Familial Mediterranean Fever Gene Mutations Research Articles

Frequency of Familial Mediterranean Fever Gene Mutation in Patients Presenting With Joint Pain and Diagnosed With Acute Rheumatic Fever.

Introduction Acute rheumatic fever (ARF) is a non-suppurative systemic inflammatory disease that manifests 1-5 weeks following a Group A beta-hemolytic streptococcal infection. On the other hand, familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized as an autosomal recessive disease, with affected individuals having pathogenic mutations in the Mediterranean fever gene(MEFV)gene located on the short arm of chromosome 16. FMF and ARF have overlapping symptoms and signs, and both disorders are common in Turkey. In ARF, the target organ is the heart, while in FMF, the target organ is the kidney; both organs can benefit from prophylactic measures. Our study aims to determine the frequency of the FMF gene mutation in patients with ARF in Turkey and detect any overlapping conditions. Method Patients who were diagnosed with a first-attack ARF between May 2015 and May 2018 were retrospectively screened. Patients who underwent MEFV gene analysis considering FMF in the differential diagnosis were included in the study. Results In this study, no statistical difference was found between the presence of MEFV gene mutations, carditis, high anti-streptolysin-O antibody (ASO) levels, and the groups with monoarthritis, polyarthritis, and polyarthralgia (p >0.05). Conclusions In conclusion, patients with ARF should be evaluated for FMF to avoid irreversible complications.

POST COVID RECURRENT FEVER IN A CHILD WITH GENETIC SUSCEPTIBILITY TO FAMILIAL MEDITERRANEAN FEVER

<h3>Introduction</h3> Children and adults with post-acute sequelae of COVID (PASC) sometimes report recurrent fevers. We present the case of 13-year-old male with PASC recurrent fever who was found to have a heterozygous mutation in the gene associated with Familial Mediterranean fever (FMF). <h3>Case Description</h3> Our patient presented with recurrent fever 6 months after acute SARs-CoV-2 infection in January 2022. He endorsed prior episodes of unexplained fever and flushing prior but his recurrent fevers (39 C) post COVID had become more frequent occurring every few days. Laboratory analysis when he was afebrile demonstrated normal serum ESR, CRP, and CMP and normal cytokine levels. Genetic (In-Vitae) panel testing for autoinflammatory syndromes revealed a pathogenic heterozygous missense mutation in MEFV (p.A744S), the gene that controls pyrin production. A trial of colchicine was recommended, and he was referred to pediatric rheumatology. <h3>Discussion</h3> FMF is a genetic disorder that causes recurrent episodes of fever and almost always presents before age 20. Clinically significant FMF gene mutations lead to poorly functional pyrin; a protein that controls inflammation. Most children look and feel well between episodes but some children have such frequent episodes that they do not fully recover. In such cases, daily use of Colchicine should be considered as a safe and effective medication to control fever episodes. This report highlights the utility of genetic testing to identify potential causes of recurrent fever after COVID. Children with PASC related recurrent fevers should have genetic testing for susceptibility to FEF as this is a potentially treatable condition.

The frequency of fibromyalgia in familial Mediterranean fever and its impact on the quality of life.

Concomitant fibromyalgia syndrome (FMS) has been known to be more frequent in patients with several rheumatic diseases. In this study, our aim was to investigate the prevalence of FMS in patients with familial Mediterranean fever (FMF), to analyze the possible factors related to this frequency, and to evaluate the impact of FMS on the functionality and quality of life (QoL) of the patients with FMF. One hundred cases with FMF and 100 controls were included to this case-control study. FMS coincidence was investigated in all participants according to revised 2016 classification criteria. Demographic features, FMF disease duration, FMF gene mutations, drugs used, attack frequency per year, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum fibrinogen levels were recorded. FMF disease severity was assessed by International Severity Scoring System for Familial Mediterranean Fever (ISSF). For the assessments of QoL and functioning, FMF-QoL, Short form 36 (SF-36), and Health Assessment Questionnaire-Disability Index (HAQ-DI) were used, and for the assessment of FMS impact, the fibromyalgia impact questionnaire (FIQ) were used. We found an FMS frequency of 33% in patients with FMF in our study using the current FMS classification criteria. This result was significantly higher than in age- and gender-similar controls (6% FMS frequency; P < 0.05). The number of woman patients and FMF disease duration were significantly higher in patients with FMF + FMS than in patients with only FMF (P < 0.001). There was no significant difference in ISSF scores, ESR, CRP, and fibrinogen levels, management regimens, and FMF gene mutation distributions between FMF + FMS and FMF groups. FMF attack frequency was reported as significantly higher in FMF + FMS patients than in others (P < 0.000). In spite of similar FMF-QoL scores, there were significant differences in HAQ-DI and SF-36 scores between groups (P < 0.05). Higher impact of FMS presented negative correlation with functioning and general health, and positive correlation with QoL in FMF + FMS (P < 0.05). Concomitant FMS was a common clinical problem in patients with FMF regardless of the severity and characteristics of FMF. The FMS impact may affect function and QoL in patients of FMF. Considerations of the FMS component in the management of FMF may contribute to the holistic approach to FMF.

Ultrasound Measurement of Femoral Cartilage Thickness in Patients with Familial Mediterranean Fever and its Relation to Amyloidosis and Other Disease Characteristics.

This study aimed to determine femoral cartilage thickness (FCT) in patients with familial Mediterranean fever (FMF) and healthy individuals and to assess the relationship of FCT with the development of amyloidosis and clinical features. Patients diagnosed with FMF according to the Tel-Hashomer criteria and healthy controls were included in the study. FCT of both knees was measured with a 7-12 MHz linear probe in maximum knee flexion. Three midpoint measurements were obtained from each knee: Lateral femoral condyle (LFC), intercondylar area (ICA), and medial femoral condyle (MFC). The patients' clinic characteristics include disease duration, medications, comorbid conditions, amyloidosis, chronic renal failure (CRF), FMF gene mutation, arthritis, sacroiliitis, PRAS score, and Physical Activity Questionnaire Short Form score were recorded. A total of 46 patients with FMF (36 women) and 20 age-sex-body mass index-matched controls (14 women) were enrolled in this study. The patients and controls' mean age were 37±12.9 and 37.5±8.6 years, respectively. Amyloidosis occurred in 7 patients (15.2%), CRF in 3 (6.5%), and knee arthritis in 8 (17%). Disease activity was mild in 55.8%, moderate in 20.9%, and severe in 23.23% of the patients. The mean FCT in millimeter values in the FMF and control groups was as follows: On the right side, LFC 1.9±0.5 and 2±0.52, ICA 2.2±0.77 and 2.25±0.97, and MFC 2±0.47 and 2.25±0.72; on the left side, LFC 1.9±0.4 and 2.05±0.55, ICA 2.25±0.87 and 2.25±0.87, and MFC 1.85±0.5 and 2.25±0.6. Patients with FMF had decreased cartilage thickness at the lateral condyle of both knees (p<0.05) and medial condyle of the left knee (p<0.05) compared with controls. FCT measurements were similar in patients with or without arthritis, amyloidosis, and CRF (p>0.05). FCT scores were not different among the disease activity groups (p>0.05). These findings suggest that patients with FMF have decreased FCT compared with controls, and there is no significant relationship between the FCT and amyloidosis and disease activity.

POS1359 REGIONAL DIFFERENCES IN DISEASE CHARACTERISTICS OF FAMILIAL MEDITERRANEAN FEVER IN TURKEY: PRELIMINARY REPORT

Background:Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease accompanied by recurrent attacks of fever and serositis. It is prevalent among Mediterranean populations, mainly Turks, Armenians; Jews and Arabs. As genetic factors are variable in the population, environmental factors can also affect phenotypic characteristics.Objectives:This study aimed to determine the geographic differences in disease characteristics and burden in patients with FMF in Turkey.Methods:Patients diagnosed with FMF according to the Tel-Hashomer criteria were included in this multi-center study. Patients were included from the different regions of Turkey. Demographic features and clinic characteristics of the patients including disease duration, medications, comorbid conditions, attack characteristics, amyloidosis, acute phase reactants, FMF gene mutations, arthritis, sacroiliitis, and febrile myalgia were recorded. PRASS disease activity score, FMF-QoL, HAD, and HAQ were assessed. Patients from different parts of Turkey were divided into 3 groups the Central Anatolia, Western, and Eastern. Disease activity, characteristics and burden were also investigated among 3 distinct geographic regions.Results:A total of 281 patients with FMF (195 women, 86 men) were enrolled in this study. The mean age of the patients was 34.9 (SD:12.3) years. While the patients in the eastern areas of Turkey were diagnosed earlier age (p&lt;0.001), the patients in the western area had a longer diagnostic delay time (p&lt;0.001). Patients enrolled from western regions tended to have higher ESR and PRASS scores than those from eastern and central Anatolian regions, but attack numbers per 6 months were similar among the regions. The highest proportion of patients who were M694V/M694V homozygous patients were in western, and then eastern and central Anatolia (19.5%, 18%, and 5.4%). While fever and arthritis were more common in the eastern, pleuritis and sacroiliitis were more common in the central anatolia. Peritonitis and erysipelas like erythema rates were similar among the regions. The majority of patients were receiving colchicine treatment in all three regions. FMF-QoL scores were highest in the eastern and lowest in the western (p=0.006). Patients enrolled in the central Anatolia region experienced more functional disability than those from the western and eastern regions (p=0.009). Anxiety and depression scores were similar between groups (p=0.385 vs p=0.549).Conclusion:These findings suggest that patients with FMF have diversity concerning the age at diagnosis, diagnostic delay time, disease activity, quality of life, and functional disability among the 3 regions. In the genotypic analysis, the M694V mutation is the most common pathogenic mutation in all regions. Regional genetic and environmental varieties may explain the areal differences. These relationships can occur more clearly in larger patient populations.

Endoplasmic Reticulum Aminopeptidase-1 (ERAP-1) Mutations in People with Familial Mediterranean Fever (FMF) Gene Mutations Without Disease

Endoplasmic Reticulum Aminopeptidase-1 (ERAP-1) Mutations in People with Familial Mediterranean Fever (FMF) Gene Mutations Without Disease

Comment on: The conundrum of juvenile spondyloarthritis classification: Many names for a single disease? Lesson learned from an instructive clinical case

Dear Editor, We read with great interest the paper titled “The conundrum of juvenile spondyloarthritis classification: Many names for a single disease? Lesson learned from an instructive clinical case” by Maniscalco et al1 which emphasizes the complexity of the clinical phenotypes of juvenile spondyloarthropathies (JSpA). All pediatric rheumatologists face these evolving phenotypes of these groups of diseases in their daily practice. To handle these classificational dilemmas, several classification criteria have been proposed for JSpA.2-4 The most recent one, International League of Associations for Rheumatology (ILAR) classification criteria for juvenile idiopathic arthritis (JIA), does not mentioned JSpA as a discrete subgroup and classifies these groups of diseases under three main groups: enthesitis-related arthritis, psoriatic arthritis and undifferentiated arthritis.2 The main concerns about these criteria are: the certain phenotypes of JSpA like inflammatory bowel disease-related arthritis, reactive arthritis were not included in these criteria, and some of the patients are classified as undifferentiated arthritis because of patients fulfilling two subtypes of JIA. It is obvious that these classification criteria are insufficient to reflect all phenotypes of JSpA and there is apparently a need for new sets of criteria.5 The nomenclature for juvenile spondyloarthropathies is not well-defined and still remains enigmatic. This term mainly encompasses enthesitis-related arthritis, psoriatic arthritis, juvenile ankylosing spondylitis, inflammatory bowel disease-related arthritis and reactive arthritis.6, 7 Contrary to adult SpA, JSpA rarely involves the axial skeleton in the early stages of the disease and it usually presents with asymmetric oligoarthritis of lower extremity joints and enthesitis. Therefore, enthesitis-related arthritis can be seen as an early presentation of JSpA. In addition to mentioned diseases, it is also shown that clinical features of JSpA can be seen in the course of familial Mediterranean fever (FMF) and Mediterranean fever gene mutation may be a susceptibility factor for enthesitis-related arthritis especially in regions endemic for FMF.8 In our cohort of patients with FMF, 10.2% of children also fulfilled classification criteria for JSpA.8 Moreover, chronic recurrent multifocal osteomyelitis (CRMO) was suggested to be an unusual form of SpA by several authors and Vittecoq et al9 showed that some of the patients with CRMO developed SpA. The insightful report by Maniscalco et al1 also supports this perspective. In adult patients, rheumatoid arthritis which is the most common cause of adult chronic arthritis and ankylosing spondylitis are well-defined as two distinct phenotypes and both of them have highly accepted classification criteria. In contrast, JSpA is considered under the JIA umbrella in ILAR classification criteria. Yet, this classification criteria obviously are not sufficient to cover this broad spectrum of JSpA (the reasons mentioned above). It is difficult to distinguish between oligoarticular JIA and JSpA especially in the early stages of disease and pediatric rheumatology societies should focus on establishing clearer definitions for JIA and JSpA and developing the new classification criteria which cover all frameworks of JSpA as a distinct disease. We think this approach will not only provide expanded covering but also, better understanding between pediatric and adult rheumatologists. No author of this paper has a conflict of interest, including specific financial interests, relationships and/or affiliations relevant to the subject matter or materials included.

The Frequency of Familial Mediterranean Fever Gene Mutations and the Correlations between Phenotype and Genotype in Turkish Children

Aim: Familial Mediterranian Fever is an autosomal recessive disease characterized by recurrent inflammatory attacks of serosal membranes. The aim of the current study was to determine the frequency of the Mediterranean fever (MEFV) gene pathogenic variants in 158 children (78 male, 80 female) diagnosed with Familial Mediterranean Fever (FMF) and to compare the phenotype-genotype correlation.&#x0D; Methods: In our retrospective case-control study, 158 FMF patients (78 males, 80 females) who were diagnosed with MEFV gene mutation in Bursa Yuksek Ihtisas Training and Research Hospital, Department of Pediatrics between January 2018 and June 2019 were included in the study. Mutation screening of the MEFV gene was performed for 12 mutations and the 8 most common mutations were taken into the study.&#x0D; Results: Abdominal pain (77.8%), fever (74%) and arthralgia (46.2%) were the most prevalent clinical features in our patients. The most frequent mutations were M694V, E148Q, V726A, M680I and P369S. In cases with M694 mutation, it was noted that the incidence of arthritis was 2.5 times, appendectomy frequency 3.1 times higher, and early diagnosis probability 3.2 times higher. The frequency of chest pain was 2.9 times higher in the M680I mutation, and the frequency of arthralgia was 2.2 times higher in the P369S mutation.&#x0D; Conclusion: Patient’s mutations in FMF patients are important for clinical expectations, and some mutations such as P369S are not as innocent as expected. However, reevaluation of phenotypes of mutations that are rare with more patients will be significant.

Kawasaki disease and familial mediterranean fever gene mutations, is there any link?

Background and aim: Kawasaki disease (KD) is an acute febrile, self-limiting, and systemic vasculitis of unknown etiology. MEFV gene has a major role in autoinflammatory disorders and innate immune reactions. Several reports revealed that MEFV gene mutations are associated with systemic vasculitis. The aim of this study was to determine the association between KD and MEFV gene mutations.Methods: The peripheral blood of 30 patients who were diagnosed with KD based on ACC criteria and 224 healthy people as a control group (113 male and 111 female), were collected and the samples screened for the 12 common pathogenic variants according to manufacturer’s instructions.Results: The mean age of patients (13 females and 17 males) was 7.7 years. Ten percent of patients showed a mutation, that was meaningfully (p<0.05%) lower than that of healthy controls (25%). E148Q was shown in two patients and compound heterozygous (E148Q-M680I) was detected in one of them with lack of FMF presentations. No significant and meaningful associations were detected between the MEFV gene variant alleles and KD.Conclusion: Unlike in other types of pediatric vasculitis, this study did not reveal any significant association between the MEFV gene mutations and KD, moreover, because of the lower frequency of mutations in these patients, it seems that this gene has a modifier and/or protective role in KD.

Familial Mediterranean Fever Gene Mutations and Gout as an Auto-Inflammatory Arthropathy.

Introduction:The auto-inflammatory diseases (AID) are a heterogeneous group of multi-system disorders of innate immunity dysregulation. MEFV gene has major role in AID.Aim:The aim of this study is to investigate the frequency of MEFV variant alleles in gout patients as an AID and their genotype-phenotype relationship.Methods:Total amount of 224 of the healthy people as a control group (113 male and 111 female) and 24 gouty arthritis patients (20 male and 4 female) entered this study. Blood samples screened for the 12 common pathogenic mutations according to manufacturer’s instructions.Results:The mean age of patients was 54 years. MTP joint was the most involved joint (91.66%). Mutations were shown in 5 patients (20.83%) that were not different from healthy population (25%). Five patients carry one mutated MEFV allele, E148Q in 4 patients and V726A in 1 patient. Control group showed 25% mutations as E148Q (18.3%), P369S (3.1%), V726A (2.2%), A744S (1.3%) respectively. The most common mutation detected in patients was E148Q (16.66%) and all of them were males. No significant and meaningful associations were detected between the MEFV gene mutations and gouty arthritis patients.Conclusion:There was not any correlation between MEFV gene mutations carriage with age, sex, the number of joint involvement and the course of disease in gouty arthritis. MEFV gene mutations were more frequent in men than women, but this is not statistically significant.

Macular and choroidal thickness of children with Familial Mediterranean Fever gene mutation

Introduction: The present study aimed to evaluate macular and choroidal thicknesses in children with MEFV gene mutations.Methods: Thirty-five children with MEFV gene mutations and 40 healthy controls were included in the study. MEFV gene profiles for the current cohort were genotyped by Pyrosequencing and direct Sanger sequencing techniques. The thicknesses of the macular and choroid of each subject’s right eye were measured using spectral-domain optic coherence tomography.Results: Mean arteriolar and venular diameters were 95.75±11.98 µm and 127.61±10.44 µm in children with the MEFV gene mutations and 110.19±11.10 µm and 138.54±10.04 µm in control group respectively. Children with the MEFV gene mutations were found to have a significantly less mean arteriolar diameter (p&amp;lt;0.001), mean venular diameter (p&amp;lt;0.001), less macular thickness (p=0.016), and less choroidal thickness (p=0.014) compared to healthy controls. Conclusion: Children with the MEFV gene mutations had narrowing of the retinal arterioles, retinal venules, and macular and choroidal thinning. Future studies should aim to investigate endothelial dysfunction in children with Familial Mediterranean Fever by non-invasive and effective methods.

The spectrum of Familial Mediterranean Fever gene (MEFV) mutations and genotypes in Iran, and report of a novel missense variant (R204H)

BackgroundFamilial Mediterranean Fever (FMF) is an autosomal recessive disorder, characterized by recurrent and self-limited episodes of fever, abdominal pain, synovitis and pleuritis. FMF as the most common inherited monogenic autoinflammatory disease mainly affects ethnic groups of the Mediterranean basin, Arab, Jewish, Turkish, Armenian North Africans and Arabic descent. Materials and methodsIn the present study, we selected 390 unrelated FMF patients according to the Tel-Hashomer criteria, and analyzed all patients for 12 most common mutations of MEFV gene by reverse hybridization assay (FMF strip assay). We also investigated exon 2 and 10 of MEFV gene in 78 patients by Sanger sequencing. ResultsAccording to strip assay results, at least one mutation was found in 234 patients (60%), and no mutation was found in other 156 patients (40%). The five most common mutations and allelic frequencies were M694V (13.6%), E148Q (10.4%), M694I (6.5%), V726A (4.1%), and M680I (3.8%). Moreover, we detected a novel missense variant (R204H, c.611 G > A) (SCV000297822) and following rare mutations among sequenced samples; R202Q, P115T, G304R, and E230K. ConclusionThis study describes the MEFV mutations spectrum and distribution in Iranian population, and shows different mutation patterns among Iranian ethnicities. Moreover, M694V is the most common MEFV mutation in Iran.

Comparing D-dimer status in children with familial Mediterranean fever during and in between acute attacks

Aim of the workTo compare the D-dimer status in children with familial Mediterranean fever (FMF) during, and in between acute attacks. Patients and methodsThe study included 50 children with FMF classified into group I (15 patients during acute attack) and group II (35 patients during attack free period) as well as and 20 matched controls. D-dimer was determined in all study population. Pattern and type of FMF gene mutation were reported from patients’ files. ResultsThe mean age of the patients was 8.7±2.8years, disease duration 4.4±2.5years and they were 28 males:22 females (1.3:1). In group I, the erythrocyte sedimentation rate (48.5±28.6mm/1st h) and aspartate transaminase (28.5±5U/L) were significantly increased compared to group II (26.6±14.7mm/1st h and 25.7±2.7U/L; p=0.012 and p=0.014 respectively). Positive D-dimer was significantly reported in 72% of FMF patients compared with 35% of control (p=0.006). There was significant difference between frequency of positive D-dimer in group I (86.7%) and group II (65.7%) compared to (35%) in control (p=0.005 and p=0.048, respectively), without a significant difference in D-dimer frequency between group I and group II patients (p=0.18). Fever and abdominal pain were significantly more frequent in patients with positive (100% and 97.2%) compared to negative D-dimer (78.6% and 71.4%) (p=0.02). No significant association was found between positive D-dimer and specific types of MEFV gene mutation. ConclusionD-dimer was significantly positive in FMF patients compared to control. These results raise the possibility of thrombosis in FMF patients regardless the presence or absence of acute attack.

Secret Underlying Unexplained Abdominal Pain, Neurological Symptoms and Intermittent Hypertension: Acute Intermittent Porphyria

Abstract A 21-year-old female patient with abdominal pain, vomiting and constipation was admitted to the hospital with the possible diagnosis of diabetic ketoacidosis. Due to increased abdominal pain and constipation the patient underwent a surgery with the diagnosis of ileus. However, no pathological findings were found in the abdominal organs apart from serous fluid in the abdominal cavity. The patient became hypertensive, tachycardic and had an episode of seizures postoperatively. Neurological manifestations with unexplained abdominal pain indicated a diagnosis of acute intermittent porphyria (AIP). Acute intermittent porphyria diagnosis is based on elevated urinary δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels as well as hydroxymethylbilane synthase (HMBS) IVS13-2 A&gt;G heterozygous mutation. Familial Mediterranean Fever (FMF) gene mutations were not confirmed. Porphyria should be considered in the differential diagnosis of patients with recurrent abdominal pain, neurological symptoms and lack of FMF gene polymorphism.

Frequency of familial Mediterranean fever (MEFV) gene mutations in patients with biopsy-proven primary glomerulonephritis.

Primary glomerulopathies are those disorders that affect glomerular structure, function, or both in the absence of a multisystem disorder. We aimed to evaluate the frequency of MEFV gene mutation to show possible coexistence of FMF in patients diagnosed with biopsy-proven primary glomerulonephritis (GN). A total of 64 patients with biopsy-proven primary GN were included in the study. MEFV gene mutations examined retrospectively. The mean age of patients was 39.6±13.4 (range 18-69), 35 of patients were female and 29 of patients were male. Of the 64 patients, 17 were mesangial proliferative glomerulonephritis (MsPGN), 15 were IgA nephropathy (IgAN), 12 were membranous glomerulonephritis (MGN), 11 were focal segmental glomerulosclerosis (FSGS), three were membranous proliferative glomerulonephritis (MPGN), three were immune complex glomerulonephritis (ICGN), two were minimal change disease (MCD), and one was IgM nephropathy (IgMN). MEFV gene mutation was detected in 35.9% (23) of these patients. The most frequently detected mutations were E148Q and M694V. Twelve cases (18.75% of GN patients) with MEFV gene mutation were diagnosed as FMF phenotype I. The frequency of MEFV gene mutation was detected at a high rate of 35.9%. Further studies with larger populations are needed to clarify the importance of these mutations on clinical progression of glomerulonephritis.

Could familial Mediterranean fever gene mutations be related to PFAPA syndrome?

The cause and pathophysiology of PFAPA syndrome is unknown. The aim of this study was to determine all MEFV gene variants relevant to familial Mediterranean fever in children with PFAPA syndrome. All MEFV gene variants were analyzed in patients with PFAPA syndrome. All patients were evaluated using the Gaslini scoring system. Serum immunoglobulin levels were also determined upon admission. We evaluated 64 patients with PFAPA syndrome. The median age at diagnosis was 37.5 (min-max: 6-96) months, and the percentage of male patients was 55.0%. The Gaslini diagnostic score for periodic fever was high in 81.0% of the patients. An MEFV gene mutation was found in 42 (66.0%) children. Mostly, heterozygous or compound heterozygous variants of the MEFV gene were found. Two patients were homozygous for R202Q. MEFV gene mutations were not detected in 22 (34.0%) patients. No significant differences in clinical or laboratory findings were observed between the two groups (p > 0.05), and there were no significant differences in period and duration of the fever episodes (p > 0.05). The fever of all 47 patients (100.0%) who received prednisolone during the episodes decreased within hours and did not recur. Eighteen of the patients using prednisolone underwent prophylaxis with colchicine, and the fever episodes of 9/18 (50.0%) patients using colchicine decreased within months. Most patients presenting with PFAPA syndrome have heterozygous MEFV gene mutations. Whether carrying a heterozygous MEFV gene is the primary cause of this syndrome requires further investigation.

Familial Mediterranean fever gene mutations in north-eastern part of Anatolia with special respect to rare mutations

We aimed to determine the frequency of mutations, carrier rates and the association of rare mutations with Familial Mediterranean Fever (FMF) symptoms. There is a need to evaluate as many different populations as possible in order to determine either specific rare mutations or a range of disease-associated mutations. The demographic data and FMF symptoms related to MEFV gene mutations were collected from 731 participants. Exon 2 and exon 10 of the MEFV gene were tested by DNA sequencing. The rare mutations were identified as: M694I (1.1%, n=12), E148V (0.6%, n=6), T267I (0.5%, n=5), L110P (0.2%, n=2), E167D (0.2%, n=2), K695R (0.1%, n=1) and an insertion G (Guanine) mutation (0.4%, n=4) at the 777th codon of exon 10. We used routine comprehensive detection systems such as Sanger sequence that can catch rare mutations, for definite diagnosis and treatment of FMF disease.

Biopsy Proven Non-Amyloid Glomerular Diseases in Patients With Familial Mediterranean Fever

AIM: Kidney involvement is the most serious organ involvement of Familial Mediterranean Fever (FMF), while the most common cause is AA type amyloidosis with serum amyloid AA deposition. However, vasculitis and other types of glomerulonephritis (GN) also have been reported. With this study we evaluated biopsy proven non-amyloid glomerular diseases in patients with FMF. Methods: At our Nephrology clinic, total 950 patients followed by diagnosis of FMF have been evaluated. Nine patients who had positive proteinuria ( >500 mg/day) but had negative amyloidosis in the tissue biopsy were made renal biopsy. Results: Nine patients underwent a renal biopsy, two patients were found to have IgA nephropathy (IGAN), three mesangioproliferative glomerulonephritis (MsPGN), three membranous glomerulonephritis (MGN) and one had immune complex glomerulonephritis. Two patients with IGAN and one patient with MGN with non-nephrotic proteinuria exhibited significant improvement with colchicine and angiotensin receptor blocker (ARB) therapy. Other patients were treated with colchicine, an ARB and immunosuppressive drugs. Upon evaluation for the FMF gene mutation, different mutations have been found for the same glomerulonephritis type. Conclusions: Other glomerular causes also must be investigated alongside amyloidosis in the case of kidney involvement in FMF patients. While patients with IGAN and other glomerulonephrities with non-nephrotic proteinuria can respond well to colchicine treatment, patients with more aggressive kidney involvement may require immunosuppressive therapy. Further studies are needed for revealing the relationship between FMF gene mutation and non-amyloid glomerular diseases.

Familial Mediterranean fever gene (MEFV) mutations and disease severity in systemic lupus erythematosus (SLE): implications for the role of the E148Q MEFV allele in inflammation.

Observed low prevalence of SLE among familial Mediterranean fever (FMF) patients in several large cohorts suggests a possible protective effect of the MEFV mutations from SLE. In contrast, SLE patient carriers for the common MEFV mutations had rather complex disease expression with an increased frequency of febrile episodes and pleurisy and a decreased renal complication rate. Our aim was to investigate the prevalence of MEFV gene mutations in patients with SLE and their effect on organ involvement in a well-defined group of biopsy-proven SLE nephritis patients. The prevalence of four MEFV gene mutations (M694V, M680I, V726A and E148Q) was investigated in 114 SLE patients and effect on disease severity was analyzed in patients with biopsy-proven SLE nephritis. None of the SLE patients fulfilled the revised Tel-Hashomer criteria. Fourteen of 114 SLE patients (12.2%) were found to carry at least one MEFV mutation. A single patient in the SLE-Nephritis group was compound heterozygous for M694V/M680I mutations and only one patient in the SLE-Mild group was homozygous for E148Q mutation. Carrier frequency was similar to controls in SLE patients (12.2 vs 18.8%, p = 0.34). After the exclusion of the less penetrant E148Q mutation, re-analysis revealed an association between exon 10 mutations and SLE nephritis (p = 0.050, odds ratio (OR) = 4.16, 95% confidence interval (CI) = 1.04-16.6). Carrier rate for the E148Q mutation decreased in the SLE group (controls vs. SLE = 20/186 vs. 3/114, p = 0.08) and E148Q mutation was absent in SLE nephritis (controls vs. SLE nephritis = 20/186 vs. 0/47, p = 0.016, OR = 11.69, 95% CI = 0.69-197.13). Carrier rate for the studied MEFV mutations was slightly lower in the SLE group, which is in agreement with previous observations that FMF may confer some protection from SLE. Exon 10 mutations were associated with SLE nephritis after the exclusion of the E148Q mutation. The significance of the E148Q as a disease-causing mutation is controversial, and whether E148Q substitution is a polymorphism generally affecting inflammatory pathways is not addressed in the current literature. In this regard, absence of the E148Q mutation in SLE nephritis may serve as a clue for further investigation into its role as a general modulatory polymorphism for inflammation. This clarification is necessary to conclude whether other more penetrant MEFV gene mutations confer susceptibility to nephritis in SLE.

A study of familial Mediterranean Fever (MEFV) gene mutations in Egyptian children with type 1 diabetes mellitus

Background/AimsAn association of type 1 DM and familial Mediterranean fever (FMF) has been newly reported in the medical literature. The aim of the present work was to investigate frequency of MEFV gene mutations in Egyptian children with type 1 diabetes mellitus. MethodsForty five children with type 1 DM were screened for Mediterranean Fever (MEFV) gene mutation. Forty one healthy control subjects were included. Identification of FMF gene mutation was done based on polymerase chain reaction (PCR) and reverse hybridization. The assay covers 12 mutations in the FMF gene: E148Q – P369S – F479L – M680I (G/C) – M680I (G/A) – I692del – M694V – M694I – K695R–V726A – A744S and R761H. ResultsAmong the screened diabetics, the overall frequency of MEFV gene mutations was 42.2% and among the control group it was 34.1% with no significant difference. Fourteen out of 45 diabetic children (31.1%) were heterozygous (E148Q in 7 children, A744S in 3 children, V726A in 2 children, M680I (G/C) in 1 child and P369S in1 child), while 5 children (11.1%) were compound heterozygous (M694V/M694I in 2 children, E148Q/K695R mutations in 1 child, E148Q/M694I in 1 child and E148Q/V726A in 1 child). The control group showed heterozygous mutation in 34.1% of cases (E148Q mutation in 14.6%, V726A in 12.2%, M680I (G/C) in 4.9% and M694V in 2.4%). ConclusionNo significant difference in mutation frequency between diabetic and non-diabetic children. We have high carrier rate of MEFV gene mutations among Egyptian population probably due to high consanguinity.