Cardiovascular Sequelae and Genetics of Familial Mediterranean Fever: A Literature Review

Introduction: Familial Mediterranean fever (FMF) is an autoinflammatory fever syndrome distinguished by recurrent attacks of spontaneous peritonitis, pleuritis, fever, and arthritis. It is specifically seen in the ethnic groups of Mediterranean origin, but sporadic cases have been reported in Eastern Europe and America due to migrations. There is a number of cardiac manifestations associated with FMF. Methods: Using PubMed as the search engine, the literature search was done for articles published between 1958 and 2020. To summarize the body of available evidence, a scoping review was carried out to find relevant articles and case reports in patients of FMF with cardiovascular manifestations. Results: In the literature, there is a number of mechanisms explaining the cause of cardiac involvement in FMF, including the subclinical inflammation and secondary (AA) amyloid deposition in the vessels and the myocardium. There is a variable and often spurious course of these manifestations and it can be associated with a poor prognosis such as an acute myocardial infarction. In FMF patients, polyarteritis nodosa and Henoch-Schönlein purpura are seen more significantly as compared to the general population with increased frequency of mutations in Mediterranean fever (MEFV) gene. Through unclear mechanisms, Behçet’s disease is associated with MEFV gene mutations and shares vascular manifestations with FMF. There is an interplay of IL-1 and MEFV gene, which impart an important role in inflammatory attacks of FMF. There is an intima-media thickening of blood vessels AA to persistent inflammation which can lead to atherosclerotic plaque formation resulting in atherosclerotic cardiovascular disease. Conclusion: FMF and its associated cardiovascular diseases are interlinked to 2 main mechanisms: subclinical atherosclerosis and amyloid deposition, and colchicine is the primary treatment of patients with FMF which shows the regression of amyloid deposits and prevents cardiovascular sequelae.

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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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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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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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R202Q/M694V as novel MEFV gene mutations in chronic periodontitis and familial Mediterranean fever

Journal of Periodontal Research ◽

10.1111/jre.12467 ◽

2017 ◽

Vol 52 (6) ◽

pp. 994-1003 ◽

Cited By ~ 3

Author(s):

Ö. Fentoğlu ◽

G. Dinç ◽

Ö. Bağcı ◽

A. Doğru ◽

İ. İlhan ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Chronic Periodontitis ◽

Mefv Gene ◽

Gene Mutations ◽

Mediterranean Fever

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MEFV Gene Mutations in Egyptian Patients with Familial Mediterranean Fever

Genetic Testing and Molecular Biomarkers ◽

10.1089/gtmb.2009.0180 ◽

2010 ◽

Vol 14 (2) ◽

pp. 263-268 ◽

Cited By ~ 10

Author(s):

Dalal A. El Gezery ◽

Abla A. Abou-Zeid ◽

Doaa I. Hashad ◽

Hesham K. El-Sayegh

Keyword(s):

Familial Mediterranean Fever ◽

Mefv Gene ◽

Gene Mutations ◽

Egyptian Patients ◽

Mediterranean Fever

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

International Journal of Inflammation ◽

10.1155/2019/2578760 ◽

2019 ◽

Vol 2019 ◽

pp. 1-5 ◽

Cited By ~ 7

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.

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