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Diagnosis of Familial Mediterranean Fever by a Molecular Genetics Method

Shlomit Eisenberg, MSc; Ivona Aksentijevich, MD; Zuoming Deng, PhD; Daniel L. Kastner, MD, PhD; and Yaacov Matzner, MD
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From Hadassah University Hospital, Mount Scopus, Jerusalem, Israel; and the Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland. Acknowledgments: The authors thank Dr. M. Pras, Heller Institute of Medical Research, Sheba Medical Center, Tel Hashomer, Israel, for providing many of the DNA samples used in this study; Dr. N. Fischel-Ghodsian, Cedars-Sinai Medical Center, Los Angeles, for providing the two Armenian DNA samples; and Dr. Alexandra Mahler for critical review of the manuscript. Grant Support: By grant 95-00588 from the United States-Israel Binational Science Foundation and grant 3191 provided by the chief scientist, Ministry of Health, Israel, to Dr. Matzner. Requests for Reprints: Yaacov Matzner, MD, Hematology Unit, Hadassah University Hospital, Mount Scopus, Jerusalem, 91240; e-mail, matzner@cc.huji.ac.il. Current Author Addresses: Ms. Eisenberg and Dr. Matzner: Hematology Unit, Hadassah University Hospital, Mount Scopus, Jerusalem, 91240.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1998;129(7):539-542. doi:10.7326/0003-4819-129-7-199810010-00005
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Background: Familial Mediterranean fever is a recessively inherited disorder characterized by episodes of fever with abdominal pain, pleurisy, or arthritis. The familial Mediterranean fever gene, designated MEFV, was recently cloned, and at least three missense mutations (M680I, M694V, and V726A) that account for a large percentage of patients with this disease were identified.

Objective: To establish a diagnostic test for familial Mediterranean fever.

Design: Cross-sectional study of a convenience sample of patients attending familial Mediterranean fever clinics.

Setting: Tertiary referral hospitals.

Patients: 107 patients with familial Mediterranean fever, their family members, and controls.

Measurements: Mutations in the 107 samples were assessed by amplifying genomic DNA with use of primers that selectively amplify the normal or altered DNA sequence of the 3 MEFV mutations (amplification refractory mutation system [ARMS]). Mutations were independently assessed by automated sequencing of genomic DNA amplified by polymerase chain reaction to evaluate the sensitivity and specificity of the ARMS assay.

Results: The ARMS assay correctly identified M680I, M694V, and V726A mutations in 82 persons with mutations documented by DNA sequencing (21 homozygotes, 2 compound heterozygotes, and 59 simple heterozygotes). Of 7 persons known from family studies to be noncarriers and 18 unrelated persons who were negative for these mutations by sequencing, none had MEFV mutations according to ARMS.

Conclusion: The ARMS assay is a rapid, cost-effective, and accurate method for detecting three common mutations in familial Mediterranean fever.


Grahic Jump Location
Figure 1.
Detection of three MEFV mutations by amplification refractory mutation system (ARMS) assay. Top.Middle.Bottom.

M680I. M694V. V726A. For each mutation, the ARMS assay consists of two ARMS reactions specific for the normal or mutant sequences per person. Samples from each study participant were analyzed for each mutation by performing the two reactions. Order of loading was kept from left to right for each reaction. Genotypes (“normal” for homozygous normal, “affected” for homozygous familial Mediterranean fever [FMF], and “carrier” for heterozygous familial Mediterranean fever) were inferred from the combined results of both reactions. Water was added as a negative control. The approximate size of the amplified fragments was 200 base pairs (bp); bands migrating anodal to the specifically amplified bands are the residual primers.

Grahic Jump Location




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