Smarter Decisions,
Better Care

UpToDate synthesizes the most recent medical information into evidence-based practical recommendations clinicians trust to make the right point of care decisions.

  • Rigorous editorial process: Evidence-based treatment recommendations
  • World-Renowned physician authors: over 5,100 physician authors around the globe
  • Innovative technology: integrates into the workflow; access from EMRs

For more information, click below.


Subscribers log in here


Pathophysiology of familial Mediterranean fever

INTRODUCTION

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 [1]. 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 [2].

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 [3]. 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) [4]. Approximately 1:300 Ashkenazi Jews and 1:25 Iraqi Jews carried two mutations, suggesting that most subjects with double mutations are unaffected by disease [4]. 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).

     

Subscribers log in here

To continue reading this article you must have access through your hospital or your group practice, log in to your personal subscription, or purchase a personal subscription. For more information, click below.
Literature review current through: Apr 2013. | This topic last updated: Nov 29, 2012.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2013 UpToDate, Inc.
References
Top
  1. Sohar E, Gafni J, Pras M, Heller H. Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 1967; 43:227.
  2. Shohat M, Livneh A, Zemer D, et al. Twin studies in familial Mediterranean fever. Am J Med Genet 1992; 44:179.
  3. 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.
  4. Kogan A, Shinar Y, Lidar M, et al. Common MEFV mutations among Jewish ethnic groups in Israel: high frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state. Am J Med Genet 2001; 102:272.
  5. 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.
  6. Livneh A. Reported at Familial Mediterranean Fever (FMF) and Beyond: The 4th International Congress on Systemic Autoinflammatory Diseases, November 6-10, 2005, Bethesda, Maryland.
  7. 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.
  8. French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997; 17:25.
  9. 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.
  10. Stehlik C, Reed JC. The PYRIN connection: novel players in innate immunity and inflammation. J Exp Med 2004; 200:551.
  11. Drenth JP, van der Meer JW. The inflammasome--a linebacker of innate defense. N Engl J Med 2006; 355:730.
  12. Aksentijevich I, The National Institute of Arthritis and Musculoskeletal and Skin Diseases, 2011, personal communication.
  13. 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.
  14. 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.
  15. Majeed HA, El-Shanti H, Al-Khateeb MS, Rabaiha ZA. Genotype/phenotype correlations in Arab patients with familial Mediterranean fever. Semin Arthritis Rheum 2002; 31:371.
  16. Centola M, Kastner D, and the International FMF Consortium. Cloning of MEVF: Implications for the pathophysiology of familial Mediterranean fever. In: Familial Mediterranean Fever, Sohar E, Gafni J, Pras M (Eds), Freund Publishing House, London 1997.
  17. Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet 2001; 9:473.
  18. Pras M. Amyloidosis of familial mediterranean fever and the MEFV gene. Amyloid 2000; 7:289.
  19. 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.
  20. 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.
  21. 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.
  22. Papin S, Duquesnoy P, Cazeneuve C, et al. Alternative splicing at the MEFV locus involved in familial Mediterranean fever regulates translocation of the marenostrin/pyrin protein to the nucleus. Hum Mol Genet 2000; 9:3001.
  23. Matzner Y, Partridge RE, Levy M, Babior BM. Diminished activity of a chemotactic inhibitor in synovial fluids from patients with familial Mediterranean fever. Blood 1984; 63:629.
  24. Matzner Y, Brzezinski A. C5a-inhibitor deficiency in peritoneal fluids from patients with familial Mediterranean fever. N Engl J Med 1984; 311:287.
  25. Ayesh SK, Azar Y, Barghouti II, et al. Purification and characterization of a C5a-inactivating enzyme from human peritoneal fluid. Blood 1995; 85:3503.
  26. Ayesh SK, Azar Y, Babior BM, Matzner Y. Inactivation of interleukin-8 by the C5a-inactivating protease from serosal fluid. Blood 1993; 81:1424.