The spectrum of Familial Mediterranean Fever (FMF) mutations

Familial Mediterranean Fever (FMF) is the prototype of a group of inherited inflammatory disorders. The gene (MEFV) responsible for this disease, comp rises 10 exons and 781 codons. Twenty-nine mutations, most located in the l ast exon, have been identified so far. It is unclear whether all are true d isease-causing mutations. Five founder mutations, V726A, M694V, M6941, M680 1 and E148Q account for 74% of FMF chromosomes from typical cases (Armenian s, Arabs, Jews, and Turks). Rare mutations are preferentially found in popu lations not usually affected by FMF (eg Europeans not from the above ancest ries). The various combinations of MEW mutations define severe to mild geno types. The trend is that genotypes including two mutations located within m utational 'hot-spots' (codons 680 or 694) of the gene are associated with s evere phenotypes, whereas mild phenotypes are associated with some other mu tations, E148Q being the mildest and least penetrant. Understanding the cor relation between the FMF phenotype and genotype is further obscured by the existence of complex alleles, modifier loci, genetic heterogeneity and poss ible epigenetic factors. Additionally, mutations in the MEW gene are though t to be involved in non FMF disorders. Carrier rates for FMF mutations may be as high as 1:3 in some populations, suggesting that the disease is under diagnosed. This review update emphasises that both clinical and genetic fea tures are to be taken into account for patient diagnosis, colchicine treatm ent and prognosis.