Familial Mediterranean Fever: Effects of Genotype and Ethnicity on Inflammatory Attacks and Amyloidosis Aviva Mimouni, MD*; Nurit Magal, PhD*; Nava Stoffman, MD*; Tamy Shohat, MD*; Ara Minasian, MD‡; Michael Krasnov, MD*; Gabrielle J. Halpern, MRCPsych*; Jerome I. Rotter, MD§; Nathan Fischel-Ghodsian, MD§; Yehuda L. Danon, MDʈ; and Mordechai Shohat, MD* ABSTRACT. Objective. The gene causing familial factors other than genotype, such as environment or genes Mediterranean fever (FMF)—an autosomal recessive dis- other than MEFV, play a role in the determination of the ease characterized by recurrent short episodes of fever severity of the inflammatory attacks in FMF. Pediatrics associated most commonly with peritonitis, pleuritis, 2000;105(5). URL: http://www.pediatrics.org/cgi/content/ and arthritis—has recently been found and several mu- full/105/5/e70; amyloidosis, specific mutation, phenotype-ge- tations identified. The most severe complication of the notype correlation, ethnicity. 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 ABBREVIATIONS. FMF, familial Mediterranean fever; MEFV, well as on the development of amyloidosis in FMF in a Mediterranean fever (the FMF gene); PCR, polymerase chain re- large and heterogeneous group of patients. action; CI, confidence interval. Methodology. We studied 382 patients from 4 ethnic origins living in different environments: North African amilial Mediterranean fever (FMF) is an auto- Jews, other Jews, Turks, Armenians living in the United somal recessive disease affecting primarily non- States, and Armenians from Yerevan, Armenia. Informa- tion regarding amyloidosis was available for 371 pa- Ashkenazi Jews, Armenians, Turks, and Ar- F1 tients. We examined the association between the muta- abs. The carrier rate in these populations is very tion M694V and the development of amyloidosis, and we high, with estimates based on family studies as high also compared the clinical characteristics of the inflam- as 1:5 to 1:7 among some non-Ashkenazi Jewish pop- matory attacks in patients from different ethnic origins, ulations,2 and 1:7 among Armenians in California.3 while controlling for the type of mutation. The disease is characterized by recurrent short epi- Results. A significant association was found between sodes of inflammation and serositis including fever, amyloidosis and the most common mutation in exon 10 peritonitis, pleuritis, synovitis,1,3,4 and, rarely, peri- of the FMF gene (MEFV), M694V (for M694V homozy- carditis.5 The clinical symptoms can vary in different -Amyloid .(2.71–1.16 ؍ CI %95 ;1.77 ؍ gotes, relative risk osis was present in 44 of 171 homozygous FMF patients patients, sometimes even in the same family. Amy- (25.7%), in 22 of 143 compound heterozygous FMF pa- loidosis, similar to that seen in other chronic inflam- tients (15.4%), and in 7 of 57 patients carrying other matory diseases such as rheumatoid arthritis, is the mutations (12.3%). In homozygotes for M694V who had most severe complication of FMF and leads to renal not been treated with colchicine before 20 years of age, failure. the risk of amyloidosis developing before this age was There is ethnic variability in the prevalence of 61.0%. In our series, there were no cases of amyloidosis in amyloidosis, which occurs in 60% of the Turks, in 16 patients carrying the common mutation E148Q. We 27% of the non-Ashkenazi Jews, and in 1% to 2% of found that the type and severity of the FMF inflamma- 6 tory symptoms were associated with both the genotype the Armenians in the United States. In untreated and the country of residence of the patient. Jewish patients of North African origin, the fre- Conclusions. In the light of the high frequency of amy- quency of amyloidosis increases progressively with loidosis in homozygotes for the mutation M694V, colchi- age, occurring in up to 75% of those over 43 years.7 cine treatment should be given to this group irrespective of Colchicine has been shown to be effective in prevent- the severity of the inflammatory attacks to prevent the ing the attacks of FMF as well as the development of development of amyloidosis. Our findings also suggest that amyloidosis.8–10 Some individuals develop amyloid- osis without having recurrent inflammatory epi- 11 From the *Department of Medical Genetics, FMRC and Beilinson Campus, sodes (FMF type 2), and therefore, identification of Rabin Medical Center and Sackler School of Medicine, Tel Aviv University, an amyloidosis-associated mutation will allow for Tel Aviv, Israel; ‡Emergency Medical Scientific Center, Yerevan, Armenia; directing prophylactic colchicine therapy to pr- §Medical Genetics Birth Defects Center, Cedars-Sinai Medical Center, and esymptomatic individuals who can greatly benefit University of California, Los Angeles, California; and ʈDepartment of Im- munology, FMRC and Beilinson Campus, Rabin Medical Center and Sack- from it. ler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Linkage between the gene responsible for FMF Received for publication Jun 29, 1999; accepted Dec 21, 1999. (MEFV) and the short arm of chromosome 16 was Address correspondence to Mordechai Shohat, MD, Department of Medical first shown in 1992,12 and locus homogeneity was Genetics, Rabin Medical Center, Beilinson Campus, Petah Tikva, 49100, 13 Israel. E-mail: [email protected] demonstrated for all ethnic groups studied. Re- 14,15 PEDIATRICS (ISSN 0031 4005). Copyright © 2000 by the American Acad- cently, the gene causing FMF has been cloned, emy of Pediatrics. and 4 common missense mutations identified in exon http://www.pediatrics.org/cgi/content/full/105/5/Downloaded from www.aappublications.org/newse70 by guestPEDIATRICS on September 29, Vol. 2021 105 No. 5 May 2000 1of7 10. More recently, additional mutations have been tic criteria and who had no family history of FMF that could found in exons 2, 3, 5, and 10.16–19 The protein en- suggest a carrier state by descent. We believe that when more FMF 14 15 mutations are discovered, these patients will be found to have 1 of coded by the gene, named pyrin or marenostrin, is these as yet undiscovered mutations. a member of a family of nuclear factors homologous The diagnosis of FMF in siblings when the proband was found to the Ro52 autoantigen. to have 2 FMF mutations was based on the presence of these same Previous phenotype/genotype correlation studies 2 mutations in the sibling, and when the proband had only 1 have shown conflicting results regarding the corre- known mutation, it was based on the demonstration of the sharing of 2 alleles with the proband, by studying polymorphic markers lation between the severity of FMF and the mutation adjacent to the MEFV gene (D16S3070, D16S3370, D16S2617, and M694V.20–22 Two of these studies20,21 found that ho- D16S3275).12 Asymptomatic individuals who were found to carry mozygosity for the mutation M694V was signifi- mutations in both alleles were considered affected. cantly associated with a more severe form of the disease, but they were both based on a population Phenotype Parameters where it was not possible to differentiate between the The phenotype variables that were determined in all the af- effect of the mutation and the effect of the environ- fected individuals were age of onset of the inflammatory attacks, ment. The same studies have also reported con- organs involved during the attacks (resulting in peritonitis, pleu- ritis, arthritis, or the presence of fever only), number of attacks flicting and inconclusive results with regard to the before the commencement of colchicine treatment, age of diagno- association between homozygosity for M694V and sis, and the presence and age of onset of amyloidosis. Age of amyloidosis21–24; however, they dealt with popula- commencement of colchicine treatment was also noted. tions with insufficient variability of mutations or For several patients, information on some of the parameters of phenotype variables was missing. The number of attacks per year where most of the affected individuals had been was considered missing when treatment with colchicine was ini- 21,24 treated. tiated less than a year after the onset of the FMF symptoms (99 of A previous study by us22 based on 138 affected 382), and the age of onset was considered missing when there was individuals showed no significant phenotype-geno- a problem with recall, usually in older patients (70 of 382). We type correlation with regard to the inflammatory excluded these patients when these parameters were analyzed. attacks, but did demonstrate a correlation between amyloidosis and the mutation M694V. Twenty out of Subjects With Amyloidosis the 138 affected individuals developed amyloidosis, Information regarding amyloidosis was available in 371 pa- tients. Amyloidosis was diagnosed in 73 of 371 patients and was but because of the small numbers involved, espe- the presenting symptom in 7 (FMF type 2). Of these 73 patients, 10 cially of those with amyloidosis, we could not make were North African Jews, 2 were other Jews (both of Iraqi origin), recommendations regarding treatment. 3 were Armenians living in the United States, 47 were Armenians The aims of this study were to investigate in a from Yerevan, and 11 were Turks. large and heterogeneous group of patients the as- Amyloidosis in the Armenians from Yerevan was diagnosed by rectal biopsy in 3 patients and by the presence of persistent pro- sociation between amyloidosis and the common teinuria (Ͼ300 mg/dL) in 44 FMF patients—all whom were on mutations in MEFV, to compare the genotype to dialysis at the time of the study. In the other ethnic groups, the phenotype in FMF patients before their com- amyloidosis was diagnosed by rectal and/or renal biopsy. In all mencing colchicine treatment, and to correlate the these cases, amyloidosis was diagnosed in previously untreated or effect of ethnicity and environment (ie, country of inadequately treated patients.