The distribution of MEFV mutations in Turkish FMF patients: multicenter study representing results of Anatolia

Background/aim: The distribution of Mediterranean fever (MEFV) gene mutations in Turkish familial Mediterranean fever (FMF) patients varies according to geographic area of Turkey. There is a need for highly representative data for Turkish FMF patients. The aim of our study was to investigate the distribution of the common MEFV mutations in Turkish FMF patients in a nationwide, multicenter study. Materials and methods: Data of the 2246 FMF patients, from 15 adult rheumatology clinics located in different parts of the country, were evaluated retrospectively. The following mutations have been tested in all patients: M694V, M680I, M694I, V726A, and E148Q. Results: There were 1719 FMF patients with available genetic testing. According to the genotyping, homozygous M694V, present in 413 patients (24%), was the most common mutation . One hundred and fifty-four (9%) of patients had no detectable mutations. Allele frequencies of common mutations were: M694V (n = 1529, 44.5%), M680I (n = 423, 12.3%), V726A (n = 315, 9.2%), E148Q (n = 214, 1%), and M694I (n = 12, <1%). Conclusion: In this large-scale multicenter study, we provided information about the frequencies of common MEFV gene mutations obtained from adult Turkish FMF patients. Nearly half of the patients were carrying at least one M694V mutations in their alleles.

Phenotype-genotype updates from familial Mediterranean fever database registry of Mansoura University Children' Hospital, Mansoura, Egypt.

BACKGROUND: Familial Mediterranean fever (FMF) is autosomal recessive disease that affects people from Mediterranean region, Europe and Japan. Its gene (Mediterranean fever [MEFV]) has more than 100 mostly non-sense mutations. OBJECTIVES: The objective of the following study is to provide some phenotype-genotype correlates in FMF by categorizing the Egyptian FMF cases from Delta governorates after analysis of the four most common mutations of MEFV gene (M680I, M694I, M694V, V726A). SUBJECTS AND METHODS: Clinically, suspected FMF cases using Tel-Hashomer criteria were enrolled in the study. Cases were referred to Mansoura University Children's Hospital that serves most of the most middle Delta governorates, in the period from 2006 to 2011. Subjects included 282 males and 144 females, mean age of onset 9.3 ± 2.2 years. All cases were analyzed for these mutations using amplification refractory mutation system based on the polymerase chain reaction technique. Five FMF patients agreed to undergo renal biopsy to check for development of amyloidosis. Analysis of data was carried out using SPSS (SPSS, Inc., Chicago, IL, USA). RESULTS: Mutation was found in 521 out of 852 studies alleles, the most frequent is M694V (35.4%) followed by M694I, V726A and M680I. 11 cases were homozygous; 7 M694V, 3 M680I and only one M694I case. Severe abdominal pain occurred in 31 (7.28%) but severe arthritis in 103 cases (24.2%). Strong association was found between arthritis and homozygous mutant compared with single and double heterozygous (72.7% vs. 33.3% and 20.24%, P < 0.001). Four amyloid cases were M694V positive. CONCLUSION: M694V allele is the most common among Egyptian FMF especially those with amyloidosis. We recommend routine check for amyloidosis in FMF cases to statistically validate this link.

MEFV gene pathogenic variants: a risk factor for dysmenorrhea in the Turkish population.

BACKGROUND/AIM: The Mediterranean fever (MEFV) gene codes for protein pyrin, which is among the modulators of inflammasome activity in innate immune cells. It was suggested that there is a relation between MEFV variations and inflammatory diseases. The aim of this study was to investigate MEFV gene variations in the patients with primary dysmenorrhea. METHODS: The prevalence of common MEFV gene variations (M694V, M680I, V726A, E148Q and R202Q) was investigated in 145 young women with primary dysmenorrhea and 135 unrelated healthy controls. MEFV gene variations were genotyped using PCR-based RFLP assay. RESULTS: Number of childbirth and marriage were significantly lower in the study group than the controls, respectvely (p < 0.001, p = 0.001). Family history was statistically higher in the patient group (p < 0.001). In total, MEFV genotype and allele frequencies were significantly higher in patients than controls, respectively (p = 0.008 and p = 0.005, respectively). It was found that MEFV gene E148Q allele was more common in patient group (p = 0.039). MEFV R202Q A allele was higher in the patients than the controls (p = 0.045). A significant association was observed when the patients were compared with the controls according to R202Q variant AA versus GG+GA genotypes (p=0.020). CONCLUSION: Our findings suggest that MEFV variations may be a risk factor for patients with dysmenorrhea in a Turkish cohort.HighlightsThere are very few studies in the literature regarding the relationship between pathological variants of MEFV and dysmenorrhea disease.The common MEFV mutations/variants were evaluated in primary dysmenorrhea patients.Family history was statistically higher in the patient group (p <.001).MEFV gene variations were found 52 (35.9%) in patients and 29 (21.5%2) in controls.MEFV gene allele frequency was significantly higher in-patient group than control (p =.005).

Frequency of MEFV mutation and genotype-phenotype correlation in cases with dysmenorrhea.

AIM: We aimed to investigate the relation between mutations and polymorphisms playing roles in the onset of clinical findings of Familial Mediterranean Fever (FMF) and clinical phenotypic reflections manifesting with painful episodes, such as dysmenorrhea. MATERIAL AND METHODS: A total of 1000 female patients who had not responded well to non-steroidal anti-inflammatory drugs in the menstrual period, and who had presented to the emergency room with the complaint of recurrent pain episodes were included in the study. All the patients were Turkish women living in Istanbul. In this study, the mutations most frequently seen in the Mediterranean Fever Gene (MEFV), namely M694V, E148Q, M680I(G/C), V726A, P369S, R761H, A744S, M694I, K695R, F479L, M680I(G/A), and I692del were examined using the DNA sequence analysis following DNA isolation. RESULTS: The number of individuals who had a mutation in at least one allele for FMF was 511 out of 1000 patients. Of these 511 patients, homozygous mutations were found in 21% (n = 109), compound heterozygous mutations were found in 27% (n = 136), and heterozygous mutations were found in 52% (n = 266). The most frequent homozygous genotype seen in our study population was M694V/M694V. The most common compound heterozygote genotypes were M694V/M680I, M694V/V726A, M694V/E148Q, and M680I/V726A; and 11.7% (n = 60) of the families in whom mutations were found had consanguinity. CONCLUSION: Women who present to the emergency room with the complaint of dysmenorrhea that is irresponsive to non-steroidal anti-inflammatory drugs may have several types of MEFV mutations that are responsible for FMF.

Possible Association of Mutations in the MEFV Gene with the Intestinal Phenotype of Behçet's Disease and Refractoriness to Treatment.

BACKGROUND: 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. METHODS: 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. RESULTS: 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-1ß (IL-1ß) showed a high expression of IL-1ß only in injured areas, suggesting that IL-1ß may be involved in the formation of ulcers in patients with intestinal BD carrying MEFV gene mutations. CONCLUSION: Mutations in the MEFV gene may be associated with intestinal lesions of BD and refractoriness to treatment.

Autoinflammatory syndromes with coexisting variants in Mediterranean FeVer and other genes: Utility of multiple gene screening and the possible impact of gene dosage.

OBJECTIVE: To assess the possible impact conferred by co-existing variants in MEditerranean FeVer (MEFV) and other genes on systemic autoinflammatory disease (SAID) phenotype. METHODS: Consecutive patients (n = 42) who underwent screening for SAIDs by next generation sequencing (NGS) targeting 26 genes, and carried at least one MEFV gene variant, were retrospectively studied. A total of 63 MEFV gene variants mainly located in exon 10 (n = 29) and exon 2 (n = 19) were identified in 21 patients with juvenile- and 21 with adult-onset disease. RESULTS: The candidate clinical diagnosis was Familial Mediterranean Fever (FMF) in 11, polygenic SAIDs (PFAPA, Still's disease, atypical SAPHO and inflammatory bowel disease) in 9, whereas the disease could not be clinically defined in 22 patients. Notably, 33 out of the 42 patients (79%) had at least one co-existing variants in 19 genes other than MEFV. NGS confirmed all clinical diagnoses and helped defining diagnosis in 59% of the remaining cases. Patients with undefined SAIDs (n = 9) or atypical FMF phenotype (n = 12) carried significantly more disease-causing variants in genes other than MEFV compared to patients with typical FMF (n = 9). More than one variants in these genes were significantly associated with adult-onset disease, while disease-causing variants in the same genes were also associated with an overall more severe SAID phenotype. CONCLUSION: Co-existing variants in SAID-related genes may explain the phenotypic variability of these diseases. Further studies should validate combined molecular and clinical data in order to better understand the cumulative gene dosage effect and improve the classification of these patients.

Autoinflammatory disease: clinical perspectives and therapeutic strategies.

The molecular platforms of the innate immune system are essential to recognize pathologic external factors that are crucial to differentiate these danger signals from host motifs. A set of sensors recognizing pathologic factors is present and defined as a membrane-bound family of Toll-like receptors as well as the cytosolic ones including the family of nucleotide-binding domain leucine-rich repeat proteins. In this regard, the inflammasomes have been identified as an innate immune sensor toward pathologic external factors as well as endogenous damage-associated molecular pattern signals transducing from the above-mentioned receptors to gene expressions. Recent research has shown novel findings in inflammasome biology and genetics which lead to the alteration of diagnosis and management in autoinflammatory diseases as well as developing novel treatments, including the examples of nucleotide-binding domain leucine-rich repeat proteins-inflammasomes and pyrin-inflammasomes. The pyrin protein is encoded by the Mediterranean Fever gene on chromosome 16 that acts as a major regulatory component of the inflammasome, and is responsible for familial Mediterranean fever. We have recently examined the whole nucleotide sequence of the Mediterranean Fever gene in Japanese familial Mediterranean fever patients and revealed single nucleotide variants associated with the susceptibility of familial Mediterranean fever from a nation-wide survey by the next-generation sequencing. In a cytokine profile analysis of familial Mediterranean fever patients, we have found that interleukin-6 is considered to be one of the most crucial cytokines in familial Mediterranean fever attack since interleukin-6 had the best performance for distinguishing familial Mediterranean fever in attack from healthy controls or familial Mediterranean fever in remission, and in vitro interleukin-6 production is regulated by microRNAs-204-3p/phosphoinositide 3-kinase g pathway. Accordingly, we have been investigating the efficacy and safety of anti-human interleukin-6 receptor monoclonal antibody, tocilizumab, in patients with familial Mediterranean fever refractory or intolerant to colchicine through an investigator-initiated clinical trial supported by the Japan Agency for Medical Research and Development. Like interleukin-1b, interleukin-18 can be processed by caspase-1 and proteinase-3 to be activated within the inflammasomes. We have also found the importance of interleukin-18 in several autoinflammatory conditions. Recently, the concept of autoinflammation is widely distributed into many common diseases; thus, the attention to a wide spectrum of diseases MEFV gene deeply involved is required.

A recurrent side-changing febrile pleural effusion revealing familial Mediterranean fever: a case report.

Familial Mediterranean Fever (FMF), characterized by recurrent polyserositis, is an autosomal recessive disease involving essentially Mediterranean populations. We report the case of a 30-year-old Tunisian military patient complaining of fever and chest pain recurring on board a Navy military vessel, due to side-changing pleural effusion. On landing, a marked improvement of symptoms was noticed. Gene testing was performed when the diagnostic survey ruled out common etiologies, revealing a homozygous mutation of the FMF gene type M680l/M680l. The prescription of colchicine and the exemption from boarding led to the resolution of the symptoms with no recurrence of pleural effusion. Therefore, the diagnosis of FMF should be considered in a context of a recurrent pleural effusion in the youth, with a negative etiological assessment, notably in an ethnic group at risk. Thus, early diagnosis and adequate treatment may prevent the development of secondary amyloidosis, a serious complication of FMF.

Mediterranean fever gene variants and colchicine therapy in periodic fever, aphthous stomatitis pharyngitis, adenitis syndrome in a Mediterranean region.

OBJECTIVES: Periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome is characterized by recurrent episodes of fever. Attenuated disease severity was considered in patients with Mediterranean fever (MEFV) gene variations. Corticosteroids are highly effective in controlling the symptoms but usually cause more frequent episodes. Frequent fever episodes either initiated after the steroid therapy or as an initial disease characteristics are the most challenging feature. METHODS: Sixty-seven patients were prospectively followed from September 2015 to January 2018. MEFV variants were searched in all patients. Colchicine therapy was initiated in patients with MEFV variants and with shortened intervals after the initiation of steroid therapy. RESULTS: Heterozygous MEFV gene variants were detected in 23 patients (34.3%). Higher exon 10 allel frequencies were found in patients with frequent fever episodes. Among 26 patients with increased episodes, colchicine treatment decreased the number of the episodes in 8 of 10 (80%) and 4 of 16 (25%) patients with and without variants, respectively (p = 0.022). Fever duration decreased (3.26 ± 1.38 vs. 1.57 ± 0.57 days, p < 0.001) at the third month of therapy in variant(+) patients. CONCLUSION: In variant positive patients colchicine prophylaxis reduced the duration of attacks at the third months of therapy. Shortened intervals due to steroid therapy were increased at the sixth months of colchicine therapy.

Prevalence of Mediterranean FeVer Gene Mutations in Turkish Cypriot Population.

OBJECTIVES: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Retinal and Choroidal Thickness in Adult Patients with Familial Mediterranean Fever.

PURPOSE: We aimed to evaluate changes in retinal, choroidal, ganglion cell complex (GCC) and retinal nerve fiber layer (RNFL) thicknesses in genetically diagnosed adult patients with familial Mediterranean fever (FMF). METHODS: A total of 50 eyes of 50 genetically diagnosed patients with FMF and 50 eyes of controls were analyzed. Patients were recruited from the Genetic Diagnostic Center of Diskapi Yildirim Beyazit Research and Training Hospital, Turkey. Retinal and choroidal thicknesses were obtained using spectral-domain optical coherence tomography from choroid, retina, GCC, and RNFL. RESULTS: Average baseline choroidal thickness was statistically significantly thinner in patients with FMF than controls at Ccenter (325.85 ± 30.8 µm and 338.97 ± 23.9 µm, respectively, p = 0.038), Cnasal500 (328.77 ± 31.6 µm and 349.00 ± 23.3 µm, respectively, p = 0.002), Cnasal1000 (324.97 ± 33.6 µm and 351.23 ± 23.8 µm respectively, p = 0.0001) and Cnasal1500 (324.75 ± 37.1 µm and 344.61 ± 27.3 µm, respectively, p = 0.008). However, there was no significant difference in temporal choroidal thickness (Ctemporal500, Ctemporal1000 and Ctemporal1500) in patients with FMF compared to controls (p > 0.05). There were no significant differences in retinal, GCC and RNFL thicknesses between the groups (p > 0.05). CONCLUSION: We hypothesize that the chronic inflammation seen in FMF could be the reason for the reduction seen in choroidal thickness in adult patients with FMF. Retinal, GCC and RNFL thicknesses did not differ from controls.

Familial Mediterranean fever gene mutations as a risk factor for early coronary artery disease.

OBJECTIVE: Cardiovascular diseases (CVD) are very common in the general population. Atherosclerosis is the main pathogenesis. Familial Mediterranean fever (FMF) is an autosomal recessive disease. The gene causing FMF, designated MEFV, encodes a protein called pyrin or marenostrin that is expressed mainly in myeloid bone marrow precursors, neutrophils and monocytes. We herein aimed to determine the prevalence of MEFV mutations (all exon 2, 10 mutations) in patients with early coronary heart disease (early CHD) and coronary heart disease (CHD) with multiple risk factors and among the healthy subjects as controls. METHODS: A total of 197 patients and 119 healthy subjects were recruited and enrolled into three groups in terms of inclusion criteria. Ninety-one patients diagnosed with early CHD enrolled into group one (men < 45 years of age, women < 40 years of age), 106 patients with CHD (men > 50 years of age) to group two and 119 healthy controls enrolled into group three. None of patients was diagnosed with FMF. The diagnosis of CHD was established on electrocardiographic changes, echocardiography and coronary angiography. RESULTS: Thirty-eight patients (41.8%) with early CHD, 17 patients (16%) with CHD and 24 healthy controls (20.2%) carried at least one mutated MEFV allele. Young patients with CHD have different risk factor profiles, clinical presentations and prognoses than older patients. Young patients with CHD usually have multiple risk factors. CONCLUSION: This study suggests that MEFV mutations in early CHD patients had significantly increased in contrast to CHD patients and healthy controls.

Common MEFV gene mutations in Turkish patients with Behcet's disease.

Behcet's disease (BD) is a chronic systemic inflammatory disorder whose etiology has not been fully established yet. The MEditerranean FeVer (MEFV) gene has been identified as the cause of Familial Mediterranean Fever (FMF). BD shows similarities with FMF, in terms of clinical findings and treatments, as well as their geographical and ethnic co-occurrence. In this study we investigated common MEFV gene mutation frequencies in Turkish patients with BD in an area of Turkey where both diseases are frequently encountered. We screened 207 BD patients who had no symptoms and family history for FMF and 200 healthy subjects for five common MEFV gene mutations (E148Q, M680I, M694V, V726A, P369S) and clinical features. Seventy-five patients were found to carry a single MEFV mutation, and six patients were compound heterozygous. The difference in the frequency of the MEFV mutation between the BD and control groups was statistically significant (p<0.001, odds ratio [OR] 2.74, 95% confidence interval [CI] 1.75-4.29). The frequencies of E148Q and M680I mutations were significantly higher in the BD group (p=0.001, p=0.046, respectively). The frequency of uveitis was significantly lower in patients with the mutation than in patients without the mutation (p=0.029, OR 0.54, 95% CI 0.30-0.98). There was no statistical significance between carriers and non-carriers with respect to gender and other manifestations of BD. The frequency of the MEFV mutation was significantly higher in patients with BD compared to the healthy control group. Based on our results, MEFV mutations appear to have a role in the pathogenesis of BD.