E148Q of the MEFV Gene Causes Amyloidosis in Familial Mediterranean Fever Patients

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

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Familial Mediterranean fever-associated mutation pyrin E148Q as a potential risk factor for multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458512437813 ◽

2012 ◽

Vol 18 (9) ◽

pp. 1229-1238 ◽

Cited By ~ 11

Author(s):

T Kümpfel ◽

L-A Gerdes ◽

T Wacker ◽

A Blaschek ◽

J Havla ◽

...

Keyword(s):

Multiple Sclerosis ◽

Risk Factor ◽

Familial Mediterranean Fever ◽

Mefv Gene ◽

German Population ◽

Gene Group ◽

Mefv Mutations ◽

Mediterranean Fever ◽

Group 2 ◽

Group 1

Background: Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease caused by mutations in the MEFV gene and characterized by recurrent febrile polyserositis. A possible association of FMF and multiple sclerosis (MS) has been suggested in cohorts from Turkey and Israel. Objective: The objective of this study was to investigate the prevalence of MEFV mutations in subjects with MS and in controls in Germany. Methods: One-hundred and fifty seven MS patients with at least one symptom or without symptoms suggestive of FMF from our outpatient clinic were investigated for mutations in exons 2, 3, and 10 of the MEFV gene (group 1). 260 independent MS patients (group 2) and 400 unrelated Caucasian controls (group 3) were screened selectively for the low-penetrance pyrin mutations E148Q and K695R Results: In group 1, 19 MS patients (12.1%) tested positive for a mutation in the MEFV gene, mainly the E148Q ( n=7) substitution. Fifteen of the 19 mutation-positive individuals reported at least one symptom suggestive of FMF. In three cases, we could identify additional family members with MS. In these pedigrees, the E148Q exchange co-segregated with MS ( p=0.026). Frequencies of the pyrin E148Q and K695R mutations were not statistically different between MS group 2 and controls but they occurred with a surprisingly high frequency in the German population. Conclusion: The MEFV gene appears to be another immunologically relevant gene locus which contributes to MS susceptibility. In particular, the pyrin E148Q mutation, which co-segregated with disease in three MS families, is a promising candidate risk factor for MS that should be further explored in larger studies.

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MEFV gene mutations in Iranian patients with familial mediterranean fever (FMF)

The American Journal of Gastroenterology ◽

10.1016/s0002-9270(03)00980-8 ◽

2003 ◽

Vol 98 (9) ◽

pp. S72-S73 ◽

Cited By ~ 1

Author(s):

M ZALI

Keyword(s):

Familial Mediterranean Fever ◽

Mefv Gene ◽

Gene Mutations ◽

Mediterranean Fever ◽

Iranian Patients

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Frequency and Disease Severity of Familial Mediterranean Fever (FMF) Related MEFV Gene Mutations Among Ankylosing Spondylitis Patients

Turkiye Klinikleri Journal of Medical Sciences ◽

10.5336/medsci.2013-34490 ◽

2014 ◽

Vol 34 (2) ◽

pp. 223-230 ◽

Cited By ~ 2

Author(s):

Aslı TUFAN ◽

Sibel Zehra AYDIN ◽

Fatih EREN ◽

Pamir ATAGÜNDÜZ

Keyword(s):

Ankylosing Spondylitis ◽

Familial Mediterranean Fever ◽

Disease Severity ◽

Mefv Gene ◽

Gene Mutations ◽

Mediterranean Fever

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Molecular Diagnosis Experience in Familial Mediterranean Fever: The Most Frequent Mutations in the MEFV Gene

Medical Bulletin of Haseki ◽

10.4274/haseki.42714 ◽

2018 ◽

Vol 56 (1) ◽

pp. 42-49 ◽

Cited By ~ 1

Author(s):

Ender Coşkunpınar ◽

Ayla Özvarnalı ◽

Kıvanç Çefle ◽

Ayşe Palanduz ◽

Ahmet Gül ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Molecular Diagnosis ◽

Mefv Gene ◽

Frequent Mutations ◽

Mediterranean Fever

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

Asian Journal of Pediatric Research ◽

10.9734/ajpr/2020/v4i230145 ◽

2020 ◽

pp. 20-26

Author(s):

Hakan Erdogan ◽

Ayse Cavidan Sonkur ◽

Orhan Görükmez ◽

Ayse Erdogan ◽

Dilek Damla Saymazlar ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Mutation Screening ◽

Mefv Gene ◽

Gene Mutations ◽

Retrospective Case ◽

Turkish Children ◽

Pathogenic Variants ◽

Frequent Mutations ◽

Training And Research ◽

Mediterranean Fever

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. 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. 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. 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.

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Novel deleterious nsSNPs within MEFV gene that could be used as Diagnostic Markers to Predict Hereditary Familial Mediterranean Fever: Using bioinformatics analysis

10.1101/424796 ◽

2018 ◽

Author(s):

Mujahed I. Mustafa ◽

Tebyan A Abdelhameed ◽

Fatima A. Abdelrhman ◽

Soada Ahmed Osman ◽

Mohamed A. Hassan

Keyword(s):

Familial Mediterranean Fever ◽

In Silico ◽

Mediterranean Basin ◽

Mefv Gene ◽

Structure And Function ◽

Diagnostic Markers ◽

Novel Mutations ◽

Bioinformatics Tools ◽

Mediterranean Fever ◽

And Function

AbstractBackgroundFamilial Mediterranean Fever (FMF) is the most common auto inflammatory disease (AID) affecting mainly the ethnic groups originating from Mediterranean basin, we aimed to identify the pathogenic SNPs in MEFV by computational analysis software.MethodsWe carried out in silico prediction of structural effect of each SNP using different bioinformatics tools to predict substitution influence on protein structure and function.Result23 novel mutations out of 857 nsSNPs that are found to be deleterious effect on the MEFV structure and function.ConclusionThis is the first in silico analysis in MEFV gene to prioritize SNPs for further genetic mapping studies. After using multiple bioinformatics tools to compare and rely on the results predicted, we found 23 novel mutations that may cause FMF disease and it could be used as diagnostic markers for Mediterranean basin populations.

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A new MEFV gene mutation in an Iranian patient with familial Mediterranean fever

Reumatismo ◽

10.4081/reumatismo.2019.1141 ◽

2019 ◽

Vol 71 (2) ◽

pp. 85-87

Author(s):

S. Farjadian ◽

F. Bonatti ◽

A. Soriano ◽

M. Reina ◽

A. Adorni ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Mutational Analysis ◽

Novel Mutation ◽

Present Report ◽

Case Reports ◽

Mefv Gene ◽

Recurrent Fever ◽

Iranian Patient ◽

Mediterranean Fever ◽

Exon 10

Familial mediterranean fever (FMF) is an inherited autoinflammatory disorder characterized by recurrent episodes of fever and painful inflammation involving the intra-abdominal organs, the lungs and the joints, which is highly prevalent in specific ethnic groups including the Iranians. We report a 12-year-old boy from Iran, with a clinical history of recurrent fever. Based on the suggestive clinical data, mutational analysis revealed the presence of the novel c.1945C>T heterozygous variant in exon 10, which leads to a leucine to phenylalanine change at position 649 of the protein. The mutation was inherited from the mother. This novel mutation lies in exon 10 of the MEFV gene, which encodes for a domain called B30.2-SPRY, located in the C-terminal region of the pyrin protein and contains the most frequent mutations associated with FMF. The present report expands the spectrum of MEFV gene mutations associated with FMF. The uniqueness of this study, compared with other published case reports, consists in the new mutation found in the MEFV gene. In fact, new mutations in this gene are of high interest, in order to better understand the role of this gene in autoinflammation.

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Familial Mediterranean Fever: an unusual cause of liver disease

Italian Journal of Pediatrics ◽

10.1186/s13052-019-0712-0 ◽

2019 ◽

Vol 45 (1) ◽

Cited By ~ 1

Author(s):

Maria Cristina Maggio ◽

Maria Castiglia ◽

Giovanni Corsello

Keyword(s):

Abdominal Pain ◽

Liver Disease ◽

Familial Mediterranean Fever ◽

Serum Amyloid A ◽

Mefv Gene ◽

Serum Amyloid ◽

Aphthous Stomatitis ◽

Homozygous Mutation ◽

Amyloid A ◽

Mediterranean Fever

Abstract Background Familial Mediterranean Fever is an autoinflammatory disease typically expressed with recurrent attacks of fever, serositis, aphthous stomatitis, rash. Only a few reports describe the association with hepatic involvement. Case presentation We describe the clinical case of a child affected, since the age of 1 year, by recurrent fever, aphthous stomatitis, rash, arthralgia, associated with abdominal pain, vomiting, lymphadenopathy. The diagnosis of Familial Mediterranean Fever was confirmed by the genetic study of MEFV gene; the homozygous mutation M694 V in exon was documented. A partial control of attacks was obtained with colchicine. The child continued to manifest only recurrent episodes of abdominal pain without fever, however serum amyloid A persisted high, in association with enhanced levels of CRP, AST and ALT (1.5 x n.v.). The dosage of colchicine was increased step by step and the patient achieved a better control of symptoms and biochemical parameters. However, the patient frequently needed an increase in the dose of colchicine, suggesting the possible usefulness of anti-interleukin-1 beta treatment. Conclusions The unusual presentation of Familial Mediterranean Fever with liver disease suggests the role of inflammasome in hepatic inflammation. Colchicine controls systemic inflammation in most of the patients; however, subclinical inflammation can persist in some of them and can manifest with increased levels of CRP, ESR, serum amyloid A also in attack-free intervals.

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