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.     

Increased frequency of MEFV gene mutations in patients with primary dysmenorrhea

Objectives

Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent attacks of fever and polyserositis and an autosomal recessive inheritance mode. Up to 15 % of FMF patients are reported to experience perimenstrual attacks. Primary dysmenorrhea could be an incomplete abdominal attack, or patients with dysmenorrhea may have increased frequency of MEFV gene mutation carriage. Therefore, we aimed to evaluate the frequency of MEFV gene mutations in patients with dysmenorrhea.

Methods

Eighty-four patients with primary dysmenorrhea attending consecutively to our gynecology department and 73 healthy female controls selected from hospital staff were included in the study, and MEFV gene mutations were analyzed.

Results

The prevalence of total allelic variants was significantly increased in dysmenorrhea patients (p = 0.015); analysis of individual variant rates revealed a significant increase in the frequency of MEFV gene mutations in dysmenorrhea patients compared with the control group (p = 0.036).

Conclusion

Gynecologists and primary care physicians must be aware of FMF in the differential diagnosis of dysmenorrhea.     

Prevalence of insulin resistance and metabolic syndrome in patients with gouty arthritis

The study was performed to confirm the high prevalence of metabolic syndrome in gouty patients and to define the relationship between insulin resistance and gouty arthritis. We recruited 83 patients with gouty arthritis and checked clinical factors according to the diagnostic criteria of metabolic syndrome from the ATP III guidelines and WHO Asia-Pacific obesity criteria recommendations. We also assessed the clinical characteristics of subjects and homeostasis model assessment of insulin resistance (HOMA-IR) and compared with previous study groups as controls. The prevalence of metabolic syndrome in patients with gout was 30.1% according to ATP III criteria and 50.6% with WHO Asia-Pacific adjustment and is significantly higher than the previous control study groups (ATP III: 5.2, 10.6%, WHO Asia-Pacific adjustment: 9.8, 13.9%). The mean value of HOMA-IR in patients with gout was 2.63 ± 1.36 and is significantly higher than control study (1.91 ± 1.01, P < 0.05). There were significant correlations between 24-h urinary uric acid excretion and waist circumference (r ² = 0.225, P = 0.049), fasting insulin (r ² = 0.241, P = 0.035), and insulin resistance (HOMA-IR) (r ² = 0.271, P = 0.017). There were significant correlations between insulin resistance and waist circumference (r ² = 0.341, P < 0.01), BMI (r ² = 0.390, P < 0.01). The value of HOMA-IR (insulin resistance) and the prevalence of metabolic syndrome in patients with gout are significantly higher than normal healthy control groups. The hyperuricemia in gout might be caused by the increased adiposity associated with insulin resistance.     

Prevalence and clinical significance of HFE gene mutations in patients with iron overload

OBJECTIVE: The HFE gene contains two mutant alleles; C282Y and H63D. The C282Y mutation occurs in 55-100% of patients with hereditary hemochromatosis. The aim of our study was to re-examine the frequencies of the C282Y and H63D mutations in patients with mild and marked iron overload and in normal subjects. METHODS: A total of 82 patients with iron overload were included in this study and had hepatic iron index determination and/or quantitation of iron stores by phlebotomy. The control group consisted of 81 healthy blood donors. HFE mutation analysis was performed on leukocyte DNA using PCR-amplified genomic DNA. RESULTS: Of patients with iron overload, 70/82 (85%) were homozygous for C282Y versus 2/81 (2.5%) in the control population. Four patients had no HFE mutations despite significant iron overload, including a sister and brother (brother not included in the study group) with hepatic iron concentrations >500 micromoles/g dry weight. CONCLUSIONS: In all, 85% of our patients with iron overload were C282Y homozygotes, although a few had no HFE gene mutations. Pooled data and analysis of chromosomes considered to be at risk for H63D indicate that H63D is associated with iron overload.     

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.     

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.     

HFE gene mutations in patients with rheumatoid arthritis

OBJECTIVE: To investigate the role of C282Y and H63D mutations in HFE gene in susceptibility to rheumatoid arthritis (RA). METHODS: The distribution of C282Y and H63D mutations in patients with RA and in healthy subjects was examined by restriction endonuclease digestion of polymerase chain reaction amplified genomic DNA. RESULTS: The prevalence of C282Y mutation in patients with RA was the same as in healthy controls. In contrast, the distribution of H63D mutation was significantly higher in the total RA patient population and in DRB1 QKRAA/QRRAA epitope positive patients compared to respective groups of controls. Analysis of data showed that (1) both H63D mutation and QKRAA/QRRAA DRB1 epitope are individually associated with RA susceptibility; (2) there is interaction between these 2 factors in development of RA; and (3) both these factors combined have stronger association with RA susceptibility than with these factors individually. CONCLUSION: H63D mutation appears to play a role in pathogenesis of RA. This study is small and must be regarded as preliminary. These data therefore need confirmation from independent studies.     

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.     

MEFV gene mutations and its impact on the clinical course in ulcerative colitis patients

Ulcerative colitis (UC) is an inflammatory disease of the colonic mucosa. The presence of gene responsible for FMF, MEFV, which frequently causes inflammation, may aggravate the clinical course of UC. We aimed to determine the prevalence of MEFV mutations in UC patients and its impact on the clinical course. Four groups were formed as group 1 UC with distal disease, group 2 UC with pancolonic disease, group 3 UC with total colectomy, and group 4 Rheumatoid Arthritis (RA) patients. Eleven mutations of FMF gene were investigated. The mean age of group 1, 2, 3, and 4 were 46.7 ± 13.9, 43.8 ± 12.9, 44.8 ± 14.2, and 45.8 ± 10.9 years, respectively. The mutations were identified in 19 of the 54 UC patients (35.2%). Homozygous E148Q in 2 patients (3.7%) and heterozygous in 17 patients (31.5%) (E148Q 11.1%, M694V 5.6%, V726A 5.6%, K695R 1.8%, M680I 1.8%, and compound heterozygous 5.6%) were determined. Frequencies of MEFV mutations in group 1, 2, and 3 were 30, 27.3, and 58.3%, respectively. The mutations were identified in 3 of the 20 RA patients (15%). All of them were heterozygous. The rate of MEFV mutations were higher in group 3 than in group 4 (P = 0.018), and the number of attacks that were treated with steroid in all UC patients with mutation positive was higher than in mutation negative (P = 0.016). FMF gene mutations may be identified in UC patients up to 58.3%. It may be suggested that the UC patients with severe form should be identified for MEFV mutations before the judgment of colectomy.     

Frequency of familial Mediterranean fever (MEFV) gene mutations in patients with biopsy-proven primary glomerulonephritis

Clinical Rheumatology - Primary glomerulopathies are those disorders that affect glomerular structure, function, or both in the absence of a multisystem disorder. We aimed to evaluate the frequency...     

MEFV gene variations in patients with systemic lupus erythematosus

Abstract

Objective The aim of this study was to investigate the frequency of familial Mediterranean fever (FMF)-associated MEFV gene variations in patients with systemic lupus erythematosus (SLE).

Methods The study group comprised 190 SLE patients and 101 healthy controls of Turkish origin with no clinical features of FMF. All individuals were genotyped for the four most common MEFV gene variations (M694V, M680I, V726A and E148Q) by PCR-restriction fragment length polymorphism analysis.

Results The frequency of carrying any of the four MEFV gene variations under study was 15 % in patients with SLE and 10 % in the healthy controls (p = 0.23). After the exclusion of the less penetrant E148Q variation, re-analysis for the three penetrant mutations revealed a significant association between exon 10 variations and pericarditis [p = 0.038, odds ratio (OR) 3.5, 95 % confidence interval (CI) 1.0–12.1], and pleural effusion (p = 0.043, OR 5.2, 95 % CI 0.8–30.9). No significant association was detected between the MEFV gene variations and a higher acute phase response.

Conclusions The MEFV gene variations analyzed in our study do not seem to increase the overall susceptibility to SLE and do not have any strong association with its clinical manifestations. The possibility of a modest effect of penetrant exon 10 MEFV variants on the development of serosal effusions needs to be explored in a larger series of patients.     

Acute gouty arthritis in 4 patients with systemic sclerosis

Gout with rheumatoid arthritis or systemic lupus erythematosus is rarely reported. There has been only one previous case report of gout with systemic sclerosis. We report 4 patients with chronic systemic sclerosis who developed acute gouty arthritis. Gout does occur in systemic sclerosis although the incidence is unknown. Synovial fluid analysis may be necessary to differentiate gout from the arthropathy of systemic sclerosis.     

MEFV mutations in familial Mediterranean fever: association of M694V homozygosity with arthritis

Objective Familial Mediterranean fever (FMF) is an autosomal recessive recurrent polyserositis with a higher prevalence in some ethnic groups, including Turks. Mutations in the FMF gene (MEFV) were found associated with FMF. The aim of this study was to analyze MEFV gene mutations in FMF patients to gain insight into the mutation phenotype correlation.Objectives We analyzed the most frequent mutations (M680I, M694V, V726A, and E148Q) in a group of young male Turkish FMF patients using an amplification refractory mutation system and a commercial kit.Results M694V mutation was detected in 80% of the patients. After making a strict diagnostic discrimination between arthralgia and arthritis, arthritis was present in 71% of homozygous and 29.4% of heterozygous patients for M694V mutation. Other mutations were not found to correlate with specific symptoms or findings.Conclusion The homozygosity of M694V mutation in the MEFV gene is associated with arthritis in FMF patients.