Evaluation of intima media thickness of the common and internal carotid arteries with inflammatory markers in familial Mediterranean fever as possible predictors for atherosclerosis

The aim of the present study was to determine whether intima-media thickness (IMT) of the common (CCA) and internal carotid arteries (ICA) was increased due to chronic inflammation occurring in familial Mediterranean fever (FMF) patients compared to healthy controls. Erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP), serum amyloid A protein (SAA), lipid profile and homocysteine levels were examined in 70 FMF patients [median age 14 years (range 4–24)] in an attack free period and in 50 healthy controls [median age 14 years (range 4–18)]. All the patients were homozygous or compound heterozygous for MEFV mutations. IMT of both CCA and ICA was evaluated with a high resolution B-mode ultrasonography. ESR, CRP, fibrinogen and SAA levels were significantly higher in FMF patients as compared to healthy controls (P < 0.05). Intima media thickness of the common carotid artery was found to be significantly higher in FMF patients when compared to those in healthy controls [0.37 mm (0.26–0.61) vs. 0.28 mm (0.21–0.35), P < 0.001]. The median ICA-IMT was significantly increased in the patients when compared to those in the controls [0.25 mm (0.18–0.44) vs. 0.22 mm (0.10–0.26), P < 0.001]. A positive correlation between CCA-IMT and SAA levels (r = 0.24, P = 0.04) was found while ICA-IMT positively correlated with ESR (r = 0.31, P = 0.008) and fibrinogen levels (r = 0.30, P = 0.012). Intima media thickness, an early predictor of atherosclerosis, may be associated with subclinical inflammation in children with FMF. Further studies will enlighten whether these patients will be predisposed more to coronary artery disease. Yelda Bilginer and Fatih Ozaltin contributed equally to this work.     

Familial Mediterranean fever gene mutation frequencies and genotype�Cphenotype correlations in the Aegean region of Turkey

Familial Mediterranean fever (FMF) is a disease characterized by recurrent, self-limiting fever and serositis and caused by altered pyrin due to mutated MEFV gene. The aim of this study was to investigate clinical manifestations and MEFV mutations among patients with FMF and healthy controls in the Aegean region of Turkey. This study included 308 patients and 164 healthy controls. Patients were divided into three groups according to Tel-Hashomer criteria; definitive, probable, and suspicious. Among the patients, 146 were women (47.4%) and 162 were men (52.6%). The mean age (±SD) of the patients at the diagnosis was 9.6 ± 3.95 (range 0.5–18). The mean age (±SD) at onset of the symptom was 6.2 ± 3.95 (range 1–18). Symptoms were seen earlier onset in definitive group than the suspicious group in our cohort (4.7 ± 3.9 years, 6.6 ± 3.9 years, respectively; P = 0.001). Clinical features were abdominal pain (83.1%), fever (55%), arthritis (17.1%), myalgia (4.5%), pleuritis (10%), and erysipelas—like erythema (7.7%). Fever, arthralgia, arthritis, chest pain, and amyloidosis were found statistically significant more in definitive group than suspicious group (P < 0.001, P < 0.001, P < 0.001, P < 0.05, and P < 0.001, respectively). MEFV gene mutations were identified in 199 patients (64.6%). The most commonly encountered MEFV mutation among the patients was M694V homozygote (25%). M694V homozygous mutation was found most frequently in definitive FMF group than other groups (49, 9, 8.9%, respectively). To our knowledge that FMF should be suspected in the case of non-specific but recurrent attacks of serositis and high fever, and molecular analysis should be performed in order to make diagnosis of FMF.     

Mediterranean fever (MEFV) gene mutation frequency is not increased in adults with rheumatic heart disease

It is well established that there are people with higher risk of developing acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Mediterranean fever (MEFV) gene mutations might be one of the genetic predisposition factors in the development of ARF/RHD since defect in familial Mediterranean fever (FMF) patients is proposed to be heightened inflammatory response to certain stimuli. Previous clinical observations suggested a relationship between FMF and ARF/RHD. The aim of this study was to investigate the role of the MEFV gene mutations in the susceptibility to RHD in Turkish patients. A total of 100 patients with RHD and 100 healthy controls were included in the study. Diagnosis of RHD was based on echocardiographic findings in which a predominant mitral stenosis was used as an inclusion criterion. Genetic analysis was carried out by sequence analysis investigating two hot spots (exons 2 and 10) for MEFV mutations. Mutation analysis showed that 22 RHD patients (22%) and 24 healthy controls (24%) carried at least one mutated allele. MEFV mutations were identified in 22 of 200 (11%) chromosomes in RHD patients while 26 of the 200 (13%) chromosomes of healthy controls were found to carry a mutated allele. No difference was found in allele frequencies and their distribution between the patients and healthy controls (p = 0.54). MEFV mutations are not associated with a predisposition to develop RHD in adult Turkish patients.     

The role of regulatory T cells in familial Mediterranean fever (FMF)

The role of regulatory T cells (T-regs) in familial Mediterranean fever (FMF) was never evaluated. Preliminary studies that we have conducted suggested a rise in the number of regulatory T cells after FMF attacks reaching a maximal level at 7 days. The aim of this study was to evaluate the percentage and activity of regulatory T cells in FMF. Six patients with refractory FMF and six healthy controls were evaluated. The percentage of T-reg cells and forkhead box protein 3 (Foxp3) expression was evaluated and compared between four states: FMF in remission, FMF at the first day of an attack, FMF 7 days after the start of the attack, and healthy controls. Four females and two males were included. All patients had FMF with high severity score, 2.8 ± 0.4 (0–3). The mean age was 31.6 ± 6.2. The mean age at onset was 9.3 ± 9.3. The mean colchicine dose was 2.6 mg ± 0.4. The expression of Foxp3 7 days after the attacks was significantly higher than in FMF at the first day of the attack, FMF in remission, and healthy controls 10.08 ± 2.36 vs. 7.005 ± 0.3 vs. 5.3 ± 1.06 vs. 4.44 ± 1.8; p < 0.05 (Fig. 1). The percentage of T-regs in peripheral blood was not statistically different between the four groups. Theexpression of Foxp3 by T-regs increases 7 days after attacks of FMF. Anti-inflammatory cytokines interleukin-10 and TGF-β are known to activate T-regs and have been reported to increase in FMF attacks in line with the present findings. It is suggested that T-regs may have a role in terminating FMF attacks.     

Familial Mediterranean fever: an association with non-alcoholic fatty liver disease

The purpose of this study is to characterize the chronic liver disease (CLD) that may be associated with familial Mediterranean fever (FMF). Twenty-seven patients (mean age, 48 ± 18 years; F/M, 16:11) with FMF who were referred for assessment of CLD were studied. Data regarding FMF and CLD were obtained from patient medical files. Liver biopsy was performed in 21 of 27 patients and deferred in six (cirrhotic coagulopathy in five and one who improved after colchicine dose reduction). Patients with FMF and non-alcoholic fatty liver disease (NAFLD) were compared to matched controls from a cohort of 150 patients with NAFLD per liver biopsy but without FMF. The mean Tel Hashomer severity score was 1.7 ± 0.9. The mean daily dose of colchicine was 1.4 ± 0.4 mg over a mean duration of 21 years ± 10. Seven of ten patients who underwent mutation analysis for FMF were homozygous for M694V. In 15 patients, there was evidence of NAFLD: five with “simple” steatosis, three with non-alcoholic steatohepatitis (NASH), and seven with NASH-cirrhosis. An additional five patients had “cryptogenic” cirrhosis, which in most patients represents the end result of unrecognized NASH, and one had normal liver tissue. Comparing FMF patients with NAFLD to matched controls with NAFLD did not reveal excess of metabolic syndrome in FMF patients. Of our FMF patients, 74% had evidence of NAFLD, 75% of which with severe manifestation. The extremely high proportion of NAFLD in our cohort of FMF patients without overt metabolic syndrome may indicate an unappreciated novel association between FMF and NAFLD.     

Early ultrasonographic markers of atherosclerosis in patients with familial Mediterranean fever

Systemic inflammation plays an important role in the development of atherosclerosis (AS). The aim of this study was to evaluate the presence of early AS in patients with familial Mediterranean fever (FMF) that is characterized by recurrent inflammatory attacks of serositis. Sixty-one FMF patients (30 Male/31 Female; 31.5 [18–54] years) and 31 healthy controls (16 Male/15 Female; 31 [22–58] years) were studied. All FMF patients were on regular daily colchicine treatment and during attack-free periods. Both the FMF patients and controls with a history of diabetes mellitus (DM), hypertension, and hyperlipidemia were excluded. Body mass index (BMI) was calculated. Serum lipids, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were assessed. Two-hour oral glucose tolerance test was performed to rule out DM and glucose intolerance. To investigate early AS “endothelium-dependent flow-mediated dilatation (FMD%),” “nitroglycerin-induced endothelium-independent peripheral vasodilatation (NTG%),” and intima-media thickness (IMT) of common carotid arteries (CCA) were measured by ultrasonograpy. The median disease duration for FMF patients was 16 (1–45) years. Age, sex, BMI, smoking status, and serum lipids were comparable in patients and controls (p > 0.05). However, ESR and standard CRP were significantly higher in the patients group (p < 0.05). There were no differences in the measurements of right, left, and averaged IMT of CCA between patients and controls ([0.49 vs 0.5], [0.51 vs 0.52] and [0.5 vs 0.51]; p > 0.05, respectively). None of the subjects had carotid artery plaques. FMD% and NTG% were also similar in patients and controls group ([18.2 vs 20.6] and [24.2 vs 22.5]; p > 0.05, respectively). This study suggests that the markers of early AS are not impaired in FMF patients on regular daily colchicine treatment.     

Familial Mediterranean fever with amyloidosis associated with novel exon 2 mutation (S1791) of the MEFV gene

Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent attacks of fever, serositis, and a risk for AA amyloidosis. FMF is caused by mutations in the Mediterranean fever gene (MEFV), which is expressed in blood cells of the myelomonocytic differentiation pathway. We identified a novel mutation S1791 in exon 2 of MEFV in two members of a family of Turkish origin. In both cases, S1791 was in compound heterozygosity with MEFV mutation M694V, and the characteristic clinical syndrome of FMF including amyloidosis was found. The location of S1791 in exon 2 is of interest because (1) amyloidosis in FMF has previously been found to be strongly associated with compound exon 10 mutations and (2) it supports the notion that the mechanism causing FMF is connected to the cytoplasmic rather than nuclear function of the molecule.     

The detailed assessment of left and right ventricular functions by tissue Doppler imaging in patients with familial Mediterranean fever

In the contrary to other rheumatologic disorders, there have been limited numbers of studies investigating the cardiac involvement in patients with familial Mediterranean fever (FMF), although the disease may carry a potential for cardiovascular disorders because of sustained inflammation during its course. In the present study, we used high usefulness tissue Doppler echocardiography for detailed analysis of cardiac changes in FMF patients. The study population included 30 patients with FMF (11 men, 19 women; mean age, 35 ± 7 years, mean disease duration, 15.4 ± 7.6 years) and 30 healthy subjects as controls (12 men, 18 women; mean age, 33 ± 7 years). The diagnosis of FMF was established according to the Tell–Hashomer criteria. Left and right ventricular functions were measured using echocardiography comprising standard two-dimensional, M-mode, and conventional Doppler as well as tissue Doppler imaging. The conventional echocardiographic paratemeters were similar apart from left ventricular relaxation time was longer (107 ± 25 vs 85 ± 10 ms, p < 0.001, respectively) in patients with FMF. According to the tissue Doppler measurements, while systolic velocities of both ventricles were not different, diastolic filling velocities of left ventricle including E′_m (12.6 ± 3.4 vs 14.7 ± 3.3 cm/s, p = 0.04), A′_m (10.1 ± 2.6 vs 8.6 ± 2.0 cm/s, p = 0.015), and E′_m/ A′_m (1.24 ± 0.4 vs 1.71 ± 0.5 cm/s, p = 0.012) values were statistically different between the groups. Left ventricular myocardial performance indices and right ventricular diastolic functions were found similar between two groups. In addition, there were no significant correlations between the disease duration, clinical features, and echocardiographic parameters. In conclusion, we have demonstrated that although systolic functions were comparable in the patients and controls, left ventricular diastolic function indices were impaired in FMF patients by using tissue Doppler analysis.     

Accurate diagnosis of acute abdomen in FMF and acute appendicitis patients: how can we use procalcitonin?

This study was conducted to define the value of procalcitonin (PCT) levels in the differential diagnosis of abdominal familial Mediterranean fever (FMF) attacks from acute appendicitis. From October 2006 to January 2007, 28 FMF (12 males, 16 females) patients with acute abdominal attacks and 34 patients (18 males) with acute abdomen who underwent operation with the clinical diagnosis of acute appendicitis were consecutively enrolled in this study. FMF patients with concurrent infectious diseases were excluded. PCT values were measured by an immunofluorescent method using the B.R.A.H.M.S. PCT kit (B.R.A.H.M.S. Diagnostica, Berlin, Germany). Erythrocyte sedimentation rate (ESR), C-reactive proteins (CRP) and leucocyte levels were also noted. Mean disease duration in FMF patients was 9.6 ± 8.1 years (range 2–33 years) and all were on colchicine therapy with a mean colchicine dosage of 1.2 ± 0.4 mg/day. Among the operated patients, 5 were excluded: 3 patients had normal findings and 2 had intestinal perforation (PCT levels were 2.69 and 4.93 ng/ml, respectively) at operative and pathologic evaluation. There were no significant differences between the two groups with respect to gender and age (p was not significant (NS) for all). Acute phase reactants and PCT levels were increased in patients with FMF compared to patients with acute appendicitis (0.529[0.12 ± 0.96] vs 0.095 [0.01–0.80] p < 0.001, respectively). PCT levels higher than 0.5 ng/ml were found in 11% (3/28) of FMF patients compared to 62% (18/29) of acute appendicitis patients (p < 0.001). Our results suggest that PCT could be a useful test in the differentiation of abdominal FMF attacks from acute appendicitis, though it should not supplant more conventional investigations.     

MEFV mutations in patients with familial Mediterranean fever in the Black Sea region of Turkey: Samsun experience [corrected

OBJECTIVE: To investigate MEFV mutations among patients with familial Mediterranean fever (FMF), their relatives, and healthy controls in the Black Sea region of Turkey; to compare 3 different MEFV mutation analysis methods; to evaluate the role of MEFV mutations in the diagnosis of FMF; and to investigate the role of M694V in the development of amyloidosis. METHODS: In total, 890 subjects (625 patients, 165 relatives, 100 healthy controls) were included in this prospective study. MEFV mutations were studied with the amplification refractory mutation system (ARMS; n = 335), polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP; n = 335), and reverse hybridization assay (FMF StripAssay; n = 693). RESULTS: All methods were used in 79 patients. The ratio of false negativity was about 2% using ARMS compared to PCR-RFLP. The FMF StripAssay was used to investigate 9 more mutations and detected 17 mutations in 14 patients. The M694V/M694V genotype was more common in patients with amyloidosis (37%) compared to patients without amyloidosis (18%) (p = 0.009). The frequency of MEFV carriers was 27%. The frequency of individuals having 2 mutations among asymptomatic relatives of FMF patients was 6%. CONCLUSION: The FMF StripAssay is a reliable and time-saving method. In spite of detection of new mutations and developments in MEFV assay technology, there were patients in whom no mutation was detected. Our data, combined with previous studies, show that patients having M694V/M694V carry a risk for amyloidosis.     

Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations

OBJECTIVE: To prospectively monitor inflammatory activity over a prolonged period in a cohort of Turkish patients with FMF, their healthy relatives and healthy controls and to relate this to their MEFV genotypes. METHODS: 43 patients with FMF and 75 of their asymptomatic relatives underwent fortnightly assessments and venesection for measurement of CRP and SAA over 5 months. 50 unrelated healthy population matched controls were also studied. MEFV genotyping was performed on all participants and comparisons were made between the different groups. RESULTS: Paired MEFV mutations were detected in 84% of FMF patients and single mutations in 12%. Substantial acute phase reactivity was seen among the patients with FMF during attacks (median SAA 693 mg/l, CRP 115 mg/l). Between attacks there was also some inflammatory activity (median SAA 6 mg/l, CRP 4 mg/l). Among healthy controls 16% were heterozygotes for MEFV mutations and 4% had two mutations. As expected there was a substantial carrier rate among healthy relatives with mutations detected in almost 92%. Asymptomatic MEFV heterozygotes had elevated acute phase proteins compared to wild type subjects. CONCLUSION: Substantial sub-clinical inflammation occurs widely and over prolonged periods in patients with FMF, indicating that the relatively infrequent clinically overt attacks represent the 'tip of the iceberg' in this disorder. Both basal and peak acute phase protein concentrations were greater in MEFV heterozygotes than in wild-type controls, regardless of mutation demonstrating a 'pro-inflammatory' phenotype among FMF carriers. Upregulation of the acute phase response among carriers of FMF may augment their innate host response and contribute to better resistance to infection.     

The frequency of sacroiliitis in familial Mediterranean fever and the role of HLA-B27 and MEFV mutations in the development of sacroiliitis

The objective of this study was to investigate the frequency of sacroiliitis in familial Mediterranean fever (FMF) patients and the role of HLA-B27 and MEFV mutations in the development of sacroiliitis. The study group consisted of 256 FMF patients (male 128, female 128, mean age 27.2 ± 6.3 years). After evaluation of the medical records, 70 patients (27.4%) were determined to have one or more of musculoskeletal manifestations. Sacroiliitis was determined in 18 (32.7%) FMF patients. The frequency of sacroiliitis among all FMF patients was found to be 7%. HLA-B27 was 47% and 6.3% in FMF patients with and without sacroiliitis, respectively. The frequency of M694V mutations in FMF patients with sacroiliitis was 93.7%. Sacroiliitis may be seen more frequently in FMF patients than expected. HLA-B27 positivity and/or M694V mutation may play a role in the development of sacroiliitis and the severity of seronegative spondyloarthropathy.     

Specific glycosylation of α1-acid glycoprotein characterises patients with familial Mediterranean fever and obligatory carriers of MEFV

BACKGROUND: Familial Mediterranean fever (FMF) is a periodic febrile disorder, characterised by fever and serositis. The acute phase response during attacks of FMF results from the release of cytokines, which in turn induce increased expression and changed glycosylation of acute phase proteins. A recent study indicated that attacks in FMF are accompanied by a rise of plasma concentrations of serum amyloid A (SAA) and C reactive protein (CRP), which remain significantly raised during remission relative to healthy controls. Another study suggested that obligatory heterozygotes also display an inflammatory acute phase response. OBJECTIVE: To determine the state of inflammation in homozygotic and heterozygotic MEFV genotypes. METHODS: CRP and SAA were studied by enzyme linked immunosorbent assay (ELISA). The glycosylation of the acute phase protein, alpha(1)-acid glycoprotein (AGP), was visualised with crossed affinoimmunoelectrophoresis with concanavalin A as diantennary glycan-specific component and Aleuria aurantia lectin as fucose-specific affinity component. RESULTS: FMF attacks were associated with an increase (p<0.05) in the serum inflammation parameters CRP, SAA, and AGP. The glycosylation of AGP showed an increase (p<0.05) in fucosylated AGP glycoforms, whereas the branching of the glycans remained unaffected. The glycosylation of AGP in the MEFV carrier group, compared with that in a healthy control group, was characterised by a significant increase (p<0.05) in branching of the glycans, whereas the fucosylation remained unaffected. CONCLUSION: The findings suggest an FMF-specific release of cytokines, resulting in a different glycosylation of AGP between a homozygotic and heterozygotic MEFV genotype.     

Mean platelet volume in children with familial Mediterranean fever

Familial Mediterranean fever (FMF) is the most common inherited periodic fever syndrome characterized by recurrent episodes of serositis. Recently, a few studies have suggested that FMF is related to increased risk of atherosclerosis. Mean platelet volume (MPV) is a marker of platelet activation. Larger platelets are associated with increased atherosclerosis risk. The aim of the study is to evaluate levels of MPV in pediatric FMF patients during and between attacks. The study consisted of 48 patients during an attack (group 1), 63 patients in attack-free period (at least 2 weeks after an attack, group 2), and 49 healthy controls (group 3). Erythrocyte sedimentation rate, C-reactive protein, white blood cell count, platelet count (PLT), and MPV levels were retrospectively recorded from the computerized patient database. Mean platelet volume was significantly lower in FMF patients during attack than in attack-free period (p = 0.00); however, there was no difference among attack-free patients and healthy controls (p = 0.38). The mean platelet counts of FMF patients during attack were higher than the healthy controls (p = 0.02). There was an inverse correlation between MPV and mean PLT in the attack-free period (r = −446, p = 0.01). This study suggests that an early atherosclerosis marker, MPV, is not elevated in pediatric FMF patients on colchicine treatment.     

Familial Mediterranean Fever: Genotype-Phenotype Correlations in Japanese Patients

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by MEditerranean FeVer gene (MEFV) mutations. In Japan, patients with FMF have been previously reported, including a mild or incomplete form. Several factors are presumed to contribute to the variable penetrance and to the phenotypic variability of FMF. We conducted the current study to investigate the correlation of variable clinical presentations and MEFV genotypic distributions in Japanese FMF patients.We analyzed demographic, clinical, and genetic data for 311 FMF patients enrolled in the study. Clinically, we classified FMF into 2 phenotypes: 1) the “typical” form of FMF, and 2) the “atypical” form of FMF according to the Tel Hashomer criteria. Patients with the typical FMF phenotype had a higher frequency of febrile episodes, a shorter duration of febrile attacks, more frequent thoracic pain, abdominal pain, a family history of FMF, and MEFV exon 10 mutations. Conversely, patients with the atypical FMF phenotype had a lower frequency of fever episodes and more frequent arthritis in atypical distribution, myalgia, and MEFV exon 3 mutations. Multivariate analysis showed that the variable associated with typical FMF presentation was the presence of MEFV exon 10 mutations. Typical FMF phenotype frequencies were decreased in patients carrying 2 or a single low-penetrance mutations compared with those carrying 2 or a single high-penetrance mutations (M694I), with an opposite trend for the atypical FMF phenotype. In addition, patients having more than 2 MEFV mutations had a younger disease onset and a higher prevalence of thoracic pain than those carrying a single or no mutations. Thus, MEFV exon 10 mutations are associated with the more typical FMF phenotype. In contrast, more than half of the Japanese FMF patients without MEFV exon 10 mutations presented with an atypical FMF phenotype, indicating that Japanese FMF patients tend to be divided into 2 phenotypes by a variation of MEFV mutations.     

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.     

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.     

Familial Mediterranean fever in the Iranian population: MEFV mutations in different ethnic groups

Background and aimsFamilial Mediterranean Fever (FMF) is an ethnically restricted genetic disease, found commonly among Mediterranean population, as well as Armenians, Turks, Arabs and Jews. The disease is caused by mutations in the MEFV gene, encoding the Pyrin protein. The aim of this study was to determine the mutation frequency in the clinically diagnosed FMF patients and the carrier rate among healthy first-degree relatives of patients from Iran.Methods59 patients (<17 years old) with clinical diagnosis of FMF in the absence of colchicine and 82 healthy family members, in three different ethnic groups were screened for the 5 most common MEFV mutations (M694V, M694I, M680I, V726A and E148Q).ResultsThe mean age of patients (27 females: 32 males) was 7.8 ± 3.23. Fever (94.9%) and abdominal pain (77.9%) was the most common clinical finding. Allele frequencies were different among different ethnic groups of Iranian population (p = 0.03). The most frequent mutation was M694V (29.6%) followed by M694I (8%), M680I (15%), V726A (16%) and E148Q (8%): homozygous (18.6%), compound heterozygous (52.5%) and simple heterozygous (16.9%). we could not detect any mutations in 16.95% of our patients. 9 (18%) healthy relatives were detected to have mutations of FMF.ConclusionsM694V was the most common MEFV mutation in various ethnic groups of Iranian patients.     

MEFV, TNF1rA, CARD15 and NLRP3 mutation analysis in PFAPA

PFAPA is a periodic fever disease, of unknown etiology, characterized by aphthous stomatitis, pharyngitis and cervical adenitis. To inquire whether genes implicated in other auto-inflammatory diseases might be involved in its pathogenesis, predominant mutations in the genes causing familial Mediterranean fever, TNF receptor-associated periodic fever syndrome, Crohn’s disease and Muckel–Wells syndrome were analyzed in PFAPA patients. Patients (n = 57) with PFAPA, according to previously published criteria were recruited, at the Meyer Children Hospital during 2006–2007. Clinical information was complemented during physicians–parents encounter. Predominant mutations in MEFV, TNF1rA, CARD15/NOD2 and NLRP3 genes were tested. Mean age at diagnosis was 30.64 ± 16.4 months. Boys (n = 33; 58%) were diagnosed earlier than girls (n = 21; 42%) at 26.18 ± 13.83 and 36.41 ± 18.32 months, respectively (P = 0.05). Fifteen patients (27%) carried an MEFV mutation; two patients (3.6%) a CARD15 mutation, one patient (1.8%) a variance in TNF1rA and another had both an MEFV and a CARD15 mutation. Clinical symptoms were equally manifested in carriers and non-carriers. The high carrier rate of MEFV mutations in our PFAPA cases compares well with that of the general population in Israel. It is debated whether MEFV mutations, when mediated by the presence of additional modifiers, may expose a transient fever condition, namely PFAPA.     

Mutations in the gene for familial Mediterranean fever: do they predispose to inflammation?

OBJECTIVE: To analyze 70 individuals who were found to have the Mediterranean fever (MEFV) gene for the presence of definite familial Mediterranean fever (FMF) and to assess if they were prone to clinical and laboratory inflammation. We also prospectively evaluated 72 patients with childhood rheumatic diseases for the presence of MEFV mutations. METHODS: Seventy patients with one MEFV gene mutation were reevaluated for the presence of a clinical FMF phenotype using a new set of criteria. They were also questioned for the presence of musculoskeletal symptoms and rheumatic diseases. They were sampled for erythrocyte sedimentation rates and C-reactive protein levels. A second group with childhood rheumatic diseases were diagnosed according to international criteria. RESULTS: Median age of the 70 heterozygous individuals was 12 years. About 1/3 (34.3%) were classified with clinical FMF phenotype according to the suggested criteria. Fifteen (21.4%) were classified as normal and 3 (4.3%) had recurrent abdominal pains but did not fulfill all criteria for clinical FMF. Overall, 28 (40.0%) had some form of rheumatic complaint and 15 (21.4%) had developed a rheumatic disease including Beh?et's disease, a vasculitis, or acute rheumatic fever. The mean ESR and CRP levels were 45.47 +/- 33.05 mm/h and 4.00 +/- 6.73 mg/dl, respectively. Among the 72 patients with rheumatic diseases of childhood, 22 (30.5%) carried one or 2 mutations of the MEFV gene. The mutated allele frequency among patients with rheumatic diseases was significantly higher than those in controls (p < 0.05). Within this group, among the 59 patients with juvenile idiopathic arthritis 15 had mutations in the heterozygous or homozygous form. CONCLUSION: We confirm the acute phase response in the carriers for MEFV mutations. We suggest that these patients may have a tendency to develop certain manifestations due to an increased baseline of inflammation, and the presence of these mutations may affect their disease course when they develop rheumatic disease.