Familial Mediterranean fever (FMF) is an inherited disease characterized by recurrent bouts of serosal inflammation. The cloning of the FMF gene (MEFV) promises to enhance our understanding of the sequence of events leading to the diverse clinical manifestations of this disorder.
This topic will review the pathophysiology of FMF. The clinical manifestations and diagnosis of FMF, as well as the approach to patients with abdominal pain, are discussed separately. (See "Clinical manifestations and diagnosis of familial Mediterranean fever" and "Diagnostic approach to abdominal pain in adults" and "Differential diagnosis of abdominal pain in adults".)
PATTERN OF INHERITANCE
Early surveys of large numbers of FMF patients and their families gave rise to the assumption that the disease is always inherited as a single-gene autosomal recessive trait . Although these studies have generally shown a transmission rate slightly less than that expected for an autosomal recessive trait, this was thought to be due to underdiagnosis of the disease rather than incomplete penetrance. This hypothesis is supported by a twin study, which showed full concordance for FMF in 10 pairs of monozygotic twins, but only 3 of 11 pairs of dizygotic twins .
While the complete concordance between genetically identical individuals helped establish the likelihood of autosomal recessive inheritance, it did not exclude the possibility of other genetic contributions to the severity and age of onset of illness.
The cloning of the MEVF gene in 1997 opened a new and much broader set of insights regarding the inheritance of FMF . For example, the frequency of the carrier state was evaluated in a study in which three cohorts of Jewish individuals (Ashkenazi, Iraqi, and Moroccan) were screened for three specific MEFV mutations (E148Q, V726A, and M694V) . Approximately 1:300 Ashkenazi Jews and 1:25 Iraqi Jews carried two mutations, suggesting that most subjects with double mutations are unaffected by disease . The authors estimated that, compared with individuals who are mutation positive with phenotypic expression, there are 20 to 40 times as many individuals who have mutations but do not have phenotypic expression of the disease. Several modifying genetic factors that influence disease expression have been described (see below).