Exploring the Role of MEFV Gene Mutations in Pediatric Drug-Resistant Epilepsy

Prevalence of the MEFV Gene Mutations in Childhood Polyarteritis Nodosa

Dear Editor-in-ChiefSome genes have an unproven role in the patho-genesis of Rheumatoid arthritis (RA). One of these suspected genes is the Mediterranean fever (MEFV) gene. MEFV is responsible for familial Mediterranean fever (FMF). Currently, more than 100 FMF-associated mutations of the MEFV gene have been identified. With most located on exon 10, five of these: E148Q, M680I, M694V, M694I, and V726A account for most of the cases of FMF worldwide (1). A result of a study showed that the E148Q, V726A, M680I and M694I mutations are the most common muta-tions in the Azeri population of Iran with FMF (2). The MEFV mutation carrier rate in the area which shows a high frequency of FMF is also high. The E148Q was the most common muta-tion followed by V726A. The other common aforementioned mutations were not found in this study. The MEFV gene mutations cause an up-regulation of the inflammatory response, which most likely favors inflammation in general.To the best of our knowledge, no study has been performed on the prevalence of MEFV gene mu-tations in RA in the Azeri population of Iran. In this study, we investigated the MEFV mutations on exon 2 and 10 in 50 patients with RA by PCR and direct sequencing and then compared disease activity between mutation carriers and non-carriers in the Azeri population of Iran. None of the participants had clinical manifestations or a family history of FMF. The RA patients were as-signed to two groups of MEFV mutation and polymorphism carriers and non-carriers. Disease activity was measured using the DAS28 score to compare the two groups.The demographical characteristics of the patients are summarized in Table 1. We identified 33 he-terozygous patients. None of our study patients had any clinical manifestations or a family history of FMF. We found 3 polymorphisms and 2 mu-tations in Exon 2 and 4 mutations in Exon 10 of RA patients.Table 2 shows the distributions of the allele and genotype frequencies for the common MEFV mutations and polymorphisms in our study par-ticipants. No significant difference was seen in the disease activity between carriers and non-carriers.This study is the first assessment of MEFV po-lymorphisms and mutations in the Azeri popula-tion of Iran with RA. Thirty three out of 50 RA patients were found to carry MEFV polymor-phisms and mutations. The most common were the D102D, G138G, and A165A polymorphisms. In comparison with the normal Azeri population the carrier state of MEFV mutations in our study patients was higher. Bonyadi et al. in a study on five common MEFV gene mutations showed that 11.5% of normal Azeri people are carriers of E148Q followed by V726A (1.75%) (3). No car-riers were found for M694V. We detected E148Q, V726A and M694V mutations in 18%, 2%, and 2% of RA patients, irrespectively. Dif-ference in disease activity in the carrier and non-carrier patients was not significant. …

Mutations of the Mediterranean fever (MEFV) gene, which encodes pyrin protein, leads to familial Mediterranean fever (FMF) and a connection between MEFV mutations and rheumatic diseases has been suggested. The aim of this study was to explore the frequency and clinical significance of MEFV mutations in children with juvenile idiopathic arthritis (JIA). In this study, children with JIA, who had no typical symptoms of FMF, were screened for the mutations in exons 2 and 10 of the MEFV gene by direct sequencing. A total of 96 children, 56 girls (58.3%), with a median age of 11 years (2-18 years) were included. Patients were classified according to JIA subgroups as oligoarthritis in 43 (44.8%), rheumatoid factor-negative polyarthritis in 22 (22.9%), rheumatoid factor-positive polyarthritis in 2 (2.1%), systemic arthritis in 12 (12.5%) patients, enthesitis-related arthritis in 16 (16.7%), and psoriatic arthritis 1 (1.04%). A total of 31 children (32.3%) had MEFV mutations: 25 heterozygous, 2 homozygous, and 4 compound heterozygous. There were 22 (11.4%) exon 10 mutations (M694V, R761H, K695R, V726A, R653H) and 15 (7.8%) exon 2 mutations (E148Q, G304R, E148V, T267I). The allele frequencies of MEFV mutations were found to be 19.27%, which is higher than the general population [p = 0.03, (odds ratio (OR):1.93, 95% confidence interval (CI): 1.09-3.41)]. MEFV mutation carrier rates were significantly higher in antinuclear antibody (ANA) negative than in ANA positive patients [p = 0.01, (OR: 0.25, 95% CI: 0.085-0.74)] and in males than in females [p = 0.001, (OR: 0.197, 95% CI: 0.078-0.495)]. Also, there was a statistically significant difference between the MEFV mutation carrier rates and the subgroups of JIA (p = 0.005). These findings suggest that mutations of the MEFV gene may be responsible for rheumatic diseases other than FMF, and patients with JIA especially males, ANA negatives, and ERA subgroups should be screened for MEFV gene mutations in countries where FMF is frequent.

The spectrum of MEFV gene mutations and genotypes in Van province, the eastern region of Turkey, and report of a novel mutation (R361T)

Background The clinical and pathological features of inflammatory bowel disease (IBD) and Familial Mediterranean Fever (FMF) are similar. Objective Here, the frequency of Mediterranean Fever (MEFV) gene mutation and its effect on the outcome of IBD were evaluated. Methods DNA sequence analysis detected the variants on the MEFV gene in patients with IBD. The relationship between mutations and the need for steroids, immunomodulators, biologics, and surgery was assessed. Results We evaluated 100 patients with IBD (55 with ulcerative colitis (UC) and 45 with Crohn's disease (CD)) and 60 healthy individuals as controls. The frequency of MEFV gene mutation was 26.7% (n = 12) and 14.5% (n = 8) for UC and CD, respectively. No relationship was found between MEFV gene mutation and the need for steroids, immunomodulators, and biologics (p = 0.446; p = 0.708; p > 0.999, resp.); however, in UC, the need for surgery in those with mutation (p = 0.018) and E148Q mutation alone was significant (p = 0.037). Conclusion The rate of MEFV gene mutations was high in patients with UC who required surgery. These patients have frequent and severe attacks, indicating that the mutations are related to disease severity. MEFV mutation as a modifier factor of IBD should be considered.

Association between sequence variations of the Mediterranean fever gene and fibromyalgia syndrome in a cohort of Turkish patients

The aim of this study was to determine the Mediterranean fever (MEFV) gene mutations and their clinical correlations in children with familial Mediterranean fever (FMF) in southeast Turkey. Clinical and laboratory characteristics of 147 (65 males, 82 females) consecutive children with FMF having a positive MEFV gene mutation were prospectively investigated. Patients with negative MEFV gene mutations or atypical FMF presentations and those from other regions of the country were excluded. Clinical manifestations and disease severity scores were recorded. The six most frequent MEFV mutations including M694V, V726A, R726H, P369S, E148Q and P369S were investigated by a reverse hybridization test method. The median age of study group was 9.0years, median age at diagnosis was 7.8years, median age at disease onset was 5.0years, and median follow-up duration was 4.0years. A positive family history of FMF and parent-to-offspring transmission was found in 58.5 and 42.2% of families, respectively. The frequencies of independent alleles, with decreasing order, were E148Q (30.7%), M694V (26.0%), R761H (13.5%), V726A (13.0%), P369S (10.5%) and M680I (6.3%) in FMF patients. The M694V subgroup had higher mean disease severity score and longer attack duration compared with E148Q and other mutations subgroups (p<0.05). Two patients with amyloidosis had the M694V homozygote genotype. In conclusion contrast to other regions and many other ethnicities of the world, the most frequent MEFV gene mutation was E148Q in southeast Turkey. The M694V mutation frequency was lower, and disease severity was relatively mild in FMF children of this region.

Renal amyloidosis in familial Mediterranean fever

Introductionrheumatoid arthritis (RA) is a systemic autoimmune disease primarily affecting the joints. Arthritic disorders are associated with mutations of the Mediterranean fever (MEFV) gene. The aim of this study is to show whether MEFV mutations will be involved in the pathogenesis of RA, to explore the frequency of these mutations and to study the genotype-phenotype correlation between mutations in this gene and a cohort of Moroccan patients with rheumatoid arthritis (RA).Methodsthe present study included 100 patients with RA and 200 control group (CG) who were unrelated individuals from the same ethnic. All patients were tested for auto-antibodies: cyclic citrullinated peptide (ACPA/anti-CCP2), rheumatoid factor (RF) and were analyzed by Sanger Sequencing of the 2 and 10 exons of MEFV gene (hot-spot according to the literature).Resultswe detected 13 missense variants already MEFV gene mutation reported in the literature (S154T, G222A, G230L, L611H, L695A, M694V, I720M, A737L, P758S, L709A, T732A, G687A and P743L). Carrier rates of MEFV gene mutations were 24/100 (24%) for the RA group and 4/200 (4%) for CG. In the RA group, we observed that no man has presented with MEFV mutation. In the RA group, while gender, BMI, RF and ACPA were significantly higher in the mutation carrier group than those of the non-carrier group (p<0.01). The level of C-reactive protein and HAQ were slightly elevated in the carrier group but not significant. No other significant differences were observed between patients with MEFV mutations and those without MEFV mutations.Conclusionthe results of this study suggest that MEFV gene mutations appear to be an aggravating factor severity of RA and consequently, patients with RA might be screened for MEFV gene mutations in countries where FMF is frequent. We report also that our study is the first one in our country Morocco.

Mediterranean fever (MEFV) gene mutations are associated with familial Mediterranean fever (FMF). Recent studies have suggested that MEFV gene mutations may act as disease modifiers in neuro‐Behçet's (NBD) disease and neuro‐Sweet disease (NSD). We investigated MEFV genes and clinical features in 17 patients with NBD or NSD. MEFV gene mutations were frequently observed (70.6%). Headaches and exertional leg pain were associated with MEFV gene mutations (P < 0.05). Moreover, higher frequency of white matter lesions without sites predilection (P < 0.05) and non‐parenchymal lesions (P < 0.05) were also observed. MEFV gene mutations may be associated with particular findings and lesion sites.

Familial Mediterranean fever (FMF) is the most common autoinflammatory disease characterized by recurrent serositis attacks and fever. The discovery of the Mediterranean fever (MEFV) gene has been a milestone in FMF etiopathogenesis. Our knowledge about the relationship between the MEFV gene and FMF phenotype increases each day. This study aims to investigate the relationship between MEFV gene mutations and the FMF clinical findings of a single-center FMF cohort. Gender, age, age at symptom onset, age at diagnosis, clinical characteristics, and MEFV gene analysis of the patients were recorded. A total of 837 FMF patients were included in this study. There were 515 females and 322 males. The age at symptom onset was 18.3±10.9 years, while the age at diagnosis was 24.4±10.9 years. The most common symptom that accompanied fever was peritonitis (91.1%), while the other common clinical findings were pleuritis (45%), myalgia (44%), and arthritis (36%). A total of 47 patients developed amyloidosis. A total of 553 (66%) FMF patients had M694V mutation, 221 (26%) of which were homozygous, while 332 (40%) were heterozygous. Exon 10 mutation frequency was 759 (91%), while the non-exon 10 mutation frequency was 78 (9%). There was no wild type among the patients. In conclusion, the fact that a vast majority of the disease burden was constituted by the exon 10, especially M694V mutations and that none of the 837 patients from our cohort had a wild-type FMF proved the significance of MEFV gene mutation analysis. Therefore, we speculate that it is necessary to examine the MEFV gene mutations in each FMF suspected case. It seems plausible to re-evaluate the FMF diagnosis for cases in which a wild type MEFV gene mutation occurs.

Mutations in the Mediterranean fever (MEFV) gene lead to familial Mediterranean fever (FMF), a pro-inflammatory state characterized by outbursts of inflammatory cytokines. The aims of this study were to identify the common mutations of MEFV gene in Egyptian patients with FMF, to study cytotoxic T lymphocyte associated antigen 4 (CTLA-4) gene polymorphism and to evaluate correlations between CTLA4-1661 polymorphisms and MEFV mutations and clinical symptoms. Four hundred and twenty-four patients with clinical pictures suspicious of FMF were enrolled in this study. Mutations in MEFV gene were confirmed by reversed hybridization. Patients with homozygous and compound heterozygous mutations and 120 healthy controls were investigated for polymorphism of -1661 CTLA4 gene and the findings correlated with disease incidence and clinical symptoms of the disease. Ninety-seven patients had single heterozygous mutations and 78 had compound heterozygous or homozygous MEFV gene mutations. M694I/V726A was the most common genotype (14.1%), followed by homozygous M694I. There was no statistically significant difference between patients and controls in incidence of -1661 A/G single nucleotide polymorphism CTLA4 (P = 0.189), nor any significant correlation with any of the clinical symptoms of FMF and MEFV gene mutations.

Familial Mediterranean fever (FMF) is the most common hereditary inflammatory periodic disease, characterized by recurrent episodes of fever, abdominal pain, synovitis and pleurisy. The aim of this study was to determine the frequency and distribution of Mediterranean fever (MEFV) gene mutations and to investigate the clinical characteristics and genotype-phenotype correlation in patients with FMF in Aydin, a province in western Anatolia, Turkey. Therefore, we retrospectively analysed MEFV gene mutations in 383 patients with suspected FMF and the clinical features of 327 among them. The MEFV gene mutations were investigated using the reverse dot-blot hybridization technique. We detected 26 different genotypes and 11 different mutations. The most common mutations in our cohort were p.M694V (41.15%), p.E148Q (20.35%), p.M680I(G/C) (12.39%) and p.R761H (9.73%). Abdominal pain (86.2%), fever (80.7%), arthralgia (57.2%), vomiting (36.1%), arthritis (34.6%), fatigue (31.5%), anorexia (22.9%) and chest pain (19.0%) were the most prevalent clinical features in our patients. This is the first study from Aydin in which the distribution of MEFV gene mutations and clinical features were evaluated in patients with FMF. We found that the most common mutation was p.M694V in our region, while the frequency of the p.R761H mutation was higher compared to other regions of Turkey with respect to extracted data from previous similar studies. Presented results supported the clinical findings in the literature that the homozygous p.M694V and compound heterozygous genotype were associated with more severe courses in FMF patients.

Introduction: Familial Mediterranean fever (FMF) is an autoinflammatory fever syndrome distinguished by recurrent attacks of spontaneous peritonitis, pleuritis, fever, and arthritis. It is specifically seen in the ethnic groups of Mediterranean origin, but sporadic cases have been reported in Eastern Europe and America due to migrations. There is a number of cardiac manifestations associated with FMF. Methods: Using PubMed as the search engine, the literature search was done for articles published between 1958 and 2020. To summarize the body of available evidence, a scoping review was carried out to find relevant articles and case reports in patients of FMF with cardiovascular manifestations. Results: In the literature, there is a number of mechanisms explaining the cause of cardiac involvement in FMF, including the subclinical inflammation and secondary (AA) amyloid deposition in the vessels and the myocardium. There is a variable and often spurious course of these manifestations and it can be associated with a poor prognosis such as an acute myocardial infarction. In FMF patients, polyarteritis nodosa and Henoch-Schönlein purpura are seen more significantly as compared to the general population with increased frequency of mutations in Mediterranean fever (MEFV) gene. Through unclear mechanisms, Behçet’s disease is associated with MEFV gene mutations and shares vascular manifestations with FMF. There is an interplay of IL-1 and MEFV gene, which impart an important role in inflammatory attacks of FMF. There is an intima-media thickening of blood vessels AA to persistent inflammation which can lead to atherosclerotic plaque formation resulting in atherosclerotic cardiovascular disease. Conclusion: FMF and its associated cardiovascular diseases are interlinked to 2 main mechanisms: subclinical atherosclerosis and amyloid deposition, and colchicine is the primary treatment of patients with FMF which shows the regression of amyloid deposits and prevents cardiovascular sequelae.

Mediterranean fever (MEFV) gene mutations are responsible for familial Mediterranean fever (FMF) and associated with other inflammatory diseases. However, the effects of MEFV gene mutations on intestinal Behçet's disease (BD) are unknown. In this study, we investigated these mutations and clinical features in patients with intestinal BD. MEFV gene analysis was performed in 16 patients with intestinal BD, 10 with BD without intestinal lesions, and 50 healthy controls. Clinical features of patients with intestinal BD were retrospectively assessed. The rates of MEFV gene mutations in patients with intestinal BD, BD without intestinal lesions, and healthy controls were 75%, 50%, and 38%, respectively. Only 2 of 12 patients with intestinal BD harboring MEFV gene mutations (17%) were controlled without immunosuppressive treatment, while 8 patients (67%) required therapy with tumor necrosis factor (TNF) inhibitors. Among patients with intestinal BD without MEFV gene mutations (four patients), three (75%) were controlled by the administration of 5-aminosalicylic acid with or without colchicine, and one (25%) required TNF inhibitors. All patients who underwent intestinal resection had MEFV gene mutations. Immunohistochemical analysis and in situ hybridization with interleukin-1β (IL-1β) showed a high expression of IL-1β only in injured areas, suggesting that IL-1β may be involved in the formation of ulcers in patients with intestinal BD carrying MEFV gene mutations. Mutations in the MEFV gene may be associated with intestinal lesions of BD and refractoriness to treatment.