants, and the changes in the R202Q and M694V could play a role in inflammatory-genetic diseases, such as FMF, FMF-associated amyloidosis and chronic periodontitis.

Is There a Long-Term Risk for Donors With Heterozygous MEFV Mutation After Kidney Donation?

BackgroundFamilial Mediterranean fever (FMF) is an autosomal-recessive autoinflammatory disorder manifested severely by systemic amyloidosis. It has been hypothesized that heterozygous carriers may also have susceptibility to certain symptoms or even diseases. Because the living kidney donors of patients with FMF are generally relatives of the kidney recipients, there is a high possibility that the donors will have a heterozygous mutation of the FMF gene. The goal of this study was to investigate the long-term kidney function of donors who are carriers of the Mediterranean fever (MEFV) gene. MethodsThe medium- to long-term outcomes of 12 asymptomatic donors were compared with MEFV gene carriers and 24 non-FMF recipients' donors. ResultsHeterozygous carriers and the control group were similar with respect to age, sex, and follow-up period. The preoperative estimated glomerular filtration rate and 24-hour urine proteinuria levels were similar in the MEFV carrier and control groups. Four years after the donation, both groups had similar estimated glomerular filtration rates, but the change in 24-hour urine protein was statistically higher in the MEFV carrier group, and no significant change was observed in the control group (P = .004). At the end of the follow-up period, neither overt proteinuria nor kidney failure was seen in either group. ConclusionsThis study showed that the medium- to long-term results of the kidney donors who are carriers of the MEFV gene seem to be safe. However, there was more of a tendency for an increase in proteinuria in the MEFV gene carriers compared with control subjects, which necessitated further long-term care for these donors.

Prevalence of Mediterranean FeVer Gene Mutations in Turkish Cypriot Population.

This study aims to determine the carrier frequency and the most common mutations of the Mediterranean FeVer (MEFV) gene in healthy Cypriot population of Turkish origin. A total of 296 healthy participants (102 males, 194 females; median age 30 years; range 1 to 81 years) were evaluated. The exon 2, 3, 5 and 10 of MEFV genes were amplified by polymerase chain reaction. The participants demonstrated an extremely high carrier rate (12.5%). Most commonly detected mutations were E148Q and A74S, with rates of 7.3% and 2.8%, respectively. Mediterranean FeVer gene mutation types and carrier rates in Turkish Cypriot population are different than other Mediterranean populations in the region. MEFV mutation carriage is frequent in North Cyprus and familial Mediterranean fever might be one of the causes for end stage renal disease in Turkish Cypriots.

Role of genetics in familial Mediterranean fever

Familial Mediterranean fever (FMF) is caused by mutations within the Mediterranean fever (MEFV) gene. These gain of function mutations lead to an increased activation of the inflammasome pyrin with asubsequent disproportional proinflammatory reaction. Classically, in FMF patients two pathogenic mutations affecting both alleles are found in the molecular genetic analysis; however, it is well known that the phenotype can also be caused either by mutations with lower penetrance or unknown significance. Furthermore, in asignificant number of patients only one or even no MEFV mutations can be detected. Heterozygous mutation carriers who do not suffer from classical FMF, can also present with other signs of inflammation, e. g. subclinical increased inflammation markers, associated inflammatory diseases or unclassified symptoms. Thus, FMF does not follow aclassical autosomal recessive inheritance and avariable gene dose effect has to be considered, which is furthermore modulated by other mostly unknown genetic variants and environmental factors. This article summarizes the broad spectrum of clinical presentations associated with MEFV mutations and analyzes the effect of the gene dose on the phenotypical expression. Furthermore, the impact of the molecular genetic analysis on the diagnostics of apatient and on the individualized management of the disease is discussed.

Effect of familial Mediterranean fever on sexual and reproductive health in women.

The aim of this study was to investigate the relationship between familial Mediterranean fever and female sexual dysfunction and premenstrual syndrome. This study included 36 patients with familial Mediterranean fever and 33 healthy volunteers. Familial Mediterranean fever was diagnosed according to the Tel Hashomer criteria and familial Mediterranean fever mutations were identified in all of the patients. The patients and healthy volunteers were compared in terms of anxiety, depression, sexual dysfunction, and premenstrual syndrome, and a model was created that describes the relationships among these variables. We found statistically significant differences between the groups in terms of anxiety, premenstrual syndrome, and Golombok Rust Inventory of Sexual Satisfaction frequency and vaginismus subscale scores. There was no difference in depression scores between the groups. Familial Mediterranean fever is a rheumatic disease that predisposes patients to sexual dysfunction and premenstrual syndrome, which emerges as direct and indirect psychological factors.

Familial Mediterranean fever-associated diseases in children.

MEditerranean FeVer (MEFV) gene encodes for the pyrin protein and a mutated pyrin is associated with a prolonged or augmented inflammation. Hence, various diseases were reported to be associated with familial Mediterranean fever (FMF) or carriers of MEFV mutations. However, systematic evaluation of all associated diseases in children with FMF has not been done previously. The aim of this study was to investigate the frequency and type of FMF-associated diseases in children. Files of FMF patients who had been seen in two reference hospitals in Ankara, in the last two years, were retrospectively evaluated. Patients with FMF and concomitant diseases were included to the study. Among 600 FMF patients, 77 were found to have a concomitant disease (12.8%). Thirty patients (5%) had vasculitis; 21 (3.5%) had juvenile idiopathic artritis (JIA); 7 (1.16%) had inflammatory bowel disease (IBD) and 19 had other diseases including 5 patients with isolated sacroiliitis. Overall, 13 (2.17%) patients had sacroiliitis in our cohort. The most frequent mutation was M694V/M694V (44%) and 81% of the patients had at least one M694V mutation. Majority of the patients (74%) developed associated diseases while they were not receiving colchicine therapy. Certain inflammatory diseases including vasculitis, chronic arthritis and IBD were more frequently detected in patients with FMF during childhood. M694V mutation is a susceptibility factor for associated diseases. In countries where FMF is prevalent, clinicians dealing with FMF and other inflammatory diseases should be aware of these associations.

Mutations of familial Mediterranean fever in Syrian patients and controls: Evidence for high carrier rate

BackgroundFamilial Mediterranean fever (FMF) is an autosomal recessive disorder caused by mutations in Mediterranean FeVer (MEFV) gene and is characterized by recurrent attacks of abdominal pain, synovitis and pleuritis. Methods and resultsTo determine the impact of mutations in MEFV on the Syrian population, we ascertained the distribution of MEFV mutations in 358 healthy controls and 302 FMF patients from Syria. Mutation detection allowed the identification of 14 different MEFV mutations in the healthy controls. The most dominant mutations detected were E148Q (7.68%), V726A (2.5%), M694I (1.68%), R408Q (1.54%), P369S (1.54%), and M694V (1.12%). In patients, M694V is the most common mutation identified in the Syrian FMF patients (24.1%), followed by E148Q (13.5%), V726A (11.4%), M680I(G/C) (10.3%), and M694I (8.2%). Conclusionsour data show that the carrier rate in healthy Syrian individuals is at least 1:3.3 (30.2%) and thus one of the highest and we confirm that some of the mentioned mutations and probably further genetic variants have variable penetrance or that FMF is underdiagnosed in the Syrian population.

Discontinuing colchicine in symptomatic carriers for MEFV (Mediterranean FeVer) variants.

Familial Mediterranean fever (FMF) is inherited autosomal recessively; however, heterozygotes may express FMF phenotype. We aimed to define the characteristics of FMF patients heterozygous for MEFV (MEditerranean FeVer) mutations in whom colchicine was stopped after a period of treatment, with close follow-up. We reviewed the charts of 182 children who were heterozygous for MEFV variants. We excluded the patients (n = 34) heterozygous for MEFV variants of unknown significance and patients with typical periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (n = 2). All patients were followed up with their routine analysis and serum amyloid A levels every 6months while on colchicine treatment and every 3-6months thereafter. MEFV gene variant analysis was performed with Sanger sequencing. Twenty-two out of 146 heterozygotes initially had FMF phenotype, but colchicine was discontinued after a treatment period. The most common MEFV variant was M694V (86.3%). The median age at diagnosis/initiation of colchicine was 76 (24-144) months. The median duration of colchicine treatment was 36 (24-110) months. The median age at colchicine cessation was 120 (55-172) months. At the time of colchicine cessation, the median attack- and inflammation-free period was 27 (24-84) months. The median follow-up after colchicine cessation was 22.5 (6-102) months. We re-started colchicine in only two patients because of recurrence of symptoms. Individuals with one mutation only can display FMF phenotype and require colchicine for the clinical and laboratory inflammation. However, in some of these patients, colchicine may be discontinued with very careful follow-up.

The role of MEFV mutations in the concurrent disorders observed in patients with familial Mediterranean fever.

This study aimed to investigate the frequency in which familial Mediterranean fever (FMF) coexists with other diseases and determine whether Mediterranean fever (MEFV) gene mutations are involved in such coexistence. In total, 142 consecutive patients with FMF investigated for MEFV mutation were enrolled in this study [Female: 87; Male: 55, mean age 32±12 years (11-62)]. All the patients were questioned for the presence of concurrent disorders, and the medical records of these patients were revised retrospectively. A previous diagnosis of inflammatory disorder other than FMF was considered true if it met the relevant criteria. MEFV mutations were divided into 2 groups, namely M694V and its subgroup (homozygous or heterozygous) (Group I) and others (Group II). Compound heterozygosity for M694V mutation was included in Group II to form a homogeneous group for Group I. Group I and Group II were compared according to phenotypical features. The presence of MEFV mutation was investigated in exons 2, 3, 5, and 10 by the multiplex-PCR reverse hybridization method. Concomitant disorders were found in 17 of 73 patients with FMF (23%) in Group I and 5 of 56 patients (8.9%) in Group II (p=0.04). Concomitant disorders in Group I were as follows: 7 cases of amyloidosis, 2 cases of Behcet's disease (BD), 4 cases of ankylosing spondylitis (AS), 1 case of antiphospholipid syndrome, 1 case of Henoch-Schonlein purpura (HSP), 1 case of combination of psoriatic arthritis, HSP, and membranoproliferative glomerulonephritis, and 1 case of AS and amyloidosis. In Group II, the following disorders were found: 1 case of amyloidosis, 1 case of BD, 1 case of AS, 1 case of ulcerative colitis, and 1 case of vitiligo. The presence of M694V mutation may predispose patients with FMF to developing other inflammatory disorders.

Distribution of MEFV gene mutations and R202Q polymorphism in the Serbian population and their influence on oxidative stress and clinical manifestations of inflammation.

BackgroundThe Mediterranean fever (MEFV) gene codes for protein pyrin, one of the regulators of inflammasome activity in innate immune cells. Mutations in this gene are considered the primary cause of Familial Mediterranean fever, but are also found in other monogenic and multifactorial autoinflammatory diseases. The aim of the study was to determine if healthy carriers of MEFV gene mutations and R202Q polymorphism have clinical manifestations of inflammation and impaired oxidative stress parameters.MethodsOne hundred DNA samples from healthy volunteers (13.3 ± 8.87 years of age (mean ± SD); range 2–35) were sequenced by ABI PRISM 310 automated sequencer (PE Applied Biosystems, Norwalk, USA). The Eurofever questionnaire was used to collect retrospectively medical history data. Oxidative stress was determined by measuring spectrophotometrically thiobarbituric acid reactive substances (TBARS) in plasma and erythrocytes, as well as advanced oxidation protein products in plasma. Superoxide dismutase (SOD) activity was determined by McCord and Fridovich method in plasma and erythrocytes, while the catalase erythrocyte activity was assessed using a catalase ELISA kit.ResultsWe found heterozygous carriers of K695R/N mutations in 5 %, E148Q/N mutations in 6 %, R202Q homozygous polymorphism in 10 % and heterozygous R202Q alterations in 45 % of healthy volunteers. The MEFV mutation carriers and R202Q polymorphism homozygotes reported significantly more often recurrent febrile episodes (p = 0.009), diffuse abdominal pain (p = 0.025), and malaise (p = 0.012) compared to non-carriers. Erythrocyte TBARS levels and plasma SOD activity were higher in persons with MEFV mutations and R202Q/R202Q (p = 0.03 and p = 0.049, respectively).ConclusionsHealthy individuals may bear E148Q and K695R MEFV gene mutations, as well as R202Q polymorphism in homozygous state. The determined gene alterations contribute to a subtle oxidative stress and may be associated with more frequent episodes of fever and unspecific inflammatory manifestations. An incomplete penetrance or variable expressivity of R202Q in populations of different ethnicity could influence the expression of autoinflammatory diseases phenotype.

Investigation of MEFV gene polymorphisms (G138G and A165A) in adult patients with familial Mediterranean fever

AimVarious mutations have been identified in the Mediterranean fever (MEFV) gene which is reported to be responsible from Familial Mediterranean fever (FMF). In our study, we aimed to determine the frequency of the MEFV mutations in our region and to investigate the impact of G138G (rs224224, c.414A>G) and A165A (rs224223, c.495C>A) gene polymorphisms on the clinical findings of the disease. MethodsOne hundred and sixteen patients diagnosed with FMF and 95 control subjects were included in this study. We used the DNA sequence analysis method to identify the most prevailing 10 mutations located in exon 2 and 10 of MEFV gene. ResultsAs a result of the MEFV mutation analysis, the most common mutation was the M694V mutation allele with a frequency rate of 41.8%. When the patients group and control group were compared in terms of frequency of both polymorphic alleles (G polymorphic allele, observed in G138G and the A polymorphic allele, observed in A165A), the variation was observed to be statistically significant (p<0.001). It was found that the MEFV mutation types have no relation with clinical findings and amyloidosis (p>0.05). ConclusionsTo our knowledge, our study is the first study in the Southern Marmara region that reports the frequency of MEFV mutations. Our findings imply that the polymorphisms of G138G and A165A may have an impact on progress of the disease. We think that more studies, having higher number of cases and investigating the polymorphisms of MEFV gene, are needed.

Investigação de polimorfismos no gene MEFV (G138G e A165A) em pacientes adultos com febre mediterrânica familiar

AimVarious mutations have been identified in the Mediterranean Fever (MEFV) gene which is reported to be responsible from Familial Mediterranean Fever (FMF). In our study, we aimed to determine the frequency of the MEFV mutations in our region and to investigate the impact of G138G (rs224224, c.414A>G) and A165A (rs224223, c.495C>A) gene polymorphisms on the clinical findings of the disease. MethodsOne hundred and sixteen patients diagnosed with FMF and 95 control subjects were included in this study. We used the DNA sequence analysis method to identify the most prevailing 10 mutations located in exon 2 and 10 of MEFV gene. ResultsAs a result of the MEFV mutation analysis, the most common mutation was the M694V mutation allele with a frequency rate of 41.8%. When the patients group and control group were compared in terms of frequency of both polymorphic alleles (G polymorphic allele, observed in G138G and the A polymorphic allele, observed in A165A), the variation was observed to be statistically significant (p<0.001). It was found that the MEFV mutation types have no relation with clinical findings and amyloidosis (p>0.05). ConclusionsTo our knowledge, our study is the first study in the Southern Marmara region that reports the frequency of MEFV mutations. Our findings imply that the polymorphisms of G138G and A165A may have an impact on progress of the disease. We think that more studies, having higher number of cases and investigating the polymorphisms of MEFV gene, are needed.

Familial Mediterranean Fever associated diseases in children

Background MEditerranean FeVer (MEFV) gene encodes for the pyrin protein and a mutated pyrin is associated with a prolonged or augmented inflammation. Hence, various diseases were reported to be associated with familial Mediterranean fever (FMF) or carriers of MEFV mutations. However, systematic evaluation of all associated diseases in children with FMF has not been done previously. Aim The aim of this study was to investigate the frequency and type of FMF-associated diseases in children. Design and methods Files of FMF patients who had been seen in two reference hospitals in Ankara, in the last two years, were retrospectively evaluated. Patients with FMF and concomitant diseases were included to the study. Results Among 600 FMF patients, 77 were found to have a concomitant disease (12.8%). Thirty patients (5%) had vasculitis; 21 (3.5%) had juvenile idiopathic artritis (JIA); 7 (1.16%) had inflammatory bowel disease (IBD) and 19 had other diseases including 5 patients with isolated sacroiliitis. Overall, 13 (2.17%) patients had sacroiliitis in our cohort. The most frequent mutation was M694V/M694V (44%) and 81% of the patients had at least one M694V mutation. Majority of the patients (74%) developed associated diseases while they were not receiving colchicine therapy. Conclusions Certain inflammatory diseases including vasculitis, chronic arthritis and IBD were more frequently detected in patients with FMF during childhood. M694V mutation is a susceptibility factor for associated diseases. In countries where FMF is prevalent, clinicians dealing with FMF and other inflammatory diseases should be aware of these associations.

The Role of Mediterranean Fever Mutation in the Clinical Course and Pathogenesis of Ankylosing Spondylitis

Objectives: This study aims to investigate the role of Mediterranean fever (MEFV) gene mutations in the pathogenesis and clinical progression of disease in ankylosing spondylitis patients. Patients and methods: The study included 88 patients (60 males, 28 females; mean age 38.7±8.7 years; range 19 to 56 years) diagnosed with ankylosing spondylitis according to modified New York criteria. The patients were evaluated for peripheral joint and hip joint involvement and treatment characteristics. Using multiplex/polymerase chain reaction reverse hybridization method, the presence of 12 different MEFV mutations was investigated. Results: Of 29 patients, heterozygote mutation was detected in 24 (83%), mutations in both alleles were detected in three (10%), and combined heterozygote mutations were detected in two patients (7%). Three most common mutations were M694V (11.3%), E148Q (8%), and V726A (4.5%). In the group with mutations, symptoms had started earlier than in the other group, and the number of peripheral joints involved was higher. When both characteristics were compared with the characteristics of the group that did not have any gene mutations, the differences were statistically significant (p<0.001 and p=0.044, respectively). The highest correlation with the number of peripheral joints involved was determined for M694V mutation (p=0.034), while onset of symptoms at younger age was correlated with E148Q mutation (p=0.010). Conclusion: Based on the findings of this study and our clinical experience, it can be said that the clinical progression of ankylosing spondylitis patients with MEFV gene mutations is more severe, and this suggests that MEFV gene mutations may be contributive to ankylosing spondylitis pathogenesis.