SeminarFamilial Mediterranean fever
Section snippets
Genetics
In the vast majority of affected families, the disease occurs in members of one generation, supporting recessive transmission. However, high consanguinity rates may account for the occurrence of FMF in two or more successive generations (pseudodominant inheritance). The carrier frequency has been estimated to be as high as 1 in 6 in north African Jews and 1 in 7 in Armenians.5, 6 A high gene frequency in a given population can be explained by several mechanisms, which include genetic drift,
Epidemiology
FMF is almost completely restricted to non-Ashkenazi Jews, Armenians, Arabs, and Turks. Patients with FMF have been reported from Germany, Poland, Australia, and Brazil1 but in most of these cases the exact ancestry was not disclosed or they could be cases of another form of periodic disease. More than 90% of Jewish FMF patients are of Sephardic or Middle Eastern origin. Sephardic Jews are descendants of those expelled from Spain in the 15th century, who were dispersed through various north
Pathogenesis
The hallmark of FMF is an inflammatory reaction affecting serosal tissues such as the pleura, peritoneum, and synovium. During attacks the chemotactic activity of the polymorphonuclear leucocytes is greatly increased and there is a massive influx of granulocytes to the affected tissues.20 Physical and emotional stress, menstruation, and a high-fat diet may trigger the attacks.
Until recently the exact biochemical and molecular basis for FMF was unknown, and several hypotheses were suggested. One
Clinical manifestations
Symptoms of FMF (panel 2) start in the first decade of life in about 50% of cases, and only 5% develop the disease after the age of 30.1, 17 The incidence in the first year of life is difficult to ascertain, although there is no doubt that symptoms can start as early as 2 weeks after birth.
A typical attack consists of fever and serositis lasting from 1 to 4 days. Between attacks, FMF patients are free of symptoms and appear healthy. The frequency of the attacks varies from weekly to one every
Genotype-phenotype correlation
The presentation and severity of the disease vary.36, 37 The more severe disease seen in north African Jews than in Iraqi Jews can now be matched with the genotype analysis. Preliminary studies38, 39, 40 reveal that the severe course of FMF correlates with homozygosity for M694V, the mutation found in about 94% of north African patients. In M694V homozygotes, FMF is characterised by an earlier onset, more frequent attacks, and by more joints being affected and by the requirement for a higher
Diagnosis
There are no specific laboratory tests for FMF. During attacks, acute-phase reactants such as C-reactive protein, fibrinogen, and serum amyloid A are increased, and the erythrocyte-sedimentation rate and the white-blood-cell-count are raised too. All these tests are usually normal between attacks. The secretion of mediators of inflammation such as interleukin-1 and tumour necrosis factor (TNF) has been reported to be increased during the acute attack, whereas interferon activity was found to be
Colchicine
Since the report of Goldfinger in 1972, colchicine remains the treatment of choice for FMF.2 The adult dose is 1·0 mg daily and in non-responsive patients it can be increased to 2·0 mg.17, 32 About 65% of patients respond with complete remission, and 20–30% experience significant improvement with a reduction in the number and severity of attacks. 5–10% are non-responders but a recent study showed that the vast majority of the non-responders are non-compliant with the treatment.46 Colchicine can
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