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Familial Mediterranean fever (FMF) is an autosomal recessive disease characterised by recurrent attacks of inflammation of serosal membranes. Amyloidosis leading to renal failure is the most severe complication in untreated patients. In Israel FMF is most frequent among Jews of North African origin. Recently the causative gene (MEFV) has been found and the common mutations characterised. The aim of this study was to investigate the carrier rates of the common MEFV mutations among 400 healthy members of four different ethnic groups (100 in each group) in Israel, and to compare the distribution of the different mutations between FMF carriers and patients. We found a high frequency of carriers among Jews from the various ethnic groups. In North African Jews it was 22%, in Iraqi Jews 39%, in Ashkenazi Jews 21%, and in Iranian Jews 6%. The distribution of the four most common MEFV mutations among healthy individuals (M694V 29%, V726A 16%, M680I 2% and E148Q 53%) was significantly different (P < 0.003) from that found in patients (M694V 84.4%, V726A 9.0%, M680I 0% and E148Q 6.6%). Six healthy asymptomatic individuals were found to carry mutations in both alleles: two homozygotes for E148Q and four compound heterozygotes E148Q/other. These results demonstrate a very high carrier rate among all Jewish ethnic groups. They confirm that mutation E148Q is associated with a milder phenotype, which explains the lower prevalence of FMF among the Ashkenazi and Iraqi Jews. This study raises the question of the need for molecular screening for

ABSTRACT. Objective. The gene causing familial Mediterranean fever (FMF)-an autosomal recessive disease characterized by recurrent short episodes of fever associated most commonly with peritonitis, pleuritis, and arthritis-has recently been found and several mutations identified. The most severe complication of the disease is amyloidosis, which can lead to renal failure. The aim of this study was to investigate the role of genetic versus nongenetic factors on the phenotype as well as on the development of amyloidosis in FMF in a large and heterogeneous group of patients.Methodology. We studied 382 patients from 4 ethnic origins living in different environments: North African Jews, other Jews, Turks, Armenians living in the United States, and Armenians from Yerevan, Armenia. Information regarding amyloidosis was available for 371 patients. We examined the association between the mutation M694V and the development of amyloidosis, and we also compared the clinical characteristics of the inflammatory attacks in patients from different ethnic origins, while controlling for the type of mutation.Results. A significant association was found between amyloidosis and the most common mutation in exon 10 of the FMF gene (MEFV), M694V (for M694V homozygotes, relative risk ‫؍‬ 1.77; 95% CI ‫؍‬ 1.16 -2.71). Amyloidosis was present in 44 of 171 homozygous FMF patients (25.7%), in 22 of 143 compound heterozygous FMF patients (15.4%), and in 7 of 57 patients carrying other mutations (12.3%). In homozygotes for M694V who had not been treated with colchicine before 20 years of age, the risk of amyloidosis developing before this age was 61.0%. In our series, there were no cases of amyloidosis in 16 patients carrying the common mutation E148Q. We found that the type and severity of the FMF inflammatory symptoms were associated with both the genotype and the country of residence of the patient.Conclusions. In the light of the high frequency of amyloidosis in homozygotes for the mutation M694V, colchicine treatment should be given to this group irrespective of the severity of the inflammatory attacks to prevent the development of amyloidosis. Our findings also suggest that factors other than genotype, such as environment or genes other than MEFV, play a role in the determination of the severity of the inflammatory attacks in FMF. Pediatrics 2000;105(5). URL: http://www.pediatrics.org/cgi/content/ full/105/5/e70; amyloidosis, specific mutation, phenotype-genotype correlation, ethnicity.