Familial Mediterranean fever (FMF) has always been considered a recessively inherited disease occurring in people with two Mediterranean fever gene mutations (MEFV) - one from each parent. However, researchers at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) recently confirmed that a substantial subset of people with FMF carry only one MEFV mutation. Their findings were published in the June issue of Arthritis & Rheumatism.

Familial Mediterranean fever is an autoinflammatory disease characterized by recurring bouts of fever that are associated with attacks of severe abdominal pain. Autoinflammatory diseases result when an overactive immune system, for unknown reasons, directs white blood cells to attack the body's own tissues. In FMF this can also lead to arthritis, chest pain, and a distinctive rash. The most severe complication of FMF is amyloidosis, a potentially deadly build-up of protein in vital organs, most often the kidneys.

The disease is most common among many Middle Eastern and Mediterranean populations, including Sephardic and Ashkenazi Jews, Turks, Armenians, and Arabs. The frequency of people who carry an MEFV mutation within these groups has been reported to be as high as 39 percent.

In the decade or so that has passed since a diagnostic test was developed to identify the MEFV gene mutations in people with FMF, researchers have been unexpectedly identifying FMF patients - up to 30 percent of them in some affected populations - who appear to have only one MEFV mutation, not two. In addition they have recognized that these patients who only have one gene mutation exhibit similar clinical symptoms to FMF patients with two mutations, and also respond to standard treatment with the drug colchicine.

To explore this mystery and to confirm the existence of such cases, a team of NIAMS researchers, led by Ivona Aksentijevich, M.D., of the NIAMS' Genetics and Genomics Branch, identified 46 patients for the study. To confirm that these people truly were "missing" the second mutation, the team used a standard genetic sequencing technique, capillary electrophoresis, to screen all of the samples and a more thorough and expensive method, hybridization-based chip technology, to scan a subset of the samples. In no case did any technique result in the detection of a second MEFV mutation. The team also did not find any mutations in the noncoding section of the MEFV gene, which is often overlooked by researchers.

Dr. Aksentijevich says her team explored the possibility that the subset of FMF patients who have only one MEFV mutation might have a second disease-associated mutation in another gene that acts in concert with MEFV. To explore this hypothesis, the team tested six candidate genes known to have functions similar to MEFV. They did not find anything definitive; however, additional research will be needed as information on other gene candidates emerges.

The study's authors concluded that identification of a single MEFV mutation in people with typical FMF symptoms is sufficient evidence for doctors to diagnose FMF and start colchicine therapy. Dr. Aksentijevich says, "Our study is also interesting because it changes our view of FMF. It is more complex than we thought, and there may be more interaction with other genes."

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health (NIH), is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at 301-495-4484 or 877-22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.

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Booty MG, Chae JJ, Masters SL, Remmers EF, Barham B, Le JM, Barron KS, Holland SM, Kastner DL, Aksentijevich I. Familial mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis & Rheumatism. 2009; 60(6):1851-61.

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