MEFV mutations in Iranian Azeri Turkish patients with familial Mediterranean fever

Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder with more than 60 disease-associated mutations in the responsible gene, MEFV . In the present study, we determined 15 MEFV mutations in Iranian Azeri Turkish FMF patients. Five hundred and twenty-four unrelated patients were tested for 15 known mutations in the MEFV gene using amplification refractory mutation system-polymerase chain reaction and polymerase chain reaction-restriction fragment length polymorphism methods. Thirty-five different genotypes were characterized among the studied patients. Of the alleles investigated, the most common mutation was p.M694V (42.4%), followed by p.V726A (17%), p.E148Q (16.2%), and p.M680I (c.2040G>C) (15.2%). The p.R761H mutation (4.7%) was found to be the most frequent among the rare mutations. The mutations p.M680I (c.2040G>A), p.I692del, p.M694del and p.K695R were not found in this cohort. The remaining mutations account for 7.7% of the identifiable mutations. Five different types of complex alleles were also identified. The results show the diversity and the frequency of the mutations in the Iranian Azeri Turkish FMF patients. The p.R761H mutation is rather prevalent in Azeri Turks; therefore, it should be included in the routine molecular diagnosis of FMF patients from this ethnic group.     

Familial Mediterranean fever in the Syrian population: gene mutation frequencies, carrier rates and phenotype-genotype correlation

BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive disease mainly affecting particularly Arabs, Non-Ashkenazi Jews, Armenians, and Turks. It is an autoinflammatory periodic disorder characterized by febrile and painful attacks due to inflammation involving the serosal membranes in the abdomen, chest or joints. Over 50 mutations have been identified in the MEFV gene responsible for FMF. OBJECTIVE: To identify the distribution and the frequency of the MEFV gene mutations in Syrian FMF patients and population and perform a genotype/phenotype correlation in the patients' cohort. PATIENTS AND METHODS: The study was carried out on 83 clinically diagnosed Syrian FMF patients and 242 healthy subjects. The tested individuals were screened for the most common five MEFV mutations (M694V, M694I, M680I, V726A and E148Q) by restriction fragment length polymorphism. Sequencing of exon 10 was performed only for the patients' DNA where just one or no mutation was detected. RESULTS AND DISCUSSION: Of the 83 patients studied, 74 (89%) were positive either for one, two or three mutations and nine (11%) had no mutations detected. Of those positive for mutations, 25 were homozygous, 30 were compound heterozygotes, three had complex alleles, and 16 patients had only one mutation. The M694V, V726A, M694I, M680I and E148Q mutations accounted for 45.8%, 26%, 13.9%, 4.8% and 6% of the alleles, respectively. The carrier rate in the Syrian population for the tested mutations was 17.5%, E148Q being the most common mutation, followed by V726A and M694V. The severity of the disease and development of amyloidosis seem to have an association with M694V, the most common mutation in Syrian FMF patients.     

Cluster of patients with Familial Mediterranean fever and heterozygous carriers of mutations in MEFV gene in the Czech Republic

Familial Mediterranean fever (FMF) is a well‐described monogenic autosomal recessive disorder with highest occurrence in the Mediterranean region. In this article, we describe the experience of a center in the Czech Republic that follows four families with members bearing mutations in MEFV gene without provable ancestry from the Mediterranean region. We also discuss the clinical picture of the heterozygous variants that were present in our cohort. The typical clinical presentation in heterozygotes corresponds to data described in the international literature. The possibility of combination of mutations and/or polymorphisms in different genes and epigenetic or environmental influences on the clinical symptoms are taken into account.     

Evidence for the involvement of mTOR inhibition and basal autophagy in familial Mediterranean fever phenotype

Familial Mediterranean fever (FMF) inflammatory attacks are often triggered by metabolic or physical stress. mTOR signaling and autophagy modulate cellular responses to metabolic danger signals. In this study, we investigated the implication of mTOR inhibition and autophagy in FMF pathophysiology. mTOR inhibition induced MEFV gene expression in polymorphonuclear cells (PMNs) from healthy individuals, whereas it had no effect on PMNs from attack-free FMF patients. A significant reduction in pyrin levels in PMNs from FMF patients after mTOR inhibition was also observed. Pyrin levels in control PMNs remained unaffected. Moreover, the basal autophagic status in PMNs from FMF patients was reduced, as indicated by the lower LC3B-II/I ratio and ATG mRNA expression levels. However, mTOR inhibition had similar effects on the induction of autophagy in the two groups. The differential pyrin expression after metabolic stress induction and the impaired basal autophagy suggest a potential role in the triggering of FMF attacks.     

Mutations in the familial Mediterranean fever gene of patients with IgA nephropathy and other forms of glomerulonephritis

Glomerulonephritis, particularly IgA nephropathy (IgAN), seems to be more common in familial Mediterranean fever (FMF), an inherited disease caused by mutations in the MEditerranean FeVer gene ( MEFV ). The present study is aimed to determine, in populations not suffering from FMF, whether carriage of MEFV mutations may modify or precipitate IgAN and other forms of primary glomerulonephritis (PGN). Forty patients with biopsy proven IgAN and 40 with PGN were surveyed for the presence of the three most common MEFV mutations (M694V, V726A and E148Q), using polymerase chain reaction amplification and restriction enzyme analysis. The rate of MEFV mutations in the patients was related to the expected carrier rate in the general population of the same ethnic extraction. The effect of mutation carriage on the disease course was determined in the IgAN patient group. The frequency of MEFV mutations in IgAN or PGN was comparable to that found in ethnically adjusted general population (p = 0.1 and 0.5, respectively). Carriage of mutated MEFV was not associated with the course and severity of the disease or findings in kidney biopsy and urine analysis. In a population, mostly of Jewish extraction, MEFV mutations do not seem to predispose to the development of IgAN and other forms of PGN or affect the phenotype.     

MEFV alterations and population genetics analysis in a large cohort of Greek patients with familial Mediterranean fever

Familial Mediterranean fever (FMF) is a disease characterized by recurrent, self-limiting bouts of fever and serositis and caused by altered pyrin due to mutated MEFV gene. FMF is common in the Mediterranean Basin populations, although with varying genetic patterns. The spectrum and clinical significance of MEFV alterations in Greece has yet not been elucidated. The aim of this study was to analyze the spectrum of MEFV alterations in FMF patients and healthy individuals in Greece. A cohort of 152 Greek FMF patients along with 140 Greek healthy controls was enrolled. Non-isotopic RNase cleavage assay (NIRCA) and sequencing allowed mutational and haplotypic analysis of the entire coding sequence of MEFV. The ARLEQUIN 2.0, DNASP 4.0 and PHYLIP software were used for population genetics analysis. Among patients, 127 (83.6%) carried at least one known mutation. The most common mutations identified were M694V (38.1%), M680I (19.7%), V726A (12.2%), E148Q (10.9%) and E230K (6.1%). The total carrier rate among healthy individuals was 0.7%. The presence of R202Q homozygosity in 12 of the remaining 25 MEFV negative FMF patients might be considered as disease related in Greeks. Population genetics analysis revealed that Greeks rely closer to the eastern rather than western populations of the Mediterranean Basin.     

The first case of familial Mediterranean fever associated with renal amyloidosis in Korea

Familial Mediterranean fever (FMF) is an auto-inflammatory disease characterized by periodic episodes of fever and recurrent polyserositis. It is caused by a dysfunction of pyrin (or marenostrin) as a result of a mutation within the MEFV gene. It occurs mostly in individuals of Mediterranean origin; however, it has also been reported in non-Mediterranean populations. In this report, we describe the first case of FMF in a Korean child. As eight-year-old boy presented recurrent febrile attacks from an unknown cause, an acute scrotum and renal amyloidosis. He also showed splenomegaly, lymphadenopathy, pleural effusion, ascites and elevated acute phase reactants. After MEFV gene analysis, he was diagnosed as FMF combined with amyloidosis.     

The M694V mutation in Armenian‐Americans: a 10‐year retrospective study of MEFV mutation testing for familial Mediterranean fever at UCLA

Familial Mediterranean fever (FMF), inherited in an autosomal recessive manner, is a systemic auto‐inflammatory disorder characterized by recurrent attacks of fever with peritonitis, pleuritis, synovitis and erysipeloid rash. The marenostrin‐encoding fever (MEFV) gene, located on chromosome 16p13.3, is the only gene in which mutations are currently known to cause FMF. To correlate specific genotypes with adverse phenotypes of affected populations residing in the Western United States, a retrospective case series review was conducted of all MEFV gene mutation testing completed at UCLA Clinical Molecular Diagnostic Laboratory between February 2002 and February 2012, followed by clinical chart review of all subjects who either have a single or double mutation. All 12 common mutations in the MEFV gene were analyzed and the M694V variant was found to be associated with an adverse FMF clinical outcome in the Armenian‐American population, manifested by earlier onset of disease, increased severity of disease, and renal amyloidosis.     

Differential mutational profiles of familial Mediterranean fever in North Africa

Familial Mediterranean fever (FMF) is a recessive autoinflammatory disease, mainly occurring in the eastern Mediterranean. In these populations, the five FMF founder mutations are differently distributed. In Algeria, the FMF-causing variants remain poorly explored. This retrospective study aims to report the mutational profile of Algerian FMF patients and to compare it with North African FMF patients. One hundred eighty-three unrelated patients clinically suspected of FMF were recruited from various Algerian hospitals (2007–2015) and tested for mutations in exon 10 of MEFV gene. Molecular analysis identified 144 mutant alleles among 87 of 183 patients (47.5%). p.M694I was the most prevalent pathogenic allele, accounting for 63.2% of mutant alleles, followed by p.M694V and p.M680I occurring with a same frequency (14.5%). Others, p.A744S (6.2%) and p.I692del (1.3%), are less frequent. Interestingly, p.M694I was the most recurrent in patients with renal AA-amyloidosis. Our results provide the first genetic data on FMF in Algeria, demonstrating the predominance of p.M694I and the absence of p.V726A, compared to other North African countries (Morocco, Tunisia, and Egypt). In conclusion, North African FMF patients display differential mutational profiles that may result from the difference in ethnic origin and the genetic heterogeneity among these populations.     

Relationship between genetic mutation variations and acute-phase reactants in the attack-free period of children diagnosed with familial Mediterranean fever

Familial Mediterranean fever (FMF) is a periodic autoinflammatory disease characterized by chronic inflammation. This study investigated the relationship between acute-phase reactants and gene mutations in attack-free periods of childhood FMF. Patients diagnosed with FMF were divided into four groups based on genetic features: no mutation, homozygous, heterozygous, and compound heterozygous. These groups were monitored for 2 years, and blood samples were collected every 6 months during attack-free periods. Erythrocyte sedimentation rate, C-reactive protein, fibrinogen, and white blood cell count were measured. A disease severity score was determined for each patient. Mean values for erythrocyte sedimentation rate and fibrinogen were significantly different in the homozygous group. White blood cell count and C-reactive protein were similar between the groups. Disease severity score was higher in patients with the M694V mutation than in individuals without the mutation, as well as in those with other mutation groups. Periodic follow-up of patients with FMF MEFV mutations in subjects with acute-phase reactants may be useful in the prevention of morbidity.     

Appendectomy history is associated with severe disease and colchicine resistance in adult familial Mediterranean fever patients

Background/aim Peritonitis attacks of Familial Mediterranean Fever (FMF) usually requires emergency medical admissions and it’s hard to distinguish a typical abdominal attack from surgical causes of acute abdomen. Therefore, history of abdominal surgery, particularly appendectomy, is very common in patients with FMF. However, history of appendectomy might also give some clues about the course of FMF in the adulthood. This study was to determine whether the history of appendectomy help to anticipate disease course of FMF in the adulthood. Materials and methods All patients recruited from FMF in Central Anatolia (FiCA) cohort, comprising 971 adult subjects. All patients fulfilled the Tel Hashomer criteria. Demographic data, FMF disease characteristics, co-morbid conditions, past medical history, surgical history and disease complications were meticulously questioned and laboratory features and genotype data (if available) were recruited from patient files. Results Appendectomy history was evident in 240 (24.7%) subjects. Disease onset was earlier and peritonitis is strikingly more prevalent (97.1% vs. 89.6%, p < 0.001) in appendectomized patients. These patients had reported almost two fold more frequent attacks in the last year compared to appendix intact patients (median 3.5 vs. 2 attacks, p = 0.001) without a difference in frequency of musculoskeletal and skin attacks. Severe disease was more common (10% vs. 5.9%, p = 0.038) due to involvement of more attack sites throughout the life and more frequent attacks. Appendectomy patients had used higher daily doses of colchicine to control disease (1.43 ± 0.6 mg vs. 1.27 ± 0.52 mg, p = 0.002) but colchicine resistance was also more common in these patients, 15% vs. 6.7% respectively, p < 0.001.ConclusionAppendectomy history is common in FMF patients and associated with frequent serositis attacks in adulthood. These patients require higher colchicine doses with a lower rate of response and more need for Interleukin-1 antagonist therapies.     

Genetic epidemiology of familial Mediterranean fever through integrative analysis of whole genome and exome sequences from Middle East and North Africa

Familial Mediterranean fever (FMF), an autosomal recessive and rare autoinflammatory disease is caused by genetic mutations in the MEFV gene and is highly prevalent in the Mediterranean basin. Although the carrier frequency of specific disease variants in the MEFV gene has been reported from isolated studies, a comprehensive view of variants in the Mediterranean region has not been possible due to paucity of data. The recent availability of whole‐genome and whole‐exome datasets prompted us to study the genetic epidemiology of MEFV variants in the region. We assembled data from 5 datasets encompassing whole‐genome and whole‐exome datasets for 2115 individuals from multiple subpopulations in the region and also created a compendium for MEFV genetic variants, which were further systematically annotated as per the American College of Medical Genetics and Genomics (ACMG) guidelines. Our analysis points to significant differences in allele frequencies in the subpopulations, and the carrier frequency for MEFV genetic variants in the population to be about 8%. The MEFV gene appears to be under natural selection from our analysis. To the best of our knowledge, this is the most comprehensive study and analysis of population epidemiology of MEFV gene variants in the Middle East and North African populations.     

The E148Q MEFV allele is not implicated in the development of familial Mediterranean fever

Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent attacks of fever and serositis, common in populations of Armenian, Arab, Sephardic Jewish and Turkish origin. Early diagnosis is crucial to start colchicine therapy that prevents the occurrence of attacks and renal amyloidosis. In the absence of functional test for FMF, the diagnosis remains clinical and is generally confirmed by molecular analysis of the MEFV gene. More than 40 missense mutations and two in-frame deletions have been reported, most of them being located in exon 10 of the gene. The M694V (c.2080A>G) mutation, the most frequent defect, is responsible for a severe phenotype when present in the homozygous state. The E148Q (c.442G>C) sequence variant, which is situated in exon 2, is also common, but its role in FMF is controversial. In order to assess the implication of the E148Q variation in FMF, we investigated 233 patients of Sephardic Jewish origin living in France and 213 disease-free relatives of these patients. The frequency of the E148Q allele was found to be similar in the two groups (3.62% and 3.75%, respectively, p=0.93). Most importantly, the frequency of the M694V/E148Q compound heterozygous genotype was comparable between the patients group (3.9%) and the healthy relatives group (4.2%, p=0.85). This population-based study, therefore, strongly supports the hypothesis that E148Q is a just a benign polymorphism and not a disease-causing mutation. Considering this variant as a mutation may lead to set false positive diagnoses and to neglect the likely existence of genetic heterogeneity in FMF.     

Dominant inheritance in two families with familial Mediterranean fever (FMF)

Familial Mediterranean fever (FMF) is an autosomal-recessive disease which affects almost exclusively people of Mediterranean and Middle Eastern origin. We examined the possibility of a dominant inheritance of FMF among our 3,000 patients in Israel. Two hundred forty FMF patients were members of 77 families in which the disease affected more than one generation. In 75 of these families the occurrence of FMF in more than one generation was found to be consistent with a recessive mode of inheritance due to a high gene frequency (q) and consanguinity among parents of the patients. In 2 families, one of Ashkenazi and the other of Georgian Iraqi origin, in which FMF occurred in 4 consecutive generations, the mode of inheritance could be explained only by autosomal-dominant inheritance. © 1995 Wiley-Liss, Inc.     

Canakinumab for the treatment of familial Mediterranean fever

Introduction: Familial Mediterranean fever (FMF) is the most frequent of all hereditary autoinflammatory syndromes. It is characterized by recurrent attacks of fever and serositis. If not treated it may be complicated with AA amyloidosis. It is caused by mutations in the MEFV gene that encodes pyrin which is involved in the regulation of IL-1β. The mainstay of treatment is colchicine, however a subset of patients requires an alternative treatment either due to inadequate response or intolerance. The accumulating data indicates that anti IL-1 drugs are effective in treating colchicine resistant FMF cases and improving their quality of life.

Areas covered: This review focuses on canakinumab, a fully human anti IL-1β antibody, treatment in FMF. The data obtained from case reports, case series, two Phase II studies and an ongoing double-blind, randomized, placebo controlled Phase III trial are analyzed. Efficacy and safety profiles of canakinumab are discussed.

Expert commentary: Canakinumab became the first approved therapy by the Food and Drug Administration for FMF very recently, which highlights its importance as the alternative treatment in FMF.     

Assessment of pyrin gene mutations in Turks with familial Mediterranean fever (FMF)

Familial Mediterranean fever (FMF) is an autosomal recessive disease clinically characterized by recurrent short self-limited attacks of fever accompanied by peritonitis, pleurisy, and arthritis and can lead to amyloidosis and renal failure in the longer term. It is prevalent mainly in non-Ashkenazi Jews, Armenians, Turks, and Arabs. Due to the lack of an accurate diagnostic test, patients often experience years of attacks and invasive diagnostic procedures before the correct diagnosis is made and adequate treatment is begun. Recently, the gene responsible for FMF, denoted pyrin, has been cloned, and three disease mutations have been described (French FMF Consortium, 1997; International FMF Consortium, 1997). In the current study we assessed the spectrum of mutations in this gene in 16 unrelated families of Turkish origin. The three previously reported missense mutations (Met-Ile at codon 680, Met-Val at codon 694, and Val-Ala at codon 726) accounted for 29 of the 34 disease alleles. In one patient in whom no disease mutation was identified, the clinical picture was atypical enough to raise questions regarding the diagnosis. These results imply that the origin of FMF in Turkey is heterogeneous, that molecular diagnosis of FMF is possible in the majority of cases and clinically helpful, and that delineation of the undiscovered disease mutation(s) in the remaining cases remains a high priority. Hum Mutat 11:456–460, 1998. © 1998 Wiley-Liss, Inc.     

The M694I/M694I genotype: A genetic risk factor of AA-amyloidosis in a group of Algerian patients with familial Mediterranean fever

Familial Mediterranean fever (FMF, OMIM 249100) is the most common hereditary fever, resulting from mutations in MEFV. FMF is characterized by episodic febrile attacks and polyserositis. Renal AA-amyloidosis is a major complication, which often leads to end-stage renal disease in untreated patients. The data about the renal AA-amyloidosis secondary to FMF are scarce in North African countries and non-existent in Algeria. We aimed to investigate the MEFV mutations associated with this complication in an Algerian patient cohort. Molecular analysis included 28 unrelated Algerian FMF patients with ascertained amyloidosis, 23 of them were symptomatic and 5 were asymptomatic. For this study, a group of 20 FMF patients without renal amyloidosis were selected as controls according to their age, disease onset and disease duration. The mutations were detected by sequencing exon 10 of MEFV. A total of 87.5% (49/56) mutant alleles were identified in 27/28 analyzed patients; p.M694I was predominant and appeared with an allele frequency of 62.5%, followed by p.M694V (17.85%), p.M680I (5.35%) and p.I692Del (1.78%). Remarkably, only p.M694I mutation was observed among the asymptomatic patients. The M694I/M694I genotype, identified in 14/27 (52%) patients, was significantly associated with the development of amyloidosis compared to group of controls (p = 0.022). This study did not link the M694V/M694V genotype to the renal complication despite the fact that it has been observed only in the patients with amyloidosis (3/27; 11%) (p = 0.349). The association of other identified genotypes to this complication was statistically insignificant. The progression of amyloidosis led to end-stage renal disease in 14 patients with 6 deaths. This study shows that p.M694I homozygosity is a potential genetic risk factor for the development of renal AA-amyloidosis in Algerian FMF patients.     

Expression of CD64 on polymorphonuclear neutrophils in patients with familial Mediterranean fever

Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent episodes of fever and serosal or synovial inflammation. We examined the utility of CD64 (FcγRI) expression in polymorphonuclear neutrophils (PMNs) as clinical and biological parameters in patients with FMF. We studied 12 Japanese FMF patients (mean age; 22·8 ± 15·5 years, male/female: 2/10), along with rheumatoid arthritis patients (RA, n = 38 male/female: 6/32, mean age; 52·2 ± 15·3 years), systemic lupus erythematosus (SLE, n = 15 male/female: 0/15, mean age; 38·5 ± 15·9 years) and 12 healthy subjects (male/female: 3/9, mean age; 37·9 ± 17·2 years). CD64 expression on PMNs was determined using flow cytometry. The quantitative expression of CD64 in patients with FMF (2439·6 ± 2215·8 molecules per PMN) was significantly higher than in healthy subjects (547·8 ± 229·5, P = 0·003) or in patients with RA (606·5 ± 228·2, P < 0·0001) and SLE (681·3 ± 281·1, P = 0·004). The increased CD64 expression on PMNs isolated from untreated FMF patients was down‐regulated by colchicine treatment. NACHT‐LRR‐PYD‐containing protein 3 (NLRP3) activation using MurNAc‐_L‐Ala‐_D‐isoGln (MDP) resulted in increased CD64 expression on PMNs from healthy subjects. Our results suggest that quantitative measurement of CD64 expression on PMNs can be a valuable tool to discriminate between FMF and autoimmune diseases.