FMF

Familial Mediterranean fever (FMF) is an ethnically restricted genetic disease, more commonly affecting Jews, originating from North African countries, Armenians, Turks, Arabs, and individuals from other people originating from the Mediterranean basin.  Closely following the pattern of autosomal recessive inheritance, FMF is recognized by two phenotypically independent manifestations: (1) acute, short-lived painful, febrile attacks of peritonitis, pleuritis, or arthritis, and (2) nephropathic amyloidosis, which can lead to terminal renal failure even at young age.  Manifestations appear early in life, in half of the patients before age ten.  Although more than 25 mutations have been identified in the Pyrin gene located on chromosome 16 of FMF patients, the exact pathogenesis of the disease remains unclear.

The identification of FMF is based on clinical findings, family history, physical examination and routine laboratory results obtained from patients experiencing attacks.  The diagnostic usefulness of genetic characterization in patients is limited because the mutations identified thus far cover only about 80% of FMF patients.  However, in atypical cases, genetic analysis may help.

The attacks are usually very severe, with tremendous pain, confining the patient to bed, or stopping his regular life. The abdomen, joints or chest are the most commonly involved sites. The skin, muscles and scrotum may also be involved with painful manifestations. Leg pain and attacks of fever alone also characterize the disease.

Linkage between FMF and other disease entities has been established, including polyarteritis nodosa, Henoch Schonlein purpura, Behcet's disease, glomerulonephritis, hematuria, hematochesia and spondyloarthropathy.

Amyloidosis affects a large number of untreated FMF patients.  Risk factors for amyloidosis include male gender, early age of desease onset, and presence of other genetic factors (e.g. alpha/alpha alleles of SAA gene). Its early stage is recognized by the appearance of proteinuria.  Colchicine treatment introduced in 1973, in 1-2 mg/day doses on a continuous basis, has been found to prevent attacks in most patients and amyloidosis in almost all.  However, amyloidosis is still encountered in uncompliant patients and in those who acquired amyloidosis prior to initiation of colchicine.

The mechanism of action of colchicine in preventing the attacks and amyloidosis of FMF has not been resolved.  However, it is evident that colchicine's action in preventing FMF attacks is unrelated to its action in arresting the formation of amyloid, since in some patients who are on colchicine therapy, the high rate of attacks does not change, but amyloidosis ceases to develop.  Colchicine treatment has been shown to be safe and entirely suitable for FMF patients. Unresponsiveness to colchicine is unrelated to the genetics and pathogenesis of FMF. It is probably associated with factors that determine colchicine absorption and metabolism. No alternative to colchicine is currently available. Injecting interferon may abolish an attack, if the drug is administered early in the course of the attack.

Primary and secondary infertility is much more common in untreated patients with FMF than it is in the general population.  In addition, the prevalence of pregnancy loss in women with FMF is considered to be high. Colchicine treatment reverts this obstetrical complication. Patients with a progressive stage of amyloidosis are advised not to conceive as amyloidosis and severe nephrotic syndrome may cause several maternal and fetal complications.

Although, no teratogenic effects of colchicine have been observed in the offspring of patients, amniocentesis is usually carried out on all pregnant FMF patients and karyotype analysis is performed for the detection of any chromosomal abnormalities in the fetus. 

Specific questions (not a summary or overview on the disease) may be answered by Professor Avi Livneh, M.D.
Contact Information:

Heller Institute for Medical Research
Sheba Medical Center
Tel Hashomer, Israel
FAX #: 011 972 3 530 7002
For prompt response, please indicate clearly your E-mail address, Fax # or regular mailing address.

In the United States, patients may elect to visit Dr. Dan Kastner at the National Institutes of Health
in Bethesda, Maryland.  Dr. Kastner may be contacted at the e-mail address: kastnerd@exchange.nih.gov

For a list of articles regarding FMF see below:

This list was put together by Dr. Livneh and is meant to help answer many of the questions regarding FMF.

1: Livneh A, Langevitz P. Diagnostic and treatment concerns in familial Mediterranean fever. Baillieres Best Pract Res Clin Rheumatol. 2000 Sep;14(3):477-98. (Review).

2: Shinar Y, Livneh A, Langevitz P, Zaks N, Aksentijevich I, Koziol DE, Kastner DL, Pras M, Pras E. Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rheumatol. 2000 Jul;27(7):1703-7.

3: Dode C, Pecheux C, Cazeneuve C, Cattan D, Dervichian M, Goossens M, Delpech M, Amselem S, Grateau G. Mutations in the MEFV gene in a large series of patients with a clinical diagnosis of familial Mediterranean fever. Am J Med Genet. 2000 Jun 5;92(4):241-6.

4: Samuels J, Aksentijevich I, Torosyan Y, Centola M, Deng Z, Sood R, Kastner DL. 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 Jul;77(4):268-97. (Review).

5: Ben-Chetrit E, Levy M. Familial Mediterranean fever. Lancet. 1998 Feb 28;351(9103):659-64. (Review)

6: Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, Migdal A, Padeh S, Pras M. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997 Oct;40(10):1879-85.

7: [No authors listed] A candidate gene for familial Mediterranean fever. The French FMF Consortium. Nat Genet. 1997 Sep;17(1):25-31.

8: [No authors listed] 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 Aug 22;90(4):797-807.

9: Livneh A, Langevitz P, Zemer D, Padeh S, Migdal A, Sohar E, Pras M. The changing face of familial Mediterranean fever. Semin Arthritis Rheum. 1996 Dec;26(3):612-27. (Review).

10: Pras E, Aksentijevich I, Gruberg L, Balow JE Jr, Prosen L, Dean M, Steinberg AD, Pras M, Kastner DL. Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. N Engl J Med. 1992 Jun 4;326(23):1509-13.

11: Zemer D, Pras M, Sohar E, Modan M, Cabili S, Gafni J. Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med. 1986 Apr 17;314(16):1001-5.

12: Zemer D, Revach M, Pras M, Modan B, Schor S, Sohar E, Gafni J. A controlled trial of colchicine in preventing attacks of familial Mediterranean fever. N Engl J Med. 1974 Oct 31;291(18):932-4.

13: 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 Aug;43(2):227-53.