MEFV mutations in Moroccan patients suffering from familial Mediterranean Fever

Familial Mediterranean Fever (FMF, MIM 249100) is an autosomal recessive disease mainly affecting patients of the Mediterranean basin. It is an autoinflammatory periodic disorder characterised by recurrent episodes of fever and abdominal pain, synovitis and pleuritis. FMF is caused by mutations in the Mediterranean Fever (MEFV) gene located on chromosome 16p13.3. Several mutations in the MEFV gene have been characterised in different populations. However, very little is known about mutations in the MEFV gene in patients with Moroccan origin. The aim of this study is to determine the clinical components of FMF and characterise mutations in the MEFV gene in Moroccan patients. The study was carried out on 120 unrelated Moroccan patients referred to the department of medical genetics in Rabat for suspicious FMF over a period of 10 years. Patients were screened for the most common MEFV mutations by direct sequencing of exons 2 and 10. Of the 120 unrelated patients investigated, 56 patients (47%) were carriers of one or two MEFV mutations, and 64 patients (53%) had no detected mutations. Of those with mutations, 24 were homozygous (44%), 13 were compound heterozygotes (24%), and 19 patients had only 1 identifiable mutation (32%). The most frequent mutation in Moroccan patients is M694V (47%), followed by M694I (32%), A744S (6.5%), M680L (4%), M694del (2%) and E148Q (6.5%). The R761H, K695R and I692del mutations were rarely encountered (less than 1%). The V726A mutation was not found in our study. Our data represent the first report of MEFV gene mutations causing FMF in Moroccans patients. The M694V and M694I mutations are the most common mutations found in MEFV gene in Moroccan population; while the most common mutation in Arabs from the Middle-East region, the V726A, was not found in our population.     

A case of familial Mediterranean fever associated with compound heterozygosity for the pyrin variant L110P-E148Q/M680I in Japan

Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent and self-limited fever attacks and serositis/arthritis. The M694V, M694I, M680I, V726A, and E148Q mutations in MEFV, the gene responsible for FMF, account for most FMF cases in Mediterranean populations. In Japan, M694I and E148Q are most frequently detected; M694V, M680I, and V726A have not been identified so far. We report the first case of FMF associated with M680I in Japan.     

The MEFV mutations and their clinical correlations in children with familial Mediterranean fever in southeast Turkey

The aim of this study was to determine the Mediterranean fever (MEFV) gene mutations and their clinical correlations in children with familial Mediterranean fever (FMF) in southeast Turkey. Clinical and laboratory characteristics of 147 (65 males, 82 females) consecutive children with FMF having a positive MEFV gene mutation were prospectively investigated. Patients with negative MEFV gene mutations or atypical FMF presentations and those from other regions of the country were excluded. Clinical manifestations and disease severity scores were recorded. The six most frequent MEFV mutations including M694V, V726A, R726H, P369S, E148Q and P369S were investigated by a reverse hybridization test method. The median age of study group was 9.0 years, median age at diagnosis was 7.8 years, median age at disease onset was 5.0 years, and median follow-up duration was 4.0 years. A positive family history of FMF and parent-to-offspring transmission was found in 58.5 and 42.2 % of families, respectively. The frequencies of independent alleles, with decreasing order, were E148Q (30.7 %), M694V (26.0 %), R761H (13.5 %), V726A (13.0 %), P369S (10.5 %) and M680I (6.3 %) in FMF patients. The M694V subgroup had higher mean disease severity score and longer attack duration compared with E148Q and other mutations subgroups (p < 0.05). Two patients with amyloidosis had the M694V homozygote genotype. In conclusion contrast to other regions and many other ethnicities of the world, the most frequent MEFV gene mutation was E148Q in southeast Turkey. The M694V mutation frequency was lower, and disease severity was relatively mild in FMF children of this region.     

Increased Frequency of Mutations in the Gene Responsible for Familial Mediterranean Fever (MEFV) in a Cohort of Patients with Ulcerative Colitis: Evidence for a Potential Disease-Modifying Effect?

The MEFV gene, responsible for familial Mediterranean fever (FMF), is involved in inflammatory reactions through altered leukocyte apoptosis, secretion of interleukin (IL)-1β, and activation of the NF-κ B pathway. Ulcerative Colitis (UC) and FMF are both characterized by a recurrent pattern of presentation with periods of remission and flares associated with neutrophilic infiltration at the site of injury. The aim of this study was to investigate the possible correlation between UC and MEFV gene alterations. Twenty-five consecutive, first-diagnosed and untreated UC patients, 28 control patients with rheumatoid arthritis, and 65 normal individuals were analyzed. Nonisotopic RNase Cleavage Assay (NIRCA) was applied as a first-step mutational screening method of exons 10 and 2 of MEFV gene; direct sequencing was subsequently performed to confirm the results. MEFVmutations were identified in 7 (3 M694V/0, 2 M680I/0, 1 E148Q/E148Q, and 1 A744S/0) out of 25 UC patients versus 1 (M694V/0) out of 28 rheumatoid arthritis patients (P = .0199) and 1 (M694V/0) out of 65 healthy controls (P = .0004). Four out of 7 patients with MEFVmutations had inflammatory arthritis, a clinical finding that was not observed in the 18 UC patients with unmutated MEFV (P = .0028). Patients with UC almost universally carried the T A C G MEFV exon 2 haplotype in contrast with normal individuals (P < .0001) and FMF patients (P = .0310). In conclusion the increased frequency of mutations of MEFV in UC patients, especially in those with episodic arthritis, suggests a possible modifying effect of MEFV in the disease process and its localization within the joint. The difference in distribution of MEFV exon 2 haplotypes between UC patients and both FMF patients and normal individuals, suggests that UC patients constitute a genetically distinct population. Larger, longitudinal studies are needed to confirm these initial findings.     

MEFV mutations in systemic onset juvenile idiopathic arthritis

Objectives. Autoinflammatory diseases constitute a large spectrumof monogenic diseases like FMF or cryopyrin-associated periodicsyndromes (CAPS) and complex genetic trait diseases such assystemic onset juvenile idiopathic arthritis (SoJIA). An increasedrate of MEFV mutations has been shown among patients with PANand HSP, in populations where FMF is frequent. The aim of thestudy is to search for MEFV mutations in our patients with SoJIAand see whether these mutations had an effect on disease courseor complications. Methods. Thirty-five children with the diagnosis of SoJIA werescreened for 12 MEFV mutations. The control data were obtainedfrom a previous study of our centre determining the carrierfrequency in Turkish population. Results. Two patients were homozygous and three patients wereheterozygous for the M694V mutation. One patient was a compoundheterozygote for the M680I/V726A mutations. Heterozygous V726Amutation was found in one patient. The overall mutation frequencyof patients was 14.28%. This figure had been compared with thepreviously published rate of disease-causing mutations in thiscountry, which is 5%. Disease-causing mutations were found tobe significantly more frequent in the SoJIA patients than thepopulation (P < 0.01). Among these, M694V was the leadingmutation with a frequency of 10% in SoJIA. Six patients carryingMEFV mutations were among the most resistant cases requiringbiological therapy. Conclusion. SoJIA patients had a significantly higher frequencyof MEFV mutations but clinical studies with large number ofpatients are needed to confirm the association of MEFV mutationswith SoJIA and its course. KEY WORDS: Familial Mediterranean fever, Systemic onset juvenile idiopathic arthritis, Mediteranean fever, Mutation Submitted 22 May 2008; revised version accepted 19 September 2008.     

MEFV mutations in Egyptian patients suffering from familial Mediterranean fever: analysis of 12 gene mutations

The objective of the study is to screen 12 MEFV gene mutations in Egyptian patients with familial Mediterranean fever (FMF) and to study the initial hypothesis that the phenotypic expression of the disease may be attributable to the existence of a particular mutation. We enrolled 136 Egyptian patients (74 males, and 62 females) with a clinical diagnosis of FMF. DNA was amplified by PCR and subjected to reverse hybridization for the detection of 12 MEFV gene mutations. The phenotypic expression of the disease was compared in two subgroups according to the presence of homozygote E148Q and M694V gene mutations. The most frequent gene mutations in the studied group were V726A, M694V, M680I, E148Q and M694I in 41.2, 32.4, 29.4, 25 and 20.6%, respectively. At least one of these main five founder mutations was present in 132 patients (97.1%). Thirty-two patients (23.5%) were homozygote for one of the main five founder mutations. The most common homozygote gene mutations were E148Q and M694V, each in 12 patients (8.8%). Significant increase in abdominal pain and arthritis was found in patients with homozygote M694V mutation compared to those with E148Q mutation. All patients with amyloidosis had M694V gene mutation. The increased frequency of V726A gene mutation and the rarity of amyloidosis in this study suggest that Egyptian patients may have a milder form of FMF compared to other populations. The five main founder mutations account for the vast majority of cases of FMF. M694V gene mutation may be associated with increased frequency of abdominal pain, arthritis and the presence of amyloidosis.     

Common MEFV mutation analysis in 36 Iranian patients with familial Mediterranean fever: clinical and demographic significance

Abstract

The aim of our study was to determine the spectrum of the 12 most common familial Mediterranean fever gene (MEFV) mutations in Iranian patients with heterogeneous ethnicity, using the familial Mediterranean fever (FMF) strip assay test. A total of 36 patients were diagnosed according to established clinical criteria. Genomic DNA from all patients was tested for 12 common mutations located in exon 2 (E148Q), 3 (P369S), 5 (F479L), 10 [M680I (G>C), M680I (G>A), I692del, M694V, M694I, K695R, V726A, A744S, R761H], respectively, using the FMF strip assay test. Of the 35 patients with mutations, ten were homozygote, 20 were compound heterozygote, and five were heterozygote. The most frequent genotype was M680I/M680I (6 patients, 16.7%). The most frequent mutation was M680I, followed by M694V, and V726A. The FMF strip assay test for common these 12 mutations was positive in 90.6% of alleles in this study, indicating that it appears to be an effective method for FMF mutation screening in Iranian patients.     

Common MEFV mutation analysis in 36 Iranian patients with familial Mediterranean fever: clinical and demographic significance

The aim of our study was to determine the spectrum of the 12 most common familial Mediterranean fever gene (MEFV) mutations in Iranian patients with heterogeneous ethnicity, using the familial Mediterranean fever (FMF) strip assay test. A total of 36 patients were diagnosed according to established clinical criteria. Genomic DNA from all patients was tested for 12 common mutations located in exon 2 (E148Q), 3 (P369S), 5 (F479L), 10 [M680I (G>C), M680I (G>A), I692del, M694V, M694I, K695R, V726A, A744S, R761H], respectively, using the FMF strip assay test. Of the 35 patients with mutations, ten were homozygote, 20 were compound heterozygote, and five were heterozygote. The most frequent genotype was M680I/M680I (6 patients, 16.7%). The most frequent mutation was M680I, followed by M694V, and V726A. The FMF strip assay test for common these 12 mutations was positive in 90.6% of alleles in this study, indicating that it appears to be an effective method for FMF mutation screening in Iranian patients.     

Association of clinical and genetical features in FMF with focus on MEFV strip assay sensitivity in 452 children from western Anatolia,Turkey

The aim of this study was to determine the relationship between clinical findings and the most common mutated alleles of MEFV gene in a childhood population and to determine the sensitivity of the 12-mutation-strip assay test in familial Mediterranean fever (FMF). Records of 452 FMF children living in western Anatolia, Turkey, (12.3 ± 4.7 years mean) were retrospectively reviewed. Of the 408 patients who met the Tel-Hashomer criteria, 364 were classified into two main groups (two-mutant/one-mutant allele) either of which had three subgroups. The two-mutant allele frequency was 51% and one-mutant allele 38%; 1% had complex-mutant alleles and 10% no mutant-alleles. The mean severity score was 8.3 ± 2.5. Most common clinical features were fever (81.9%), abdominal pain (86.3%) and myalgia (58.8%), and the least common ones: diarrhea (1.7%), protracted febrile myalgia (1.2%) and acute orchitis (1.5%). We detected 33 different genotypes of the MEFV gene: the most common mutant allele was M694V followed by symptomatic allele mutation of E148Q. Although not significantly associated with clinical findings, P369S mutation was not rare (7.5%). Phenotype–genotype correlation revealed that patients with two-allele mutations had more severe clinical presentation and high constipation rate (22.5%); 32.6% of patients with M694V/M694V had splenomegaly. Acute orchitis and protracted febrile myalgia as rare clinical findings were more common in M694V homozygotes. Comparisons of clinical findings among patients with one-mutation allele were made for the first time, but no significant association was found. Positive predictive value of strip assay screening for 12 mutations was recorded as 89%. We suggest that whole sequence analysis for supportive diagnosis of FMF should be performed for selected patients only.     

Familial Mediterranean Fever and Seronegative Arthritis

Familial Mediterranean fever (FMF) is characterized by recurrent, self-limited episodes of polyserositis, with articular involvement also being a common manifestation. The pattern and joint predilection of arthritis show many similarities to those of spondyloarthritis. Moreover, case series suggest an increased prevalence of ankylosing spondylitis or spondyloarthritis among FMF patients. FMF is caused by mutations in the MEFV gene encoding pyrin, which is believed to be involved in regulation of interelukin-1β activation. Recent studies conducted in populations with a high background carrier rate of MEFV variants have reported an increased frequency of M694V among AS patients with no personal or family history of FMF. These findings are of interest, as both candidate gene and genome-wide association studies suggest that the interleukin-1 cytokine pathway may be implicated in the pathogenesis of ankylosing spondylitis. Therefore, association of M694V with ankylosing spondylitis can be recognized as a geographic region–specific risk factor affecting a common inflammatory pathway in the disease pathogenesis.     

MEFV-Mutationsspektrum bei famili?rem Mittelmeerfieber (FMF)

Objectives

Familial Mediterranean fever (FMF), an autosomal recessive autoinflammatory disorder, is characterized by recurrent, self-limiting fever and serositis which is frequently seen in Mediterranean populations. In this study, we retrospectively evaluated the MEFV gene mutation distribution of 883 citizens of the Aegean region with preliminary diagnosis of FMF who were referred to the Tepecik Research and Education Hospital??s Tissue Typing and Molecular Diagnostic Laboratory (Izmir, Turkey) between 2006 and 2009.

Methods

The FMF Strip Assay? (ViennaLab Diagnostics, Vienna, Austria) was used to determine the 12 most common MEFV gene mutations in patients prediagnosed with FMF.

Findings

Allelic frequencies of the major mutations in the mutation positive groups, including M694V, E148Q, M680I(G>C), and V726A, accounted for 48.4, 16.5, 13.5, and 9.7%, respectively.

Conclusion

The M694V mutation was found to be the most common mutation among FMF patients in the Aegean region, which is in accordance with mutation studies reported from other regions of the country and different ethnic populations. An English full-text version of this article is available at SpringerLink as supplemental.     

High frequency of MEFV gene mutations in patients with myeloid neoplasm

We aimed to investigate the rate of MEFV, the gene mutated in familial Mediterranean fever, mutations in patients with myeloid neoplasm and to determine if known mutations of MEFV cause a tendency for myeloid neoplasms. The frequency of the five most common MEFV gene mutations (M694V, M680I, V726A, E148Q and M694I) was determined in 26 patients with myeloid neoplasm. We identified 1 homozygous (E148Q/E148Q), 1 compound heterozygous (M694V/E148Q) and 5 heterozygous MEFV gene mutations; none had their own and/or family history compatible with familial Mediterranean fever. The mean overall mutation rate was 0.269. We found a high frequency of carriers in patients with myelodysplastic syndrome (66.6%), polycythemia vera (33.3%) and acute myeloid leukemia (28.6%). However, there was no MEFV gene mutation in patients with chronic myeloid leukemia. In conclusion, this study reports for the first time a possibly high prevalence of MEFV gene mutations in patients with myeloid neoplasm, especially myelodysplastic syndrome, polycythemia vera and acute myeloid leukemia. Our findings could open new perspectives for MEFV gene mutations in myeloid neoplasms and its association with tumor promotion. Further research is needed to determine the actual role of MEFV gene mutations in these malignancies.     

Prevalence and significance of the MEFV gene mutations in childhood Henoch–Schönlein purpura without FMF symptoms

Familial Mediterranean fever (FMF) has been reported more frequently in patients presenting with Henoch–Schönlein purpura (HSP) than in the general population. But, there is no clear knowledge about MEFV mutations in patients with HSP. We investigated the prevalence of MEFV mutations in children with HSP and without FMF whether these mutations have any effect on the disease course or complications. A total of 76 children with HSP who had no typical symptoms of FMF were screened for the mutations in exon 2 and exon 10 of the MEFV gene. Eleven of 76 patients (14.4 %) were heterozygous (E148Q in 5, M694V in 4, M680I in 1, E148V in 1), 5 (6.6 %) were homozygous (M694V/M694V in 4, V726A/V726A in 1), and 2 (2.6 %) were compound heterozygous (E148Q/M694V mutations in 1 and L110P/E148Q mutations in 1). Altogether, 7 patients carried 2 mutated MEFV alleles (9.2 %), which was higher than that observed in the general Turkish population (1 %). No significant differences in joint, gastrointestinal, renal involvement, or subcutaneous edema, and also acute phase reactants including leukocyte count, erythrocyte sedimentation rate, and serum C-reactive protein concentration were found between the groups. The prevalence of the two allele-MEFV mutations in patients with HSP was found higher than that of the general population. However, it seems that MEFV gene mutations may not have any effect on the clinical presentation of HSP.     

Prevalence and significance of MEFV gene mutations in patients with gouty arthritis

Gouty arthritis is a chronic erosive autoinflammatory disease. Pyrin has anti-inflammatory effects in the regulation of inflammasome and is encoded by the MEFV gene. The relationship between different rheumatic diseases and the MEFV gene mutations was demonstrated. The aim of this study was to determine the frequency of MEFV gene mutations in patients with gouty arthritis and identify a possible correlation with disease phenotype. Ninety-three patients with gouty arthritis and 102 healthy controls, compatible with age, gender and ethnicity, were included in the study. MEFV gene mutations were investigated by PCR method. Out of 93 patients with gouty arthritis, 36 (38.7 %) showed MEFV gene mutations carriage, whereas 20.6 % in healthy control group. Distribution of mutations identified in patients with gouty arthritis was as; R202Q in 18 (19.3 %), E148Q in 5 (5.4 %), K695R in 4 (4.3 %), M680I in 2 (2.1 %), V726A in 2 (2.1 %), P369S in 2 (2.1 %), R408Q in 2 (2.1 %), M694 V in 1 (1.1 %), respectively. Three patients were identified with compound heterozygosity. Distribution of MEFV gene mutations carriage in healthy controls was; E148Q in 11 (10.7 %), M694 V in 2 (1.9 %), M694I in 1 (0.9 %), M680I in 2 (1.9 %), V726A in 1 (0.9 %), A744S in 1 (0.9 %), K695R in 2 (1.9 %), and P369S in 1 (0.9 %) patients, respectively. Higher MEFV gene mutations carrier frequency was observed in patients with gouty arthritis, compared with the control group (p = 0.009). Heterozygous R202Q was the most common mutation detected in patients with gouty arthritis, while heterozygous E148Q in healthy control group. Statistically significant difference was not detected between clinical findings of gouty arthritis and the MEFV gene mutations (p > 0.05). We determined higher prevalence of MEFV gene mutations in patients with gouty arthritis compared with the healthy control group. The most frequently detected mutation was heterozygous R202Q, whereas E148Q in healthy controls. High carriage rates of MEFV gene mutations in gouty arthritis suggest that it may play an important role in the pathogenesis of the disease and predisposition to the disease.     

Familial Mediterranean fever in three Japanese patients,and a comparison of the frequency of <Emphasis Type="Italic">MEFV</Emphasis> gene mutations in Japanese and Mediterranean populations

We report on three Japanese patients (two families) with familial Mediterranean fever (FMF), a rare disease in the Far East. Two of the patients (siblings with definite FMF) were heterozygous for both E148Q and M694I, and the remaining patient (with probable FMF and no family history of the disease) was heterozygous for both P369S and R408Q. Although the M694I mutation is less common among Mediterranean populations, it was present in 22 (76%) of 29 Japanese patients with FMF (previously reported cases). We therefore investigated the allele frequency of M694I in the healthy Japanese population, as well as other FMF-causing mutations in exon 10 (M680I, M694V, and V726A) and polymorphisms (E148Q, P369S, and R408Q) of the Mediterranean fever gene (MEFV). The allele frequencies of disease-causing mutations, even M694I, were <0.001. While those of E148Q, P369S, and R408Q were 0.23, 0.057, and 0.054, respectively. Because of the low allele frequencies of disease-causing mutations, FMF is an extremely rare disease among Japanese individuals. However, FMF is an important component of hereditary autoinflammatory syndrome, and a diagnosis of FMF is crucial for the choice of treatment, because of the benefit of colchicine therapy.     

The clinical and genetical features of 124 children with Familial Mediterranean fever: experience of a single tertiary center

The aim of the present study was to evaluate the clinical features of childhood-onset Familial Mediterranean fever (FMF) patients and to assess the phenotype–genotype correlation. The study included patients with childhood-onset FMF that followed up over a period of 18 years in the Division of Pediatric Allergy and Immunology clinic. Twelve MEFV mutations were investigated in all patients. The patients were classified into four groups according to mutations: 1, M694V homozygote; 2, M694V heterozygote; 3, compound heterozygote for M694V; and 4, other-other gene mutation group. The following parameters were evaluated: gender, age of onset, age at diagnosis, time interval between disease onset and diagnosis, fever, abdominal pain, chest pain, arthralgia, arthritis, myalgia, vomiting, diarrhea, constipation, headache, erysipela-like erythema, protracted febrile myalgia, splenomegaly, hepatomegaly, consanguinity, number of attacks before and after treatment, severity score, response to colchicine treatment. Of the 124 patients included in the study, 105 had at least one MEFV gene mutation. M694V homozygosity was the most common mutation, followed by M694V heterozygotes and M694V—M680I compound heterozygotes. Severity score was found significantly higher in patients with M694V homozygote and compound heterozygote for M694V compared with other groups. The data supported the findings in literature that FMF patients with M694V homozygote and compound heterozygote for M694V gene mutations experience a more severe clinical course.     

A very frequent mutation and remarkable association of R761H with M694V mutations in Turkish familial Mediterranean fever patients

Familial Mediterranean fever (FMF) is an autosomal-recessive disease. It is characterized by recurring fever, abdominal pain, and serositis. The Mediterranean fever (MEFV) gene is localized on 16p13.3 and more than 35 mutations have been described to date. There are some differences in the gene mutations of FMF in the various ethnic groups. The aim of this study is to determine the frequency of the mutations which has been reported comparatively rare, to define the most effective mutation set, and to select the most suitable DNA analysis system for Turkish FMF patients. Mutations in 330 Turkish FMF patients with typical phenotypes from various regions of Turkey were evaluated for the research purposes. These patients were analyzed for six MEFV gene mutations by the NanoChip® Molecular Genetics Workstation. The most frequent mutation was M694V, identified in 50.00% of the alleles examined; M680I followed with 14.10% and V726A—9.70%. Consequently, we determined that R761H (n?=?23; 3.48%) was the most frequent rare mutations in Turkish FMF patients. Frequency of the rare mutations were R761H (3.48%), E148Q (1.36%), and M694I (1.21%). All of these mutations were in the compound heterozygote state. Our study showed that R761H mutations were higher than it has been reported in literature until now and were mainly associated with M694V. We suggest that mutation R761H should be included in the mutation scanning analysis researches or considered if the patient has M694V/? mutation especially in Turkish FMF patients. Larger serial studies need to be done to investigate the rate and coexistence of these mutations.     

Association of familial Mediterranean fever–related MEFV variations with ankylosing spondylitis

Objective

The pathogenesis of ankylosing spondylitis (AS) has a strong genetic contribution. Familial Mediterranean fever (FMF) is an autosomal recessively inherited autoinflammatory disorder caused by MEFV gene missense variations, and a clinical association between FMF and AS has been reported previously. The aim of this study was to analyze the association of common MEFV variations (M694V, M680I, V726A, and E148Q) with AS in a group of Turkish patients.

Methods

The study group comprised 193 patients with AS and 103 matched healthy control subjects. All individuals were genotyped for 4 MEFV variations and HLA–B27 using genomic DNA, and association of the variations with the clinical and laboratory features of the patients was analyzed.

Results

The MEFV missense variations were significantly more frequent in patients with AS (22.3%) compared with healthy control subjects (9.7%; odds ratio [OR] 2.67, 95% confidence interval [95% CI] 1.28–5.56). This difference was more prominent for exon 10 variations (M694V, V726A, M680I) (OR 3.75, 95% CI 1.41–9.97), especially for the most‐penetrant variation M694V (OR 4.73, 95% CI 1.39–16.12). MEFV variations were more frequent in HLA–B27–negative patients with AS, and the difference was statistically significant in patients carrying exon 10 variants.

Conclusion

FMF‐related MEFV variations are associated with AS, and these variations may contribute to the pathogenesis of AS, especially in populations in which the prevalence of FMF is high.

     

Familial Mediterranean fever: high gene frequency and heterogeneous disease among an Israeli-Arab population

OBJECTIVE: Familial Mediterranean fever (FMF) is an autosomal recessive disease that primarily affects non-Ashkenazi Jews, Armenians, Arabs, and Turks. The FMF (MEFV) gene responsible for the disease has been recently identified. Four missense mutations in exon 10 of the FMF gene seem to account for 86% of the DNA variations identified in patients with FMF. We conducted a phenotype/genotype correlation study in a homogenous population of Israeli-Moslem Arab patients with FMF and performed a mutational screening analysis on DNA samples from healthy individuals of this ethnic group. METHODS: Sixty-five patients clinically diagnosed as having FMF underwent molecular genetic studies using polymerase chain reaction and restriction endonuclease digestion methods to detect the presence of the 4 mutations (M694V, V726A, M680I, M694I). We then correlated the presence of each mutation with age of onset, clinical manifestations, and disease severity; patients whose allelic combination included M694V were then excluded from further statistical analysis, since the association of severe disease with the M694V allele has already been shown. In addition, we screened for FMF mutations the DNA samples from 318 healthy Moslem Arab individuals for the presence of these mutations. RESULTS: Among the 65 patients who were clinically diagnosed as having FMF, 78.5% had one or 2 mutation-bearing chromosomes. The most prevalent mutation was V726A, followed by M680I, M694V, and M6941. No significant difference in phenotypic characteristics was found between the patients with the diverse mutations. The total carrier frequency for the 4 mutations was 10.4% (95% confidence interval 0.07 to 0.137). CONCLUSION: A high FMF gene frequency was found among an Israeli-Moslem Arab population. Among the FMF patients from this ethnic group, several mutations were detected, none of which was found to correlate with a severe course of the disease.     

Clinical and diagnostic value of genetic testing in 216 Israeli children with Familial Mediterranean fever

OBJECTIVE: Familial Mediterranean fever (FMF) is an autosomal recessive disease with diverse clinical presentation. The FMF gene (MEFV) has recently been cloned and 30 point mutations causing the disease have been identified. We appraised the value of mutation analysis as a diagnostic test for FMF in symptomatic pediatric patients, and explored the possible correlations between MEFV genotypes and the diverse phenotypic expression of the disease. METHODS: Two hundred sixteen children who met the clinical criteria for FMF underwent molecular genetic studies to detect the 3 most common mutations in the Israeli FMF patient population (M694V, V726A, E148Q). The mutations found were related to clinical presentation and disease severity, using the Tel-Hashomer severity score. RESULTS: Of the 216 children who fulfilled the diagnostic criteria for FMF, 82 (38.0%) had 2 of the tested mutations, 73 (33.8%) had only one mutation, and 61 (28.2%) had none of the mutations studied. The M694V was the most frequent mutation, detected in 174 of 432 MEFV alleles (40.0%). The V726A mutation was found in 39 alleles (9.0%) and the E148Q mutation in 25 (5.8%). The severity score correlated with the number of mutations. Children with no mutations presented at an older age compared to children with one or 2 mutations. Children homozygous for the M694V mutation presented at a younger age, had a higher severity score, and more commonly had arthritis. CONCLUSION: Limited genetic molecular testing for MEFV mutations may explain some of the FMF clinical variability, but is diagnostically ineffective. The use of clinical criteria remains essential in establishing the diagnosis of FMF.