Nilgün Çakar

MEFV mutations in Turkish patients suffering from familial Mediterranean fever

Familial Mediterranean fever (FMF) is a recessive inherited disorder affecting Sephardic Jews, Arabs, Armenians and Turks. The gene responsible for FMF was recently cloned and several disease‐associated mutations have been described. We have evaluated seven MEFV mutations in 460 chromosomes of 230 unrelated patients with FMF living in Turkey, using PCR methods. The M694V allele accounted for 43.5% of the alleles studied and 19.1% of the patients were homozygous. The M680I, V726A and M694I mutations were responsible for 12.0%, 11.1% and 2.8% of the patients respectively. R761H, K695R and E148Q were rarely encountered. Two thirds of the disease alleles were attributed to three common mutations: M694V, M680V and V726A, but only 54% of the patients carried one or two of the three mutations. Adding the four rarer mutations increased these figures to 72% and 60%, respectively. Altogether, 79.6% of the patients bore at least one of the main mutations, and 84.3% carried at least one of the seven mutations studied. The 28 patients suffering also from amyloidosis carried at least one of five mutations, M694V being the most common. These results suggest that the origin of FMF in Turkey is heterogenous, all common mutations are associated with amyloidosis. Further, rapid and accurate molecular diagnosis of FMF is feasible in most cases. Hum Mutat 15:118–119, 2000.

Spectrum of Steroid-Resistant and Congenital Nephrotic Syndrome in Children: The PodoNet Registry Cohort

BACKGROUND AND OBJECTIVES Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant nephrotic syndrome, congenital nephrotic syndrome, or persistent subnephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. RESULTS Steroid-resistant nephrotic syndrome manifested in the first 5 years of life in 64% of the patients. Congenital nephrotic syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 (n=138), WT1 (n=48), and NPHS1 (n=41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasing manifestation age: from 66% in congenital nephrotic syndrome to 15%-16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%-45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% (n=4) of patients with a genetic diagnosis. CONCLUSIONS The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.

Blood pressure nomograms for children and adolescents in Turkey

Abstract In order to obtain data on blood pressure (BP) distribution in Turkish children, a total of 5,599 Turkish children from birth to 18 years were studied. BP rises with age, and both systolic and diastolic BP showed a positive correlation with height and weight in both sexes. As the sampling was representative of Turkish children at different ages, the mean systolic and diastolic BP levels were compared for each age with the results reported in the study of the Second Task Force. The mean systolic and diastolic BP of Turkish children and the increase with growth and development were different from the Second Task Force study. Genetic, ethnic, and environmental factors were suggested to be responsible for this variation. In conclusion, normal BP curves should be applied with caution in childhood, and every population should use their own normal standards to define a measured BP level in children.

CLINICAL, LABORATORY AND MOLECULAR CHARACTERISTICS OF CHILDREN WITH FAMILIAL MEDITERRANEAN FEVER-ASSOCIATED VASCULITIS

Familial Mediterranean Fever (FMF) is an autosomal recessive disease characterized by recurrent self‐limited attacks of fever accompanied by peritonitis, pleuritis and arthritis. Approximately 5% of individuals with FMF have been reported to have Henoch‐Schonlein purpura (HSP) and about 1% have polyarteritis nodosa (PAN). Protracted febrile myalgia is another vasculitis‐associated clinical entity among patients with FMF. Recently, the gene responsible for FMF, MEFV, has been cloned and four missense mutations (M680I, M694V, V726A and M694I) have been described. In this report, we present clinical and laboratory findings and mutation results of 23 children with FMF‐associated vasculitis. HSP, PAN and protracted febrile attacks have been diagnosed in 11, 2 and 10 children, respectively. Mutation analysis shows that 3 children are homozygotes for the M694V mutation and 11 are compound heterozygotes for 2 of the studied mutations. M694V/V726A mutations were identified in 8, M694V/M694I in 2 and M680I/M694V in 1 of these children. In six children only one mutation was found and in three none of the studied mutations were identified. This study confirms that most children with FMF‐associated vasculitis have identifiable mutations in the MEFV gene. Environmental and/or other genetic factors are possibly involved in the pathogenesis of vasculitis in FMF; elucidation of these mechanisms will help to understand pathogenesis of childhood vasculitides. ?Children, Familial Mediterranean Fever, MEFV mutations, vasculitis

MEFV mutations in multiplex families with familial Mediterranean fever : is a particular genotype necessary for amyloidosis?

Familial Mediterranean fever (FMF) is an autosomal recessive disease. It is characterized by recurrent febrile episodes in association with peritonitis, pleuritis, and arthritis. Progressive systemic amyloidosis is the most important complication of FMF that inevitably leads to chronic renal failure. Recently, the gene for FMF, MEFV, has been cloned and four missense mutations have been described: M694V, M680I, V726A, and M694I. Initial studies have suggested that the presence of the M694V mutation carries a significant risk for the development of amyloidosis. In this study, we present seven families, in which at least two individuals have been diagnosed with FMF and at least one with amyloidosis. Among 18 individuals, in whom molecular testing was performed for the four aforementioned mutations, ten had amyloidosis. None of these ten individuals was found to be homozygous for the M694V mutation. In three families, there were two sibs with amyloidosis. None of the sib‐pairs with amyloidosis was found to have the same genotype. There were two or more sibs with the same genotype in four families. Only one sib from each family developed amyloidosis in these families. These results provide evidence that FMF patients without the M694V mutation are also at risk for the development of amyloidosis. Particular mutations themselves do not appear to be sufficient to explain the occurrence of amyloidosis in all cases with FMF.

The value of the levels of acute phase reactants for the prediction of familial Mediterranean fever associated amyloidosis: a case control study

In order to determine the role of levels of acute phase proteins (APPs) for the development of amyloidosis in familial Mediterranean fever (FMF) patients, the levels of serum amyloid A (SAA), C reactive protein (CRP), fibrinogen and erythrocyte sedimentation rate were measured in paired sera of 36 FMF patients during and in between acute attacks, 39 of their healthy parents (obligate heterozgotes), and 15 patients with FMF associated amyloidosis. To compare the levels of APPs, 39 patients with chronic infections or inflammatory diseases who may develop secondary amyloidosis, 20 patients with acute infections who are known to have elevated acute phase response but will never develop amyloidosis and 19 healthy controls were included. The median levels of all APPs are increased in the patients with FMF during attacks and a significant decrease was observed after the attack was over. The level of SAA was above reference range in all FMF patients during the attack free period and the level of at least one other APP was also above normal in 64% of the patients. Both CRP and SAA levels were found to be higher in obligate heterozygotes compared to controls. The levels of SAA in patients with FMF during the attack-free period, obligate heterozygotes and patients with FMF-amyloidosis were found to be similar. The levels in each group were found to be higher than SAA levels found in healthy controls yet lower than the levels measured in the patients with acute infections and patients with chronic inflammation or chronic infections. In conclusion, our results show that SAA level reflects subclinical inflammation with high sensitivity but its value for the prediction of amyloid formation process seems to be low.

Familial mediterranean fever and acute rheumatic fever: A pathogenetic relationship?

Abstract: The frequency of acute rheumatic fever (ARF) in patients with familial Mediterranean fever (FMF) was documented and the effects of preceding streptococcal infections on the exacerbation of FMF were determined. In the first part of the study, 162 individuals with FMF were investigated for a history of ARF in a retrospective study. In the second part of the study, antistreptolysin-O (ASO) titres were measured in 130 individuals with FMF. Thirty-six patients had an arthritic attack (group A1), 55 patients had a typical FMF attack without arthritis (group A2) and 39 patients were in the attack-free interval (group B) during the investigation. Nine patients with FMF (5.5%) were considered to have ARF and three of them (1.85%) also had rheumatic heart disease. This prevalence of rheumatic heart disease in FMF is higher than that of the normal population (0.65%) reported in Turkey. Elevated ASO titres were found in 75%, 42% and 38% of the patients in groups A1, A2 and B, respectively. These percentages were found to be significantly higher in group A1 than in both groups A2 (p<0.01) and B (p<0.01). We concluded that patients with FMF might be more prone to the late complications of streptococcal infections.

The coexistence of familial Mediterranean fever and polyarteritis nodosa; report of a case

We describe a 14-year-old boy with a 5-year history of familial Mediterranean fever (FMF), treated with colchicine, who developed polyarteritis nodosa (PAN). He was admitted to our hospital with fever, general weakness, arthritis, and purpura. Five weeks after adminission, hypertension was noted. Skin biopsy showed perivascular leukocyte infiltration in the epidermis. An aortography revealed multiple aneurysms of the renal, common hepatic, and intercostal arteries. He was treated with intravenous methylprednisolone, oral cyclophosphamide, and azathioprine. The known rare association of FMF and PAN is discussed.

Global left-ventricular function by tissue Doppler imaging in pediatric dialysis patients

Cardiovascular abnormalities are observed in most children with end-stage renal disease (ESRD). The aim of this study was evaluation of left-ventricular (LV) myocardial performance using tissue-Doppler imaging (TDI) in patients with ESRD. Twenty-five patients with ESRD and 25 healthy gender- and age-matched control subjects were assessed with conventional M-mode echocardiography, pulsed-wave Doppler (PWD), and TDI. Myocardial Performance Index (MPI) and LV mass index (LVMI) were calculated. MPI and conventional echo-Doppler indices were compared in the ESRD and control groups. Significant differences were present in the mean systolic and diastolic blood pressure (BP) between children with ESRD and healthy children (p = 0.007 and p < 0.001, respectively). The mean LVMI was significantly greater in the patient group (p < 0.001). The tissue-Doppler MPI of patients was significantly higher than that in healthy children (p < 0.001). LVMI was significantly correlated with systolic and diastolic BP. MPI obtained by TDI was significantly correlated with LVMI. Our study confirms that LV dysfunction is present in patients with ESRD and hypertension is an important risk factor.

Cardiac involvement in childhood polyarteritis nodosa.

In this report, we evaluated the cardiac findings of 15 children with polyarteritis nodosa. The age range of the patients was 4-14 years; with a mean of 10 years. All have had systemic involvement of the disease. The most common findings in cardiac evaluation were diminished left ventricular systolic functions and mild mitral and/or tricuspid valve regurgitation. One patient had pericardial thickening with no effusion. One had sinus tachycardia. There were no signs of myocardial infarction or ischemia clinically or electro-cardiographically. In conclusion, we did not find cardiac complications, such as pericarditis or myocardial infarction, to be as frequent as in previous reports. However, even in asymptomatic patients, systolic dysfunction or valvular involvement were common findings in patients with polyarteritis nodosa, which were not reported previously. These findings may be due to the histological changes of the myocardium or atrioventricular valves. Although these were not severe and fatal lesions, long-term follow-up of these patients with echocardiography may help to determine the course of cardiac involvement.