Project description:BACKGROUND:Familial Mediterranean fever (FMF) is an autoinflammatory disease that has self-limiting inflammatory attacks during polyserositis. Hepcidin is a protein, and interleukin-6 stimulation increases hepcidin levels. Calprotectin (CLP) is a recently defined cytokine released from monocytes and neutrophils in response to tissue trauma and inflammation. There are studies in the literature showing that it can be used as a biomarker in rheumatic diseases such as ankylosing spondylitis and rheumatoid arthritis. Here, we compared the levels of hepcidin and CLP in healthy individuals and FMF patients during an attack-free period and show its relation to genetic mutations. METHODS:This is a cross-sectional study. Between July 2017 and December 2017, 60 patients diagnosed with FMF an admitted to the Cumhuriyet University Faculty of Medicine Department of Internal Medicine Rheumatology as well as 60 healthy volunteers without any rheumatic, systemic, or metabolic diseases were enrolled in this study. Blood was collected from a peripheral vein to measure serum CLP and hepcidin levels. Blood tests were examined by ELISA; the study protocol was approved by the local ethics committee. RESULTS:Median serum hepcidin level was 468.1 (210.3-807.8) pg/mL in FMF group and 890.0 (495.0-1,716.9) pg/mL in the healthy control (HC) group. There was a statistically significant difference between the two groups (P < 0.001). The median serum levels of CLP in the FMF group were measured as 1,331.4 (969.3-1,584.6 pg/mL and 73.8(45.0-147.9) pg/mL in the HC group. There was a statistically significant difference between the two groups (P < 0.001). Receiver operating characteristic analysis showed that the sensitivity was 66.7% and the specificity was 71.7% at serum hepcidin < 581.25 pg/mL (P < 0.05); the sensitivity was 96.7% and specificity was 100% at CLP > 238 pg/mL (P < 0.05). There was no significant difference between serum hepcidin and CLP levels in FMF patients with M694V homozygous and M694V heterozygous (P > 0.05). There was no significant difference in serum hepcidin levels between FMF patients with and without arthritis, proteinuria, and amyloidosis (P < 0.05). There was no significant correlation between laboratory findings, gender, age, and serum CLP and hepcidin levels (P > 0.05, r < 0.25). CONCLUSION:Serum CLP levels in FMF patients during an attack-free period are significantly higher than in the HC groups. Serum hepcidin levels in FMF patients are significantly lower than in the HC group. Low levels of hepcidin may be explained by including FMF patients during an attack-free period in the study. CLP may be an important biomarker in FMF. A better understanding of the role of these biomarkers in the diagnosis of FMF is needed to evaluate the results in a more comprehensive way.
Project description:ObjectivesAlthough Familial Mediterranean fever (FMF) is categorized as autosomal recessive, frequent exceptions to this model exist and therefore we aimed to search epigenetic modifications in this disease.MethodsTen M694V homozygous FMF patients (the most severe phenotype) were recruited for this study. Patients with inflammatory flare were excluded. Total RNA was extracted from peripheral blood, and microRNA expression profiled using NanoString nCounter technology. These patients were compared to 10 healthy age- and sex-matched controls.ResultsSeven hundred nighty-eight mature human miRNAs were probed, 103 of which had expression levels above the negative control probes. Seven miRNAs showed significant differences in expression in samples from FMF patients compared to healthy controls: four miRNAs were upregulated (miR-144-3p, miR-21-5p, miR-4454, and miR-451a), and three were downregulated (miR-107, let-7d-5p, and miR-148b-3p).ConclusionIn this pilot study, we identified epigenetic modifications in clinically quiescent FMF patients. More studies are required for exploration of their contribution to FMF pathogenesis and their potential role as clinical biomarkers.
Project description:Familial Mediterranean fever (FMF, MIM 249100) is an autosomal recessive disease affecting mainly patients of the Mediterranean basin. It is an autoinflammatory periodic disorder characterized by recurrent episodes of fever and abdominal pain, synovitis, and pleuritis. The major complication of FMF is the development of renal AA amyloidosis. Treatment with colchicine prevents the occurrence of recurrent seizures and renal amyloidosis. The disease is caused by mutations in the MEFV gene. We report here the cases of two unrelated patients, who have been late diagnosed with FMF complicated by renal amyloidosis. We focus on the importance of early diagnosis of FMF, both to start rapidly treatment with colchicine and avoid renal amyloidosis, and to provide genetic counseling to families.
Project description:Familial Mediterranean Fever (FMF) and COVID-19 show a remarkable overlap of clinical symptoms and similar laboratory findings. Both are characterized by fever, abdominal/chest pain, elevation of C-reactive protein, and leukocytosis. In addition, colchicine and IL-1 inhibitors treatments that are effective in controlling inflammation in FMF patients have recently been proposed for off-label use in COVID-19 patients. Thus, FMF may resemble a milder recapitulation of the cytokine storm that is a hallmark of COVID-19 patients progressing to severe disease. We analyzed the sequence of the MEFV-encoded Pyrin protein - whose mutations cause FMF- in mammals, bats and pangolin. Intriguingly, although Pyrin is extremely conserved in species that are considered either a reservoir or intermediate hosts for SARS-CoV-2, some of the most common FMF-causing variants in humans are present as wildtype residues in these species. We propose that in humans, Pyrin may have evolved to fight highly pathogenic infections.
Project description:Familial Mediterranean fever (FMF); is an autosomal recessively inherited autoinflammatory disease caused by the mutations in the Mediterranean Fever (MEFV) gene. Recent studies have shown that epigenetic control mechanisms, particularly non-coding RNAs, may play a role in the pathogenesis of autoinflammation. microRNAs (miRNAs) are small non-coding RNAs that play critical roles in regulating host gene expression at the post-transcriptional level. The phenotypic heterogeneity of FMF disease suggests that FMF may not be a monogenic disease, suggesting that epigenetic factors may affect phenotypic presentation. Here we examined the potential anti-inflammatory effect of miR-197-3p, which is a differentially expressed miRNA in FMF patients, by using inflammation related functional assays. We monitored gene expression levels of important cytokines, as well as performed functional studies on IL-1β secretion, caspase-1 activation, apoptosis assay, and cell migration assay. These experiments were used to evaluate the different stages of inflammation following pre-miR-197 transfection. Anti-miR-197 transfections were performed to test the opposite effect. 3'UTR luciferase activity assay was used for target gene studies. Our results obtained by inflammation-related functional assays demonstrated an anti-inflammatory effect of miR-197-3p in different cell types (synovial fibroblasts, monocytes, macrophages). 3'UTR luciferase activity assay showed that miR-197-3p directly binds to the interleukin-1beta (IL-1β) receptor, type I (IL1R1) gene, which is one of the key molecules of the inflammatory pathways. This study may contribute to understand the role of miR-197-3p in autoinflammation process. Defining the critical miRNAs may guide the medical community in a more personalized medicine in autoinflammatory diseases.
Project description:Introduction. Familial Mediterranean fever (FMF) is an auto-inflammatory disease characterized by attacks of fever and polyserositis. FMF is often associated with other autoimmune diseases such as rheumatoid arthritis, polyarteritis nodosa (PAN), and Behcet. Uveitis is an inflammatory process caused by underlying infectious and inflammatory disorders. This study investigates the probable relationship between idiopathic uveitis and FMF. Methods. Patients with idiopathic uveitis were analyzed for the 12 most common MEFV mutations (P369S, F479L, M680I(G/C), M680I(G/A), I692del, M694V, M694I, K695R, V726A, A744S, R761H, E148Q) by a reverse hybridization assay (FMF StripAssay,Vienna lab,Vienna, Austria). Results. 12 patients with idiopathic uveitis were enrolled in this study. 10 of them were female. The youngest patient was a 7-year-old child and the oldest was 57. The most common complaints of patients were blurred vision and then eye redness. One patient was heterozygous for R761H. Genetic analysis of the 12 most common MEFV mutations in the patients with idiopathic uveitis didnot have any positive results. Conclusion. According to the analysis of the 12 most common MEFV gene mutations, FMF is not an underlying cause of idiopathic uveitis. On the other hand, uveitis merely could not be the first presentation of FMF.
Project description:Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder affecting individuals with biallelic pathogenic mutations in the MEFV gene. The disease is characterized by recurrent attacks of fever and serosal inflammation as manifested by abdominal and chest pain. This case report presents an FMF case with a 3-year history of pain crises consisting of severe abdominal pain and fever, lasting up to 72 h. Genetic investigation identified an uncommon heterozygous mutation in the MEFV gene. This mutation is associated with a more severe phenotype of FMF and may lead to an early onset of the disease.
Project description:Familial Mediterranean fever (FMF) (OMIM #249100) is the most common hereditary autoinflammatory disease in the world. FMF is caused by gain of function mutations of MEFV gene which encodes an immune regulatory protein, pyrin. Over the last few years, we have witnessed several new developments in the pathogenesis, genetic testing, diagnosis, comorbidities, disease related damage and treatment approaches to FMF. Elucidation of some of the pathogenic mechanisms has led to the discovery of pathways involved in inflammatory, metabolic, cardiovascular and degenerative diseases. The use of next generation sequencing in FMF has revealed many new gene variants whose clinical significance may be clarified by developing functional assays and biomarkers. Clinically, although FMF is considered an episodic disease characterized by brief attacks, recent systematic studies have defined several associated chronic inflammatory conditions. Colchicine is the mainstay of FMF treatment, and interleukin (IL)-1 antagonists are the treatment of choice in refractory or intolerant cases. Experience of IL-1 antagonists, anakinra and canakinumab, is now available in thousands of colchicine resistant or intolerant FMF patients. In this contemporary review, we surveyed current FMF knowledge in the light of these recent advances.
Project description:OBJECTIVE:Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent febrile attacks accompanied by serosal and synovial membrane inflammation. FMF is caused by mutations in the MEFV gene and are found usually among Mediterranean populations, Armenians, Turks, Arabs and Jews. The aim of this study was to determine the frequency of MEFV gene mutations among FMF patients in the Azeri Turk population in North-West of Iran. MATERIALS AND METHODS:In this descriptive study, 130 FMF patients with Azeri Turk origin were screened for mutations in four exons (2, 3, 5 and10) of MEFV gene. Genomic DNA was extracted from whole blood and entered in ARMS-PCR and PCR-RFLP reactions. When cases were negative in ARMS-PCR and PCR-RFLP, the exons were amplified and subjected to direct sequencing. RESULTS:Our results showed that the most common mutations in this study population was M694V (40.19%) followed by E148Q (17.64%), V726A (13.72%), M680I (12.74%) and M694I (2.94%) mutations. Four new mutations including K618N, K716M, S614F and G136E were identified in our study. CONCLUSION:The prevalence of five common mutations in our study was highly similar to previous studies analysing the Mediterranean basin populations. Investigation by sequencing also revealed four new variants in the study population. The main genotypephenotype correlation finding was the presence of M694V mutation in homozygote or compound heterozygote state in the patients with renal manifestations.