Novel Deleterious nsSNPs within MEFV Gene that Could Be Used as Diagnostic Markers to Predict Hereditary Familial Mediterranean Fever: Using Bioinformatics Analysis.

Background Familial Mediterranean fever (FMF) is the most common autosomal recessive autoinflammatory disease worldwide, mainly affecting patients of Mediterranean origin. It is the first hereditary periodic fever syndrome whose MEFV gene has been identified. Correlation between the mRNA level of the MEFV gene and FMF pathogenesis is elusive. Aim This study aims to investigate the relationship between common mutations in MEFV gene and the mRNA expression in Egyptian patients with FMF, as well as the phenotype/genotype correlation. Patients and methods This study included 65 patients with FMF, who were chosen based on clinical criteria as well as 26 healthy controls. Mutation detection was performed by direct Sanger sequencing and restriction fragment length polymorphism. Quantitative real-time PCR was employed to assess the relative expression level of the MEFV gene. Results The data revealed significantly lower MEFV gene expression in patients compared with healthy controls (P = 0.001). MEFV mRNA expression level was lower in patients with identified mutations compared with those with undetected mutations. However, the difference was statistically insignificant. Additionally, we found that the MEFV gene expression level was not associated with age, consanguinity, disease severity, or serum amyloid A levels. Conclusion The study confirmed the relation between reduced MEFV expression level and the FMF disease, which emphasizes the role of gene expression in the pathogenesis of this disease.

The article is devoted to the analysis of the current state of the problem of the most common autoinflammatory disease – familial Mediterranean fever (FMF). The authors provide data on the prevalence of FMF, the genetic mechanisms of its development, the influence of MEFV gene mutations on the manifestation of FMF and its clinical phenotypes. The polymorphism of the mutated MEFV gene in various ethnic populations is discussed. Particular attention is paid to the combination of FMF with other rheumatic processes, primarily with spondyloarthritis. It has been shown that immunoinflammatory comorbidity is characteristic of the early onset of FMF, a more severe course of this disease, and is determined by the specific genotype of the patient. In this regard, the importance of genetic analysis is emphasized not only for the timely verification of FMF, but also for determining the prognosis in terms of the risk of developing spondyloarthritis and amyloidosis. An analysis of works on the pharmacotherapy of FMF showed that although colchicine remains the first-line drug, interleukin-1 inhibitors are actively used in the treatment of patients with FMF. The results of multicenter studies demonstrate the high efficacy and safety of the intelekin-1 inhibitor canakinumab in the treatment of FMF and other autoinflammatory diseases in children and adults. In this regard, with the development of colchicine resistance or poor tolerability of colchicine, interleukin-1 inhibitors are considered as the optimal therapeutic option.

The Genetic Basis for Periodic Fever

Introduction: Familial Mediterranean Fever (FMF) is a common autoinflammatory disease, especially in Mediterranean populations. FMF typically occurs with fever and serositis attacks and can negatively affect the individual's life. In our study, we aimed to investigate the effects of working conditions and the disease course on the work life of FMF patients.
 Methods: The adult patients with pathogenic or likely pathogenic mutations in the MEFV gene who applied to our medical genetic outpatient clinic of the Faculty of Medicine, Çanakkale Onsekiz Mart University between 01.01.2010 and 01.08.2020 were included in our study. We created a questionnaire of 34 questions, which included sociodemographic data, information about the FMF course of the patients, and the effects of work conditions and FMF on the work life of these patients. The questionnaire link, created over Google Drive, was sent to the patient's current mobile phone numbers via text message, and the answers received until 31.12.2020 were evaluated.
 Results: A total of 154 survey responses were obtained, and 113 were eligible for our study. Twenty-four of 104 (23.1%) participants who have worked in any job so far stated that they have changed or quit their jobs because of increased or worsening FMF attacks. Of 72 participants who have been working actively for the last year, 4 (5.6%) of them we are reported that they have a health problem in the workplace due to FMF disease. The statistically significant relationships were found between the FMF-induced changing or quitting job and the attack number in the last year regardless of attack severity, work-related adverse psychological effects, the mode of transportation to work, and the physical conditions in the working environment.
 Conclusion: We suggest that the regulation of work environments, considering the factors that trigger attacks in FMF patients, will contribute to the increase in quality of life and work performance in these patients.

BackgroundThe most common autoinflammatory disease which occurs in Armenian ethnos is familial Mediterranean fever (FMF). FMF is a hereditary disorder characterized by recurrent attacks of fever and serosal inflammation. The...

Background: Familial Mediterranean fever (FMF) is the most common autoinflammatory disease caused by recessive mutations in the MEFV gene. If not treated, FMF patients may develop renal AA-amyloidosis that leads to renal failure and death. Both mutations and polymorphisms in MEFV and SAA1 genes, respectively, have been associated with AA-amyloidosis in several populations. In Algeria, as FMF is still under-estimate and misdiagnosed, genetic data on renal complication are largely lacking. We thus explored the contribution of MEFV and SAA1 loci in the development of amyloidosis in Algerian patients with FMF. Methods: This study included 64 unrelated FMF patients (21 without and 43 with renal amyloidosis) and 13 healthy controls. The entire exon 10 was sequenced after PCR amplification to detect MEFV mutations. Genotypes of SAA1 locus (SAA1.1, SAA1.5, and SAA1.3) were determined by PCR-RFLP (restriction fragment length polymorphism). Results: Analyze of MEFV gene showed that the percentage of homozygous for p.M694I mutation was significantly higher in patients with amyloidosis compared to patients without amyloidosis (p=0.032). The SAA1.1/1.1 genotype was significantly predominant in patients with amyloidosis compared to those without AA-amyloidosis (p=0.001) and controls (0.001). The SAA1.5/1.5 genotype was identified only in patients without amyloidosis and controls. The most patients with renal complications were homozygous for p.M694I and SAA1.1 alleles. Conclusion: Our data suggest a positive correlation between the p.M694I/M694I and SAA1.1/1.1 genotypes and the development of AA-amyloidosis secondary to FMF in Algerian patients.

Next-generation screening of a panel of genes associated with periodic fever syndromes in patients with Familial Mediterranean Fever and their clinical characteristics

Sir, We read the article by Devrimsel et al. reporting a patient with systemic lupus erythematosus (SLE) and familial Mediterranean fever (FMF). We believe some statements made in this article need clarification. The authors stated that FMF and SLE were autoimmune diseases and that they had similar clinical signs and symptoms. However, FMF, which is the most common autoinflammatory disease around the world, is not an autoimmune disease. TheMEFV gene encoding pyrin is mutated in FMF patients. Pyrin forms a part of the NLRP3 inflammasome complex, and dysfunctional pyrin causes increased interleukin 1b production through hyperactivated inflammasome. This is not an autoimmune process. The phenotypes of SLE and FMF are also not alike. FMF is an autoinflammatory disease characterized by attacks of polyserositis and fever lasting for 0.5 to 3 days, while SLE is an autoimmune disease with severe morbidity and mortality characterized by the presence of autoantibodies and involvement of multiple systems. Mutations in the MEFV gene may cause a tendency to certain rheumatic diseases, such as acute rheumatic fever, rheumatoid arthritis and systemic juvenile idiopathic arthritis, whereas SLE is not one of them. We have previously suggested that the rarity of SLE in FMF patients might be because of the high levels of C-reactive protein (CRP) which mediates the removal of apoptotic cells. This process eliminates a potential contributor to the pathogenesis of SLE. Funding

The MEFV gene and its association with familial Mediterranean fever, severe atopy, and recurrent respiratory tract infections

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease (AID) affecting mainly the ethnic groups originating from Mediterranean basin. The disease is characterized by self-limited inflammatory attacks of fever and polyserositis along with elevated acute phase reactants. FMF is inherited autosomal recessively; however, a significant proportion of heterozygotes also express the phenotype. FMF is caused by mutations in the MEFV gene coding for pyrin, which is a component of inflammasome functioning in inflammatory response and production of interleukin-1β (IL-1β). Recent studies have shown that pyrin recognizes bacterial modifications in Rho GTPases, which results in inflammasome activation and increase in IL-1β. Pyrin does not directly recognize Rho modification but probably affected by Rho effector kinase, which is a downstream event in the actin cytoskeleton pathway. Recently, an international group of experts has published the recommendations for the management of FMF. Colchicine is the mainstay of FMF treatment, and its regular use prevents attacks and controls subclinical inflammation in the majority of patients. Furthermore, it decreases the long-term risk of amyloidosis. However, a minority of FMF patients fail to response or tolerate colchicine treatment. Anti-interleukin-1 drugs could be considered in these patients. One should keep in mind the possibility of non-compliance in colchicine-non-responders. Although FMF is a relatively well-described AID and almost 20 years has passed since the discovery of the MEFV gene, there are still a number of unsolved problems about it such as the exact mechanism of the disease, symptomatic heterozygotes and their treatment, and the optimal management of colchicine resistance.

NOD2/CARD15 Gene Mutations in Patients with Familial Mediterranean Fever

Background:When FMF patients with cirrhosis were compared with FMF patients without cirrhosis, those with cirrhosis had a significantly later diagnosis of hepatopathy: Familial Mediterranean fever (FMF) is the most common...

Sir, We read the article by Devrimsel et al. reporting a patient with systemic lupus erythematosus (SLE) and familial Mediterranean fever (FMF). We believe some statements made in this article need clarification. The authors stated that FMF and SLE were autoimmune diseases and that they had similar clinical signs and symptoms. However, FMF, which is the most common autoinflammatory disease around the world, is not an autoimmune disease. TheMEFV gene encoding pyrin is mutated in FMF patients. Pyrin forms a part of the NLRP3 inflammasome complex, and dysfunctional pyrin causes increased interleukin 1b production through hyperactivated inflammasome. This is not an autoimmune process. The phenotypes of SLE and FMF are also not alike. FMF is an autoinflammatory disease characterized by attacks of polyserositis and fever lasting for 0.5 to 3 days, while SLE is an autoimmune disease with severe morbidity and mortality characterized by the presence of autoantibodies and involvement of multiple systems. Mutations in the MEFV gene may cause a tendency to certain rheumatic diseases, such as acute rheumatic fever, rheumatoid arthritis and systemic juvenile idiopathic arthritis, whereas SLE is not one of them. We have previously suggested that the rarity of SLE in FMF patients might be because of the high levels of C-reactive protein (CRP) which mediates the removal of apoptotic cells. This process eliminates a potential contributor to the pathogenesis of SLE. Funding

Familial Mediterranean Fever (FMF) is an inherited autoinflammatory disease caused by mutations in the MEFV gene. These patients typically present with lymphocytosis and thrombocytosis during periods of inflammation; however, some patients may manifest leukopenia along with other symptoms. Demographic data, medical history, laboratory data, and genetic findings of the cases were collected by reviewing clinical records of the patient. Whole-genome sequencing test revealed a mutation in MEFV gene. A systematic searched was conducted in four databases: PubMed, Web of Science, Scopus, and PerQuest, using keywords related to blood abnormalities in FMF disease. A mutation in the MEFV gene was confirmed in a 29-year- old patient with FMF. He experienced periodic and regular decreases in the number of neutrophils, lym- phocytes, and platelets during periods of inflammation. Our literature review revealed neutropenia (17.6%), lymphopenia (8.8%), thrombocytopenia (11.8%), leukopenia (61.8%), and anemia (20.6%) are the frequent most common hematologic complications. Genetic analysis in 28 patients revealed M694V as the most prevalent mutation (57.1%), followed by E148Q (21.4%), M680I (10.7%), and others. Reporting this case and others highlights that hematological manifestations in FMF can be observed periodic and simultaneous decreases in neutrophils, lymphocytes, and platelet counts can in patients with FMF

Familial Mediterranean fever (FMF) is an autosomal-recessive autoinflammatory disease in the group of Hereditary periodic fever syndromes (HPFS), characterized by recurrent, self-limited attacks of fever and polyserositis, which last 2-4 days. It manifests mainly in childhood and often has early onset, resolve without sequels. Genetic testing of FMF is efficient and allows diagnosing of atypical cases. FMF is a significant health care problem in Armenia because of high frequency of carriers of MEFV mutations 1:3 - 4 (0.21) and marked FMF prevalence 54.7 per 10`000 of the total population. Articular symptoms are found in about 45% of cases. They usually manifest as acute recurrent arthritis (ARA) or arthralgia, but more rarely also chronic arthritis can be found. We aimed to investigate clinical and genetic characteristics of the joint manifestations in Armenian children with FMF. The charts of all 715 patients with proven diagnosis of FMF at the National Pediatric Center (NPC) for FMF were reviewed for joint manifestations. The diagnosis of FMF and disease severity were determined according to the Tel-Hashomer criteria and molecular-genetic detection of 12 MEFV mutations common for Armenians. The characteristics of joint manifestations and overall FMF disease were then compared to MEFV mutation analysis. There were 438 boys and 277 girls with an age at diagnosis between 3 months and 17 years (mean age: 8.64±0.17). Joint involvement was observed in 56.4% of all 715 cases. The manifestation was ARA in 30.5%, arthralgia in 21.2% and chronic arthritis (CA) in 4.7%, which would also qualify for a diagnosis of JIA. The frequency of ARA was associated with M694V mutation, mainly M694V homozygous and M694V heterozygous genotypes. The risk of CA depended on MEFV genotype of the FMF patients and was the highest in M694Vheterozygotes and M694Vhomozygotes. M694V heterozygous genotype was noticed significantly more frequently among FMF patients with spondyloarthritis in comparison to those without it. The probability of the development of CA among FMF patients without M694V mutation was significantly higher also in heterozygotes in comparison to compound-heterozygotes. We concluded, that the frequency of joint involvement among Armenian pediatric FMF patients was high - 56.4%, especially for CA. Chronic arthritis may be the first manifestation of FMF and occurred usually in patients with severe M694V mutations. Patients of Armenian origin with refractory arthritis should be asked for isolated febrile attacks, hemorrhagic vasculitis, episodes of pleuritis and family history to rule out FMF.