Familial Mediterranean fever: Epidemiology and pathogenesis
- Stephen E Goldfinger, MD
Stephen E Goldfinger, MD
- Professor of Medicine Emeritus
- Harvard Medical School
Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder characterized by recurrent bouts of fever and serosal inflammation. This topic will review the epidemiology 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".)
FMF is most prevalent in individuals of North African Jewish, Armenian, Turkish, Greek, Italian, 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 groups. FMF has also been reported at a lower prevalence in many other populations . In the United States, for example, FMF is frequently encountered in Ashkenazi Jews. FMF shows considerable variability in severity and type of manifestations by region. It is unclear if this variability is due to differences in MEFV mutations or due to associated environmental factors. (See 'Genotype-phenotype correlation' below.)
MEFV gene mutations — Familial Mediterranean fever (FMF) is usually 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. Phenotypic expression of FMF has been reported in a significant subset of patients who carry only one MEFV mutation . However, approximately 10 to 20 percent of individuals who meet diagnostic criteria for FMF have no MEFV mutations [8,9].
Genotype-phenotype correlation — M694V homozygotes have a severe phenotype and are more likely to have arthritis, renal amyloidosis, erysipelas-like skin lesions, higher fever, splenomegaly, and more frequent attacks as compared with individuals with other MEFV mutations [10,11]. In addition, they require higher doses of colchicine to prevent attacks as compared with patients with other genotypes. Mutations in E148Q have reduced penetrance, and E148Q homozygotes usually have mild disease; amyloidosis is rare . Individuals with one or no pathogenic MEFV mutation tend to have milder disease as compared with those with biallelic pathogenic variants . FMF has an incomplete penetrance and variable expression, and some individuals who have MEFV mutations do not have symptoms of the disease . (See "Clinical manifestations and diagnosis of familial Mediterranean fever", section on 'Differential diagnosis'.)
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