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The last two years have been marked by many studies trying to better characterize the clinical features of FMF in children and proposal of new treatment for those who are resistant to colchicine. In addition, many studies tried to address the potential effect of genetic modifiers on FMF and the potential effect of MEFV mutations on other inflammatory diseases. The main points arose from these studies include a breakthrough in the therapeutic approach for FMF and the lack of consistency regarding the reciprocal effect of MEFV mutations on other diseases and the effect of genetic modifiers on FMF. The highlights of these studies, their potential clinical implications and the unmet needs, which are still to be addressed, are summarised in this review.

Introduction: Familial Mediterranean fever (FMF) is an autosomal recessive disease, caused by mutations in the FMF gene MEFV (MEditerranean FeVer). It has a large phenotypic diversity even in patients with similar genotypes. Despite evidence that environmental factors (EFs) and genetic factors, including MEFV mutations (such as M694V, E148Q) and background modifier genes (MGs), affect the clinical manifestations of FMF, the relative contribution of each remains unknown., Methods: To investigate the relative contribution of environmental and genetic factors to the phenotype of FMF, we compared the intra-pair clinical concordance of 10 mono and 7 dizygotic twins with FMF. The part played by EFs was determined by the phenotypic discordance of the monozygous twins, and the MGs effect was determined by deducing the environmental effect, computed for MZ twins, from the phenotypic discordance of the dizygous twins., Results: The mean±SD of intra-pair concordance was higher in the MZ than in DZ twin group (88.1±13.2 vs. 70.7±14.1 respectively, P value<0.05). Based on the concordance in clinical manifestations in MZ and DZ twins, the environmental effect on the phenotype of FMF is estimated as 11.9%±6.6% and the MGs effect as 17.4%±15.5% in average., Conclusions: In FMF the phenotype is affected by MEFV mutations, MGs and EFs in an estimated ratio of about 6:1.5:1 respectively., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome is a sporadic disease, characterized by periodic attacks of inflammation. Mutations in the MEFV, the gene associated with familial Mediterranean fever (FMF), may lead to subclinical inflammation in asymptomatic carriers and modify the phenotype of some inflammatory diseases. We aimed at investigating the effect of MEFV gene mutations on disease phenotype in PFAPA., Patients and Methods: The cohort of this ongoing prospective study consisted of 124 children with PFAPA syndrome, followed in a single referral center, who were tested for MEFV mutations. Demographic data, clinical characteristics, and disease course of 65 PFAPA patients with and 59 without MEFV mutations (M+ and M-, respectively) were compared., Results: PFAPA attacks in carriers of MEFV mutations were shorter compared with patients without mutations (3.8 ± 1.7 versus 4.8 ± 1.9 days, P < 0.01). The difference was more pronounced in those carrying the M694V mutation. In M+ patients, the rates of patients with regularity of their attacks (49.2%) and oral aphthae (24.6%) were lower, compared with M- patients (74.5% and 43.9%, respectively, P < 0.05 for each of the 2 comparisons). M+ patients needed a lower corticosteroid (beclomethasone) dose to abort the attacks (0.16 ± 0.07mg/kg versus 0.19 ± 0.08, P = 0.028). No differences were observed in all other clinical and laboratory parameters, over a follow-up period of 4.3 years., Conclusion: In PFAPA, MEFV is a modifier gene associated with an attenuated disease severity., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To define the molecular basis of familial Mediterranean fever (FMF) in patients with only 1 mutation in the MEFV gene., Methods: Genetic analysis was performed in 20 FMF patients, including full sequencing of complementary DNA (cDNA) samples and multiplex ligation-dependent probe amplification analysis. In patients with first-degree relatives with FMF, haplotype analysis was also performed., Results: A second mutation was found in 2 patients. In the other 18 patients, we could not identify additional mutations, large genomic deletions, or duplications. Analysis of single-nucleotide polymorphisms along the cDNA ruled out a lack of expression of 1 of the alleles. In 2 of the 3 families in which more than 1 sibling had FMF, we showed that the affected siblings inherited a different MEFV allele from the parent who did not have the MEFV mutation., Conclusion: These findings are highly consistent with the existence of a clinical phenotype among some patients who are heterozygous for FMF and could explain the vertical transmission in some families. A single mutation in the MEFV gene may be much more common than was previously thought and may include up to 25% of patients who are diagnosed as having FMF.

Familial Mediterranean fever (FMF) is a disease caused by mutations in the MEditerranean FeVer gene (MEFV), and in Israel it most commonly affects Jews of North African extraction, in whom the mutation carrier rate is as high as 1 in 5. To assess the protective as well as the modulating affect of MEFV mutation carriage on various inflammatory disease states, we sought to define the frequency of MEFV mutations in Israeli Jewish individuals of various ethnicities, including those with low frequency of FMF, which were not in the focus of our attention hitherto. A total of 163 adults of Bucharian, Turkish, Georgian, Yemenite and Bulgarian origin comprised the study group. The prevalence of the most frequent MEFV mutations in the Israeli Jewish population, namely: M694V, V726A and E148Q, was assessed. The association of mutation carriage with a personal history of FMF-like phenomena, as well as various inflammatory and non-inflammatory diseases, was evaluated. A high MEFV mutation frequency was found among Jews of Bucharian, Georgian and Bulgarian origin (20%), whereas intermediate and low rates were detected in Jews of Turkish and Yemenite extraction (14 and 8%, respectively). FMF-like manifestations and related diseases were observed more often in MEFV mutation carriers than in their counterparts. MEFV mutation frequency, directly assessed by DNA analysis, exceeds the rate calculated from disease prevalence in Israeli Jewish individuals originated from ethnicities with a low prevalence of FMF. MEFV mutation carriage in this subgroup is associated with various inflammatory disorders.