Cazeneuve Cécile, Hovannesyan Zaruhi, Geneviève David, Hayrapetyan Hasmik, Papin Stéphanie, Girodon-Boulandet Emmanuelle, Boissier Brigitte, Feingold Josué, Atayan Karine, Sarkisian Tamara, Amselem Serge
Service de Biochimie et de Génétique Moléculaire, INSERM (Unité 468), Hôpital Henri-Mondor, 51 Avenue du Maréchal de-Lattre-de-Tassigny, Créteil F-94010, France.
Arthritis Rheum. 2003 Aug;48(8):2324-31. doi: 10.1002/art.11102.
Familial Mediterranean fever (FMF) is an autosomal-recessive disorder that is common in Armenian, Turkish, Arab, and Sephardic Jewish populations. Its clinical diagnosis is one of exclusion, with the patients displaying nonspecific symptoms related to serosal inflammation. MEFV gene analysis has provided the first objective diagnostic criterion for FMF. However, in the absence of an identified mutation (NI/NI genotype), both the sensitivity of the molecular analyses and the involvement of the MEFV gene in FMF are called into question. The present study was designed to further evaluate the diagnostic value of MEFV analysis in another population of Mediterranean extraction.
The MEFV gene was screened for mutations in 50 patients living in Karabakh (near Armenia) who fulfilled the established criteria for FMF. In addition, we analyzed published series of patients from the above-mentioned at-risk populations.
The mutation spectrum in Karabakhian patients, which consisted of only 6 mutations (with 26% of NI alleles), differed from that reported in Armenian patients. Strikingly, among patients from Karabakh and among all classically affected populations, the distribution of genotypes differed dramatically from Hardy-Weinberg equilibrium (P = 0.0016 and P < 0.00001, respectively). These results, combined with other population genetics-based data, revealed the existence of an FMF-like condition that, depending on the patients' ancestry, was shown to affect 85-99% of those with the NI/NI genotype.
These data illuminate the meaning of negative results of MEFV analyses and show that in all populations evaluated, most patients with the NI/NI genotype had disease that mimicked FMF and was unrelated to the MEFV gene. Our findings also demonstrate the high sensitivity of a search for very few mutations in order to perform a molecular diagnosis of MEFV-related FMF.
家族性地中海热（FMF）是一种常染色体隐性疾病，在亚美尼亚、土耳其、阿拉伯和西班牙裔犹太人群中较为常见。其临床诊断是一种排除性诊断，患者表现出与浆膜炎症相关的非特异性症状。MEFV基因分析为FMF提供了首个客观诊断标准。然而，在未检测到突变（NI/NI基因型）的情况下，分子分析的敏感性以及MEFV基因与FMF的关联都受到质疑。本研究旨在进一步评估MEFV分析在另一地中海血统人群中的诊断价值。
对居住在卡拉巴赫（靠近亚美尼亚）的50例符合FMF既定标准的患者进行MEFV基因突变筛查。此外，我们分析了上述高危人群已发表的患者系列。
卡拉巴赫患者的突变谱仅由6种突变组成（NI等位基因占26%），与亚美尼亚患者报道的不同。令人惊讶的是，在卡拉巴赫患者以及所有典型受累人群中，基因型分布与哈迪-温伯格平衡有显著差异（分别为P = 0.0016和P < 0.00001）。这些结果与其他基于群体遗传学的数据相结合，揭示了一种类似FMF的病症的存在，根据患者的血统，显示该病症影响了85 - 99%的NI/NI基因型患者。
这些数据阐明了MEFV分析阴性结果的意义，并表明在所有评估人群中，大多数NI/NI基因型患者患有类似FMF的疾病，且与MEFV基因无关。我们的研究结果还证明了在进行与MEFV相关的FMF分子诊断时，寻找极少数突变的高敏感性。
