scholarly journals Spectrum of Mutations of Familial Mediterranean Fever Gene by Whole Sequencing Method in Iranian Patients

2021 ◽  
Vol 3 (2) ◽  
Author(s):  
Helal Nemat Farahzadi ◽  
Mohammad Taghi Akbari ◽  
Reza Shiari ◽  
Shohre Zare Karizi ◽  
Shirin Farivar
Keyword(s):  
Familial Mediterranean Fever ◽  
Age Of Onset ◽  
Periodic Fever ◽  
Mefv Gene ◽  
Western Mediterranean ◽  
Compound Heterozygous ◽  
Mediterranean Population ◽  
Pathogenic Mutations ◽  
Sequencing Method ◽  
Mediterranean Fever

Background: Familial Mediterranean fever (FMF) is the most common type of periodic fever syndrome. The disease is most prevalent in the western Mediterranean population, but today it is widespread in the world due to the large ethnic migrations of Turks, Jews, Arabs and Armenians. The MEFV gene is the only gene known to be associated with the disease. Objectives: The aim of this study was to characterize pathogenic mutations in patients with typical FMF symptoms by sequencing the entire MEFV gene. Methods: This is a descriptive-analytical study that was performed during ten years from 2009 to 2019. On 252 patients after clinical diagnosis based on existing criteria to determine mutations referred to Tehran Medical Genetics Laboratory and the whole sequencing method for MEFV gene was used to determine mutations. Results: Out of 252 patients, 143 (56.7%) had pathogenic variants, and 109 (43.3%) had no variants reported as pathogenic mutations. Variants were identified as fallow: (1) 8.7% as homozygous; (2) 22.2% as compound heterozygous; (3) 25.7% as heterozygous. The most common variants were M694V (c.2080A > G) and E148Q (c.442G > C). Conclusions: This study showed that the age of onset of the disease was in the first and second decades of life amongst our patients and the most common complaints of patients were periodic fever and abdominal pain. The most frequent allele was M694V (c.2080A > G) followed by E148Q (c.442G > C) allele.

scholarly journals POS1302 THE MUSCULOSKELETAL SYSTEM MANIFESTATIONS IN CHILDREN WITH FAMILIAL MEDITERRANEAN FEVER

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 933.1-933
Author(s):  
F. Demir ◽  
S. Canbek ◽  
B. Sözeri
Keyword(s):  
Familial Mediterranean Fever ◽  
Periodic Fever ◽  
Mefv Gene ◽  
Clinical Manifestations ◽  
Musculoskeletal Symptoms ◽  
Compound Heterozygous ◽  
M694v Mutation ◽  
Musculoskeletal Manifestations ◽  
Mediterranean Fever ◽  
Calf Pain

Background:Familial Mediterranean fever (FMF) is a monogenic inherited periodic fever syndrome presenting with episodes of self-limiting fever and inflammation of serosal membranes. The attacks emerge with arthritis were defined as one of the major diagnostic criteria besides involvement of serosal membranes. Non-specific musculoskeletal findings such as myalgia, arthralgia, transient synovitis, and more rare manifestations like protracted febrile myalgia can also be seen in FMF patients attacksObjectives:We aim to reveal the frequency and genotype association of musculoskeletal manifestations in children with FMF.Methods:The patients diagnosed with FMF between January 1, 2017 and June 1, 2019, and followed for at least 6 months in our pediatric rheumatology clinic were included in the study. Musculoskeletal manifestations of patients were enrolled. The patients were grouped according to the “Mediterranean Fever” (MEFV) gene variants. Musculoskeletal manifestations of the patients were compared between the groupsResults:The study group included 634 children with FMF (336 female and 298 male, F/M: 1.13/1). The clinical manifestations of patients in attack period were as follows: 99% of the patients had fever, 87.3% had abdominal pain, 20.7% had chest pain, 11.3% had vomiting, 10.7% had erysipelas like erythema, and 9.3% had headache. The musculoskeletal symptoms were accompanied by 58.6% (n: 372) of the patients during the attack period. The most common musculoskeletal manifestation was found as arthralgia (32.6%, n: 206). Also, the other musculosceletal manifestations were found as follows during attacks; arthritis in 23.7% (n: 150), myalgia in 20.5% (n: 130), exertional calf pain in 6.5% (n: 41), and protracted febrile myalgia in 1% (n: 7) of the patients. It was observed that the musculoskeletal manifestations were significantly higher in patients with homozygous M694V variant in exon-10 (p=0.017). Also, it was found that the musculoskeletal manifestations are more common in the attack periods of patients carrying the M694V variant in at least one allele (p = 0.019).Conclusion:It was determined that the musculoskeletal manifestations were seen as an attack symptom in more than half of FMF patients. Also, homozygous and compound heterozygous MEFV mutations including M694V variant found as a risk factor for emerge of musculoskeletal manifestations. In children with unexplained and recurrent musculoskeletal symptoms, especially in ethnicities with the high frequency of FMF, analysis of MEFV gene can help reveal the underlying cause.References:[1]Brik R, Shinawi M, Kasinetz L, Gershoni-Baruch R. The musculoskeletal manifestations of familial Mediterranean fever in children genetically diagnosed with the disease. Arthritis Rheum 2001;44:1416-9.[2]Jarjour RA, Dodaki R. Arthritis patterns in familial Mediterranean fever patients and association with M694V mutation. Mol Biol Rep 2011;38:2033-6.Disclosure of Interests:None declared

AB0980 CASE-REVIEW ON FAMILIAL MEDITERRANEAN FEVER IN A SPECIALIZED CENTRE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1784.1-1784
Author(s):  
R. Dos Santos Sobrín ◽  
M. Martí Masanet ◽  
B. Lopez-Montesinos ◽  
L. Lacruz Pérez ◽  
I. Calvo
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Familial Mediterranean Fever ◽  
Periodic Fever ◽  
Severe Disease ◽  
Strong Association ◽  
Mefv Gene ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Case Series ◽  
Case Review ◽  
Mediterranean Fever

Background:Familial Mediterranean Fever (FMF) is a genetic autoinflammatory disorder caused mostly by mutations in MEFV gene. Its inheritance is autosomal recessive and is the most frequent periodic fever syndrome. First-line treatment is based in colchicine use, so biologics (anti-IL-1) are reserved for refractory cases1, 2.Objectives:To account for clinic and treatment features of patients with FMF in a specialized center as opposed to non-referent centers.Methods:This study was developed in the Pediatric Rheumatology Service in Hospital Universitario y Politécnico La Fe de Valencia. Demographic, clinic and treatment data were collected from patients diagnosed of FMF since January 2004 to September 2019.Results:106 patients met last FMF criteria3. 55% had a pathogenic mutation in genetic analysis. 52% were female. Before 10 years old, 71% of patients had the diagnosis (51% before 4 years old). Arthralgia/myalgia (73%), periodic fever (62%) and abdominal pain (54%) were the most common symptoms. Systemic Juvenile Idiopathic Arthritis (JIA, 6), other forms of JIA (9) and vasculitis (10) were the most prevalent comorbidities. When talking about treatment, 76,4% received Colchicine (60,5% with good response), 22,6% needed a classical disease modifying antirheumatic drug (mostly Methotrexate) and 22 patients got biologic treatment (73% anti-IL-1).Conclusion:When analyzing this case-review, JIA has a strong association with our patients, so it could explain severe disease activity and more articular involvement. This could be an illustration to the higher use of Methotrexate. Also, the most relevant symptom was arthralgia while fever is the most frequent in literature. Likewise, age of diagnosis has been earlier than other case-series (this would be more frequent in other autoinflammatory syndromes, as literature relates)1, 2, 4.References:[1]Ozdogan H, Ugurlu S. Familial Mediterranean Fever. Presse Med. (2019).[2]Ozen S, Demirkaya E, Erer B, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis 2016;75:644-651.[3]Sag E, Demirel D, Demir S, et al. Performance of the new “Eurofever/PRINTO classification criteria” in FMF patients. Semin Arthritis Rheum. 2019;19:30369-5.[4]Rozenbaum M, Rosner I. Severe outcome of juvenile idiopathic arthritis (JIA) associated with familial Mediterranean fever (FMF). Clin Exp Rheumatol. 2004;22:S75-8.Disclosure of Interests:Raquel Dos Santos Sobrín: None declared, Miguel Martí Masanet: None declared, B Lopez-Montesinos: None declared, Lucía Lacruz Pérez: None declared, Inmaculada Calvo Grant/research support from: Bristol-Myers Squibb, Clementia, GlaxoSmithKline, Hoffman-La Roche, Merck Sharpe & Dohme, Novartis, Pfizer, Sanofi, Speakers bureau: AbbVie, GlaxoSmithKline, Hoffman-La Roche, Novartis

Genetic Screening of Familial Mediterranean Fever in Japan.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3846-3846
Author(s):  
Yasuko Miyahara ◽  
Kouhei Yamashita ◽  
Takashi Miyoshi ◽  
Akifumi Takaori ◽  
Masataka Sasada ◽  
...  
Keyword(s):  
Familial Mediterranean Fever ◽  
Genetic Screening ◽  
Large Scale ◽  
Periodic Fever ◽  
Mefv Gene ◽  
Unknown Origin ◽  
Polymorphonuclear Cells ◽  
Exon 2 ◽  
Mediterranean Countries ◽  
Mediterranean Fever

Abstract There have been few reports of the patients with Familial Mediterranean Fever (FMF) in Japan, probably because FMF patients are preoccupied to be rare in Japan. We experienced 10 cases likely to be clinically diagnosed as FMF with periodic fever of unknown origin. FMF is an autosomal recessive disease resulting from the genetic mutations in the FMF gene (MEFV), which codes for a protein named Pyrin. Pyrin is expressed in mainly polymorphonuclear cells and monocytes and it is proposed that it regulates inflammation. The MEFV gene is located on chromosome 16p13.3 and comprises 10 exons. Several mutations in the MEFV gene have been identified, however the mutations are mostly located in exon 2 and 10. Therefore, we performed genetic screening of exon 2 and 10 in the 10 patient samples. The median age of the patients was 34 (17–49) years old. They are four males and six females. DNA was isolated from polymorphonuclear cells of the patients and PCR was performed with selective primers of exon 2 and 10 of MEFV gene, respectively. Thereafter, direct sequence of exon 2 and 10 of the PCR products was performed. As a result, the mutations of E148Q in exon 2 and M694I in exon 10, which are commonly observed in previous reports, were identified in seven and six out of 10 patients, respectively. All patients had either E148Q or M694I mutation. Three patients have both E148Q and M694I mutations. One 50-year-old female patient, who had a homozygous M694I mutation, suffered from severe renal AA amyloidosis. The mutation at M694 has been mostly reported as M694V, particularly in Mediterranean countries, however interestingly, all of the mutations of M694 were M694I, not M694V in our 10 Japanese patients. It is reported that healthy carrier frequency of the E148Q mutation was about 16% in Japan, so it is suggested that E148Q mutation may be profoundly involved in cause of disease, because E148Q mutation is observed among 70% of our patients. We herein report the unique genetic features of FMF patients in Japan. A further large scale of investigation would be necessary for confirming the significance of E148Q and M694I mutations in FMF patients in Japan.

scholarly journals Molecular Patterns of MEFV Gene Mutations in Egyptian Patients with Familial Mediterranean Fever: A Retrospective Cohort Study

2019 ◽  
Vol 2019 ◽  
pp. 1-5 ◽  
Author(s):  
Amal R. Mansour ◽  
Ayman El-Shayeb ◽  
Nihal El Habachi ◽  
Mohamad A. Khodair ◽  
Doaa Elwazzan ◽  
...  
Keyword(s):  
Familial Mediterranean Fever ◽  
Mefv Gene ◽  
Gene Mutations ◽  
Signs And Symptoms ◽  
High Serum ◽  
Compound Heterozygous ◽  
Amyloid A ◽  
Egyptian Patients ◽  
Sequencing Studies ◽  
Mediterranean Fever

Background. Familial Mediterranean Fever (FMF) is a hereditary autosomal recessive disease which is mainly seen in the Turks, Armenians, Arabs, and Jews. It is characterized by recurrent episodes of fever, polyserositis, and rash. MEFV gene, encoding pyrin protein, is located on the short arm of chromosome 16. FMF is associated with a broad mutational spectrum in this gene. Certain mutations are more common in particular ethnic groups. To date, different mutations of MEFV were observed in studies carried out in different regions worldwide. However, most of these studies did not extensively investigate the Egyptian population, in spite of the high prevalence of FMF in this geographical region. Aim. To identify the frequency of MEFV gene mutations among the patients who presented with FMF like symptoms and, to characterize the different genetic mutations and their association with increased Amyloid A among Egyptian patients. Methods. FMF Strip Assay (Vienna Lab Diagnostics, Vienna, Austria) was used. This test is based on reverse hybridization of biotinylated PCR products on immobilized oligonucleotides for mutations and controls in a parallel array of allele-specific oligonucleotides. Results. Among the 1387 patients presenting with signs and symptoms suggestive of FMF, 793 (57.2%) were of undefined mutations, whereas 594 had MEFV gene mutations. 363 patients (26.2%) were heterozygous mutants, 175 patients (12.6%) were compound heterozygous mutants, and 56 patients (4%) were homozygous mutants. The most commonly encountered gene mutations in heterozygous and homozygous groups were E148Q (38.6%), M694I (18.1%), and V726A (15.8%). The most commonly encountered gene mutations in the compound heterozygous groups were E148Q+M694I observed in 20.6% of the patients, followed by M694I+V726A and M6801+V726A found in 18.9% and 11.4 %, respectively. The most commonly encountered gene mutation associated with abdominal pain, fever, and high serum Amyloid A was E148Q allele (37.5%). Conclusions. Unlike all previous publications, E148Q allele was found to be the most frequent in the studied patients. Moreover, this allele was associated with increased Amyloid A. 793 patients were free of the 12 studied Mediterranean mutations, which implies the necessity to perform future sequencing studies to reveal other mutations.

Clinical significance of E148Q heterozygous variant in paediatric Familial Mediterranean Fever

Rheumatology ◽  
2021 ◽  
Author(s):  
Irit Tirosh ◽  
Yonatan Yacobi ◽  
Asaf Vivante ◽  
Ortal Barel ◽  
Yishay Ben-Moshe ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Familial Mediterranean Fever ◽  
Clinical Significance ◽  
Mefv Gene ◽  
Clinical Manifestations ◽  
Leg Pain ◽  
Compound Heterozygous ◽  
Phenotype Correlation ◽  
Heterozygous Variant ◽  
Mediterranean Fever

Abstract Objectives Familial Mediterranean Fever (FMF) results from mutations in the Mediterranean fever (MEFV) gene. The p.E148Q is one of the most frequent protein alternations in the MEFV gene, yet the exact E148Q genotype–phenotype correlation remains unclear. The aim of this study was to examine clinical significance of heterozygous E148Q variant in a paediatric FMF cohort. Methods We compared the clinical manifestations and disease severity score of four genetic sub-groups: (1) patients harboring a single heterozygous p.E148Q variant (n = 6); (2) patients harboring a single p.M694V heterozygous variant (n = 88); (3) patients harboring compound heterozygous p.M694V and p.E148Q variants (n = 36) and (4) homozygotes for p.M694V variant (n = 160). Results Of 646 FMF children from our centre, only 1% (6 patients) of our genetically characterized FMF cohort had a single E148Q variant, most presenting with recurrent fevers and abdominal pain. None of the participants were found to harbor homozygous E148Q. Overall, M694V/E148Q compound heterozygosity did not exhibit a more severe phenotype compared to patients with a single M694V variant. The former group were less likely to have abdominal pain and exertional leg pain (p < 0.004 and p < 0.001 respectively) and more likely to have chest pain (P < 0.01). Both sub-groups showed milder clinical phenotype compared to patients with M694V homozygosity. Conclusion Our findings demonstrate that a single heterozygous E148Q variant is unlikely to cause FMF in children and that E148Q/M694V is clinically indistinguishable from a single M694V variant. Thus, E148Q heterozygosity does not result in clinically meaningful phenotype in children.

scholarly journals Small Intestinal Bacterial Overgrowth Affects the Responsiveness to Colchicine in Familial Mediterranean Fever

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
E. Verrecchia ◽  
L. L. Sicignano ◽  
M. La Regina ◽  
G. Nucera ◽  
I. Patisso ◽  
...  
Keyword(s):  
Familial Mediterranean Fever ◽  
Periodic Fever ◽  
Mefv Gene ◽  
Bacterial Overgrowth ◽  
Colchicine Treatment ◽  
Small Intestinal Bacterial Overgrowth ◽  
Centre Database ◽  
Mediterranean Fever ◽  
Small Intestinal ◽  
Glucose Breath Test

Objective. Familial Mediterranean fever (FMF) is an autosomal recessive disease due to a MEFV gene mutation. Since Helicobacter pylori infection has been described to increase the severity and frequency of FMF attacks, we evaluate if overgrowth of small intestinal bacterial (SIBO), associated with a release of bacterial products, can affect the response to colchicine in FMF patients poorly responsive to colchicine. Methods. We revised our Periodic Fever Centre database to detect FMF patients who were poorly responsive to colchicine, without a well-defined cause of drug resistance. They were evaluated for SIBO presence, then treated with decontamination therapy. Results. Among 223 FMF patients, 49 subjects show colchicine resistance, and no other known causes of colchicine unresponsiveness has been found in 25 patients. All 25 patients underwent glucose breath test; 20 (80%) of them were positive, thus affected by SIBO. After a successful decontamination treatment, 11 patients (55%) did not show FMF attacks during the following three months (p<0.01), while 9 of them revealed a significant reduction of the number of attacks compared to three months before (p<0.01). Conclusion. The SIBO eradication improves laboratory and clinical features of FMF patients. Thus, patients with unresponsiveness to colchicine treatment should be investigated for SIBO.

scholarly journals Atypical Familial Mediterranean Fever in a Japanese Boy with Heterozygous MEFV p.Ser503Cys Exon 5 Variant

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Tomonobu Sato ◽  
Shunichiro Takezaki ◽  
Takeru Goto ◽  
Shinichi Ishikawa ◽  
Kazumi Oura ◽  
...  
Keyword(s):  
Familial Mediterranean Fever ◽  
Periodic Fever ◽  
Mefv Gene ◽  
Colchicine Treatment ◽  
Clinical Findings ◽  
Hereditary Periodic Fever ◽  
Fever Syndromes ◽  
Mediterranean Fever ◽  
Accompanying Symptoms

Periodic fever syndromes are heterogeneous diseases. Familial Mediterranean fever (FMF) is one of the hereditary periodic fever diseases caused by a Mediterranean fever (MEFV) gene abnormality. FMF can be categorized as typical or atypical, based on clinical findings and genetic screening. Atypical FMF has a wide variation of clinical findings and disease-causing mutations of MEFV. Therefore, it is sometimes difficult to diagnose an unknown fever as FMF. To date, a large number of various typical and atypical FMF cases have been reported in Japan. Here, we describe a Japanese boy with heterozygous MEFV p.Ser503Cys exon 5 variant who developed periodic fever. He was treated with colchicine; a complete eradication of his fever and various accompanying symptoms have been subsequently achieved for more than a year. Given that there have been a few reports about patients with this variant, little is known about the genetic and phenotypic role of heterozygous MEFV p.Ser503Cys exon 5 variant. It is therefore imperative to consider atypical FMF as a differential diagnosis when a periodic fever is encountered. Furthermore, we suggest that it is worthwhile to integrate MEFV gene analysis with the potential effects of colchicine treatment in patients with periodic fever.

scholarly journals A case report of a boy suffering from type 1 diabetes mellitus and familial Mediterranean fever

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Maria Francesca Gicchino ◽  
Dario Iafusco ◽  
Angela Zanfardino ◽  
Emanuele Miraglia del Giudice ◽  
Alma Nunzia Olivieri
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Familial Mediterranean Fever ◽  
Autoimmune Diseases ◽  
Type 1 Diabetes Mellitus ◽  
Medical Literature ◽  
Periodic Fever ◽  
Mefv Gene ◽  
Mediterranean Fever

Abstract Background Type 1 diabetes mellitus could be associated with other autoimmune diseases, such as autoimmune thyroid disease, celiac disease, but the association with Familial Mediterranean Fever is rare, we describe a case of a boy with type 1 Diabetes Mellitus associated with Familial Mediterranean Fever (FMF). Case presentation A 13 year old boy already suffering from Diabetes Mellitus type 1 since the age of 4 years, came to our attention because of periodic fever associated with abdominal pain, chest pain and arthralgia. The fever appeared every 15–30 days with peaks that reached 40 °C and lasted 24–48 h. Laboratory investigation, were normal between febrile episodes, but during the attacks revealed an increase in inflammatory markers. Suspecting Familial Mediterranean Fever molecular analysis of MEFV gene, was performed. The genetic analysis showed homozygous E148Q mutation. So Familial Mediterranean Fever was diagnosed and colchicine treatment was started with good response. Conclusion Familial Mediterranean Fever could be associated with other autoimmune diseases such as Ankylosing Spondylitis, Rheumatoid Arthritis, Polyarteritis Nodosa, Behcet disease, Systemic Lupus, Henoch-Schönlein Purpura, and Hashimoto’s Thyroiditis. Association of type 1 Diabetes Mellitus and Familial Mediterranean Fever has been newly reported in the medical literature, this is the third association of these two diseases described in the medical literature so far.

scholarly journals The spectrum of MEFV gene mutations and genotype-phenotype correlation in Egyptian patients with familial Mediterranean fever

2017 ◽  
Vol 5 (4) ◽  
pp. 1388 ◽  
Author(s):  
Fahmy T. Ali ◽  
Mostafa M. Elhady ◽  
Hanan H. Abbas ◽  
AbdAllah Y. Mandouh
Keyword(s):  
Familial Mediterranean Fever ◽  
Mefv Gene ◽  
Gene Mutations ◽  
Compound Heterozygous ◽  
Homozygous Mutation ◽  
Clinical Criteria ◽  
Egyptian Patients ◽  
Mediterranean Fever ◽  
The Mediterranean ◽  
Severity Of The Disease

Background: Familial Mediterranean fever (FMF) is an autosomal recessive disease mainly affecting subjects of the Mediterranean origin. It is an auto-inflammatory periodic disorder that is caused by mutations in the Mediterranean fever gene (MEFV) located on chromosome 16.Methods: The current study was designed to assess the prevalence and frequency of different MEFV gene mutations among 104 FMF clinically diagnosed Egyptian patients and to evaluate the change extent in the values of some biochemical markers (ESR, CRP, Fibrinogen-C, SAA and IL1) in different participants with different FMF severity scores.Results: According to allele status 28 patients (27%) were homozygous mutation carriers, 38 (36.5%) were with compound heterozygous mutations and 38 (36.5%) were identified as heterozygous for one of the studied mutations. Of the studied mutations, M694I, E148Q, V726A, M680I, and M694V accounted for 28.1%, 26.8%, 16.9%, and 11.3% of mutations respectively. The R761H and P369S mutations were rarely encountered mutations (1.4%). The clinical features with M694I were associated with more severe clinical course. There is a drastic elevation in the levels of estimated parameters as their levels were increased as long as the severity of the disease increased.Conclusions: The diagnosis of FMF cannot be performed on the basis of genetic testing or clinical criteria alone. So, we recommended the combination between clinical and molecular profiling for FMF diagnosis and scoring.

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