Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis
- Eldad Ben-Chetrit, MD
Eldad Ben-Chetrit, MD
- Professor of Medicine
- Hadassah-Hebrew University Medical School
- Section Editors
- David S Pisetsky, MD, PhD
David S Pisetsky, MD, PhD
- Section Editor — Lupus
- Professor of Medicine and Immunology
- Duke University Medical Center
- J Thomas Lamont, MD
J Thomas Lamont, MD
- Editor-in-Chief — Gastroenterology/Hepatology
- Section Editor — Anorectal Disorders and Misc. Lower GI Disease; Nutrition, Malabsorption, and Misc. Upper GI Disease
- Professor of Medicine
- Harvard Medical School
- Deputy Editors
- Monica Ramirez Curtis, MD, MPH
Monica Ramirez Curtis, MD, MPH
- Deputy Editor — Rheumatology
- Instructor of Medicine, Part-time
- Harvard Medical School
- Shilpa Grover, MD, MPH, AGAF
Shilpa Grover, MD, MPH, AGAF
- Deputy Editor — Gastroenterology/Hepatology
- Assistant Professor of Medicine, Part-time
- Harvard Medical School
Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder characterized by recurrent attacks of fever and serosal inflammation. This topic will review the epidemiology, genetics, and pathogenesis of FMF. The clinical manifestations, diagnosis, and management of FMF are discussed in detail separately. (See "Clinical manifestations and diagnosis of familial Mediterranean fever" and "Management of familial Mediterranean fever".)
Familial Mediterranean fever (FMF) is most prevalent in individuals of Turkish, Armenian, North African, Jewish, and Arab descent. Among Armenians, the carrier rate for FMF is approximately one in seven, with an observed disease rate of roughly 1 in 500  Among the Jewish population in Israel, the carrier rate varies from one in eight in those of Ashkenazi origin, to one in six in those of North African origin, to one in four in those of Iraqi origin .
However, FMF is not restricted to these ethnic groups. It has also been reported at a lower prevalence in many other populations such as in Greece, Italy, and even Japan [2,3]. In the United States, FMF is frequently encountered in Ashkenazi Jews and immigrants from the Middle East and Armenia. In Germany, most FMF patients are of Turkish origin. In France, there is a relatively large FMF population that originated in North Africa. In the Balkans, the number of FMF patients and the rate of MEFV mutations carriage is decreasing as the country is farther from Turkey . Similarly, the prevalence of FMF is highest in southern Italy and decreases gradually toward the northern area. It is hypothesized that the origin of FMF was more than 3000 years ago in Mesopotamia . From there, the disease was spread to Armenia and Turkey in the Ancient World. In the modern world, the spread of the disease to countries far from the Mediterranean basin can be explained by easy transportation overseas and later by the air.
FMF shows considerable variability in severity and type of clinical manifestations by region. This variability is probably due to differences in MEFV mutations, additional genetic modifiers, and associated environmental factors. (See "Clinical manifestations and diagnosis of familial Mediterranean fever" and 'Genotype-phenotype correlation' below.)
MEFV gene mutations — Familial Mediterranean fever (FMF) is usually considered an autosomal recessive disease, and affected individuals have biallelic pathogenic mutations in the MEFV gene located on the short arm of chromosome 16 (16 pm 13.3) [3-5]. Five founder mutations, V726A, M694V, M694I, M680I, and E148Q, account for approximately 75 percent of FMF chromosomes from typical cases in Armenians, Arabs, Jews, and Turks . Among them, M694V is the most frequent mutation in all four populations, with a prevalence ranging from 20 to 65 percent. However, approximately 10 to 20 percent of individuals who meet diagnostic criteria for FMF have no MEFV mutations [7,8].
- Sarkisian T, Ajrapetian H, Beglarian A, et al. Familial Mediterranean Fever in Armenian population. Georgian Med News 2008; :105.
- Livneh A. Reported at Familial Mediterranean Fever (FMF) and Beyond: The 4th International Congress on Systemic Autoinflammatory Diseases, November 6-10, 2005, Bethesda, Maryland.
- Ben-Chetrit E, Touitou I. Familial mediterranean Fever in the world. Arthritis Rheum 2009; 61:1447.
- Debeljak M, Toplak N, Abazi N, et al. The carrier rate and spectrum of MEFV gene mutations in central and southeastern European populations. Clin Exp Rheumatol 2015; 33:S19.
- Samuels J, Aksentijevich I, Torosyan Y, et al. Familial Mediterranean fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine (Baltimore) 1998; 77:268.
- Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell 1997; 90:797.
- Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet 2001; 9:473.
- Booty MG, Chae JJ, Masters SL, et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum 2009; 60:1851.
- French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997; 17:25.
- Padeh S, Shinar Y, Pras E, et al. Clinical and diagnostic value of genetic testing in 216 Israeli children with Familial Mediterranean fever. J Rheumatol 2003; 30:185.
- Ben-Zvi I, Herskovizh C, Kukuy O, et al. Familial Mediterranean fever without MEFV mutations: a case-control study. Orphanet J Rare Dis 2015; 10:34.
- Marek-Yagel D, Berkun Y, Padeh S, et al. Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum 2009; 60:1862.
- Rowczenio DM, Iancu DS, Trojer H, et al. Autosomal dominant familial Mediterranean fever in Northern European Caucasians associated with deletion of p.M694 residue-a case series and genetic exploration. Rheumatology (Oxford) 2017; 56:209.
- Aldea A, Campistol JM, Arostegui JI, et al. A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: an unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder? Am J Med Genet A 2004; 124A:67.
- Migita K, Uehara R, Nakamura Y, et al. Familial Mediterranean fever in Japan. Medicine (Baltimore) 2012; 91:337.
- Stoffels M, Szperl A, Simon A, et al. MEFV mutations affecting pyrin amino acid 577 cause autosomal dominant autoinflammatory disease. Ann Rheum Dis 2014; 73:455.
- Tchernitchko D, Legendre M, Cazeneuve C, et al. The E148Q MEFV allele is not implicated in the development of familial Mediterranean fever. Hum Mutat 2003; 22:339.
- Jéru I, Hentgen V, Cochet E, et al. The risk of familial Mediterranean fever in MEFV heterozygotes: a statistical approach. PLoS One 2013; 8:e68431.
- Koné Paut I, Dubuc M, Sportouch J, et al. Phenotype-genotype correlation in 91 patients with familial Mediterranean fever reveals a high frequency of cutaneomucous features. Rheumatology (Oxford) 2000; 39:1275.
- Shinar Y, Livneh A, Langevitz P, et al. Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rheumatol 2000; 27:1703.
- Ben-Chetrit E, Lerer I, Malamud E, et al. The E148Q mutation in the MEFV gene: is it a disease-causing mutation or a sequence variant? Hum Mutat 2000; 15:385.
- Touitou I, Picot MC, Domingo C, et al. The MICA region determines the first modifier locus in familial Mediterranean fever. Arthritis Rheum 2001; 44:163.
- Cazeneuve C, Ajrapetyan H, Papin S, et al. Identification of MEFV-independent modifying genetic factors for familial Mediterranean fever. Am J Hum Genet 2000; 67:1136.
- Bakkaloglu A, Duzova A, Ozen S, et al. Influence of Serum Amyloid A (SAA1) and SAA2 gene polymorphisms on renal amyloidosis, and on SAA/C-reactive protein values in patients with familial mediterranean fever in the Turkish population. J Rheumatol 2004; 31:1139.
- Tidow N, Chen X, Müller C, et al. Hematopoietic-specific expression of MEFV, the gene mutated in familial Mediterranean fever, and subcellular localization of its corresponding protein, pyrin. Blood 2000; 95:1451.
- Stehlik C, Reed JC. The PYRIN connection: novel players in innate immunity and inflammation. J Exp Med 2004; 200:551.
- Xu H, Yang J, Gao W, et al. Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature 2014; 513:237.
- Drenth JP, van der Meer JW. The inflammasome--a linebacker of innate defense. N Engl J Med 2006; 355:730.