F. Belgin Ataç

PAI-1 gene 4G/5G polymorphism, cytokine levels and their relations with metabolic parameters in obese children

Obesity is associated with the changes of plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-alpha (TNFalpha) and transforming growth factor beta (TGFbeta) levels. However, the precise effect of the 4G allele on obesity is still contradictory. Here, we aimed to elucidate the role of the 4G/5G polymorphism of the PAI-1 gene on the PAI-1 level and determine the associations between cytokines, glucose and lipid metabolism parameters in obese children. Thirty-nine obese children (mean age 11.4 +/- 3.3 years) and 38 age-matched healthy control group (mean age 10.3 +/- 3.5 years) were included in the study. In all cases, serum levels of glucose, lipid and insulin were measured, homeostasis model assessment of insulin resistance (HOMA-IR) was calculated, and 4G/5G polymorphism of PAI-1 gene, plasma PAI-1 level and serum TNFalpha and TGFbeta levels were studied. The mean relative body mass index (BMI) and HOMA-IR score, VLDL, TG, insulin, PAI-1, TNFalpha levels were higher, and HDL and TGFbeta levels were lower in the obese group. The frequency of the 4G/4G genotype was considerably higher in obese children than in controls. Also, a positive correlation was found between PAI-1 and TNFalpha levels, and relative BMI, HOMA-IR score, insulin, TG, HDL levels. TGFbeta was inversely correlated only with relative BMI. There was no correlation among three cytokines. In conclusion, childhood obesity contributes to higher PAI-1 and TNFalpha and lower TGFbeta levels. Especially PAI-1 and TNFalpha accompany insulin resistance and dyslipidemia.

Analysis of prothrombotic mutations and polymorphisms in children who developed thrombosis in the perioperative period of congenital cardiac surgery.

In this study, we investigated some of the prothrombothic mutations and polymorphisms in 15 children with congenital cardiac malformations who developed severe thrombosis in the perioperative period following surgical repair. The mutations and polymorphisms included in the study were Factor V Leiden, prothrombin G20210A, methylentetrahydrofolate reductase C677T, endothelial nitric oxide synthase intron 4 VNTR, alpha-fibrinogen Thr312Ala, Factor XIII Val34Leu, and insertion or deletion of angiotensin 1 converting enzyme. Compared to the healthy Turkish subjects, our patients had a similar rate of mutation of Factor V Leiden, Factor XIII Val34Leu, and endothelial nitric oxide synthase a/b polymorphisms, but higher frequency of the prothrombotic angiotensin 1 converting enzyme deletion/deletion genotype, and lower frequency of the antithrombotic alpha fibrinogen Thr/Thr genotype. None of the patients exhibited mutations involving prothrombin G20210A or methylentetrahydrofolate reductase C677T. The results of our study suggest that, in addition to prothrombotic mutations such as Factor V Leiden, single-nucleotide polymorphisms should be considered in all children with congenital cardiac malformations who develop thrombosis. Malformations of the heart are the most common of all serious lesions that are present at birth, with an incidence of 4 to 8 cases per 1,000 live births. If needed, corrective surgery is usually the optimal treatment for these anomalies, but perioperative morbidity and mortality still remain high due to several factors. Arterial or venous thrombosis, or both varieties of thrombosis, is among these factors. Prior to surgery, the most frequent time at which these children develop thrombosis is during cardiac catheterization. Postoperative thrombosis in this group of patients is a more complex disorder, which can affect both small and large vessels, and is associated with a high morbidity and mortality. Recent studies indicate that both point mutations and single-nucleotide polymorphisms of genes that encode proteins involved in the coagulative and anticoagulative cascades are important risk factors for development of thrombosis. Patients with these risk factors are most likely to develop thrombosis when triggering elements, such as placement of catheters, prolonged immobilization, or surgery, are also present. In this study, we investigated some of the above-mentioned mutations and polymorphisms in children who developed thrombosis in the perioperative period after correction of congenital cardiac malformations.

Thrombosis in children with cardiac pathology : analysis of acquired and inherited risk factors

The present study was conducted to analyze the features and risk factors of childhood thrombotic events in patients with cardiac defect followed-up at our hospital. The clinical and laboratory findings of 59 patients diagnosed with cardiac defects and thromboses between 1997 and 2006 were retrospectively analyzed. Thirty-one children (52.5%) had venous system thromboses, 21 (35.6%) had arterial system thromboses, and seven (11.9%) had venous and arterial system thromboses. Presence of congenital heart disease and cardiomyopathy (CMP) were significant risk factors for developing intracardiac thrombosis. In addition, presence of congenital heart disease was the significant statistical risk factor for developing left atrium and right ventricle thromboses. Presence of congenital heart disease was a significant risk factor for developing a central nervous system thrombosis. Presence of pulmonary stenosis and aortic coarctation were significant risk factors for developing a peripheral arterial system thrombosis. Acquired risk factors including major surgery, angiography, central venous catheter, systemic infection, and hypoxia were identified in 49 of the 59 patients. Many patients had more than one of these acquired risk factors. Analysis of the relationship between thrombosis and type of major surgery demonstrated a statistically significant relationship between an intracardiac thrombosis and total correction of tetralogy of Fallot and a peripheral venous system thrombosis and a Blalock Taussig shunt. Twenty-three of the 52 patients (44.2%) had at least one thrombophilic mutation. Overall, a heterozygous factor V Leiden mutation was found in nine patients (17.3%), a methylenetetrahydrofolate reductase 677C-T mutation in 15 patients (28.8%), and a PT 20210G-A mutation in three patients (5.8%). Our data suggest that cardiac defects are common risk factors for developing a childhood thrombosis. The type of disorder determines the site of thrombosis. Acquired risk factors may contribute to the development of a thrombosis. The results of this study also indicate that to ensure early diagnosis, routine screening for thrombosis should be performed in patients with a cardiac defect and that screening for factor V Leiden and PT 20210G-A mutations and other genetic risk factors should be included when assessing all patients with cardiac defects who present with a thrombosis, whether or not a predisposing factor has been identified.

Methylenetetrahydrofolate Reductase C677T Mutation and Nonalcoholic Fatty Liver Disease

A mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is known as one of the causes of hyperhomocyteinemia. The oxidation products of homocysteine can initiate lipid peroxidation, which has a central role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We aimed to assess the possible role of the MTHFR C677T mutation in the progression of simple steatosis to an advanced form of NAFLD. Thirty-four patients with NAFLD diagnosed by histologic analysis and 282 healthy controls were included in the study. The discrimination of nonalcoholic steatohepatitis (NASH) from another NAFLD was made by NAFLD activity score (NAS), and a NAS≥5 was considered NASH. Patients with either NASH or nonalcoholic fatty liver (NAFL) and controls were evaluated for frequency of the MTHFR C677T mutation. The frequency of the MTHFR C677T mutation was 53.5% (CT, 44.7%; TT, 8.9%) in controls and 41.5% (CT, 37.7%; TT, 3.8%) in patients (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.34–1.12). There was no statistical difference in the frequency of this genotype between patients with NAFL and those with NASH (36% [CT, 28%; TT, 8%] vs 46.4% [CT, 46.4; TT, 0%]; OR, 0.65; 95% CI, 0.22–1.96). According to this study, the MTHFR C677T mutation does not seem to be a risk factor for the progression of NAFL to NASH.

Endothelial Nitric Oxide Synthase Gene Intron 4 (VNTR) Polymorphism and Vascular Access Graft Thrombosis

Vascular access thrombosis is a leading cause of vascular access failure in hemodialysis patients. Thrombosis is a multifactorial condition and genetic makeup can affect thrombosis risk. We conducted a study to investigate for possible associations between ecNOS gene intron 4 variable-number tandem repeat (VNTR) polymorphism and thrombosis of polytetrafluoroethylene hemodialysis arteriovenous access grafts (AVG) in Turkish patients. Fifty-five patients with end-stage renal disease who had AVGs implanted between 2000 and 2002 and 167 healthy individuals representing our healthy population were enrolled in this prospective study. Each subject provided a venous blood sample from which DNA was isolated, and polymerase chain reaction analysis was done to identify genotypes (aa, bb, ab) for ecNOS gene intron 4 VNTR polymorphism. All grafts were placed in brachioaxillary position. The subjects were divided into two groups based on duration of graft patency. The thrombosis group (Group I) comprised 26 patients who developed AVG thrombosis in the first 12 months after placement. The no-thrombosis group (Group II) comprised 29 patients whose grafts remained patient for at least 12 months. The frequency of the aa genotype in Group I was significantly higher than that in Group II (p =. 005). At 6, 12, and 24 months, the primary patency rates for the AVGs in patients with the aa genotype were significantly lower than the corresponding rates for the bb and ab genotype groupings (p =. 01, p =. 01 and p =. 04 for the three respective time points; Kaplan–Meier). ecNOS gene intron 4 VNTR polymorphism is linked with the pathogenesis of vascular access thrombosis in Turkish patients undergoing hemodialysis.

Plasminogen activator inhibitor-1 gene 4G/5G polymorphism in Turkish children with asthma and allergic rhinitis

Plasminogen activator inhibitor (PAI-1) has an essential role in tissue remodeling after inflammation. Recent literature revealed only one study evaluating PAI-1 4G/5G gene polymorphism in children with asthma and none in children with allergic rhinitis. We aimed to investigate distribution of PAI-1 4G/5G polymorphism in a group of Turkish children with asthma and allergic rhinitis and compare these findings with those obtained in normal peers. Patients with physician-diagnosed asthma (n = 106) and allergic rhinitis (n = 99) and 83 healthy peers were included in this study. We evaluated PAI-1 4G/5G polymorphism genotype as well as the possible association between PAI-1 4G/5G polymorphism and pulmonary function tests, serum total immunoglobulin E (IgE), total eosinophil count, and skin-prick test positivity in our study. The prevalence of the 4G allele significantly exceeded the values found in the controls both in patients with asthma (p = 0.001) and in patients with allergic rhinitis (p = 0.002). Interestingly, comparison of asthmatic patients revealed that mean baseline percent forced expiratory volume in 1 second and forced vital capacity were significantly higher in patients who bear 5G/5G genotype than in those who have 4G/4G or 4G/5G genotypes. No statistically significant relationship were found between PAI-1 polymorphism and total serum IgE levels, total eosinophil count, or selected skin test responses to aeroallergens. Our study suggests that Turkish children with asthma or allergic rhinitis have a higher prevalence of PAI-1 4G allele compared with their healthy peers.

Angiotensin I‐Converting Enzyme Gene (I/D) Polymorphism in Patients With Migraine

In addition to the wide expression in many tissues including vascular endothelial cells, production of angiotensin II and degradation of bradykinin may indicate that angiotensin‐converting enzyme could be involved in vascular tension and blood pressure. It has been reported that the deletion allele of the angiotensin‐converting enzyme gene is associated with increased serum angiotensin‐converting enzyme levels and linked to cerebrovascular diseases. In this study, the possible association of migraine with aura with the angiotensin‐converting enzyme deletion–deletion (DD) and the angiotensin–converting enzyme insertion–deletion (ID) genotype was investigated in Turkish patients. To investigate the role of the angiotensin‐converting enzyme I/D polymorphism in Turkish patients with migraine with aura, we analyzed the I/D genotype of 53 patients with that disorder. Twenty‐two control subjects, who are volunteer Turkish patients without migraine, were included in the study. The frequency of the angiotensin‐converting enzyme D/D genotype was statistically significant more frequent in patients with migraine with aura (81.1%) than in controls (59.1%) (P < .05). No differences were found regarding the I/I genotype and the I/D genotype between the 2 groups (P > .05). The results of our study revealed that the angiotensin‐converting enzyme D/D genotype was more frequent in patients with migraine with aura than in controls. This might suggest that the angiotensin‐converting enzyme D/D genotype may be a genetic risk factor for migraine with aura in Turkish patients.

Familial Parkinsonism with Apathy, Depression and Central Hypoventilation (Perry’s Syndrome)

A rare and unique form of familial parkinsonism with autosomal dominant inheritance that is characterized by all cardinal features of parkinsonism, apathy, depression, central hypoventilation, weight loss, and rapid progression was first described by Perry et al.1 Thereafter, four additional families from different ethnic background have been reported (Table 1).2–6 In most of these affected individuals, disease presented between ages of 40–55, with symptoms of apathy, psychomotor slowness and/or depression, usually accompanied or followed by moderate degrees of parkinsonism and weight loss. Central type of hypoventilation developed eventually and caused death in most of the patients due to sudden apnea or complications of respiratory insufficiency. Pathology differs from idiopathic Parkinson’s disease by severe neuronal loss and gliosis in substantia nigra with no or very few Lewy-body formation,1,2,4,5 and in some patients, by extension of neuronal loss to locus ceruleus, caudate, pallidum and medulla. 2’4

The effect of plasminogen activator inhibitor-1 gene 4G/5G polymorphism on glucose and lipid metabolisms in Turkish obese children

Objective Obesity is a metabolic disorder that is associated with increased plasminogen activator inhibitor‐1 (PAI‐1) concentration in the circulation. This increase is related to insulin resistance, dyslipidaemia and cardiovascular disease. Some studies have demonstrated a relationship between plasma PAI‐1 concentrations and the 4G/5G gene polymorphism in the PAI‐1 gene, while other studies have not. It is well known that plasma PAI‐1 levels are increased in obesity; however, the relationship between the polymorphism and obesity remains unclear. In this study, we aimed to elucidate the effect of the PAI‐1 4G/5G polymorphism on glucose and lipid metabolism parameters in Turkish obese children.

Atypical phenotypes of DYT1 dystonia in three children.

UNLABELLED DYT-1 dystonia is the most common primary dystonia seen in childhood. It is an autosomal dominantly inherited disorder caused by deletion of a GAG triplet in exon 5 of the DYT1 gene. It characteristically starts in a distal limb during late childhood, subsequently spreads to involve other body regions sparing oromandibular muscles. However, clinical presentation can vary remarkably with respect to age, site of onset and progression. In this study we present three early-onset DYT-1 dystonia patients who are atypical according to age of onset and localization. Dystonia has started at 2, 3 and 7years of age and generalized to involve other limbs in all patients and also oromandibular muscles in one patient. None of them have benefited from medical treatments including L-dopa. All had normal brain MRI scan, a history of normal birth without significant perinatal asphyxia, infection or trauma and all are neurodevelopmentally otherwise normal. CONCLUSION In children with dystonia; if brain imaging is unremarkable and when there is no history of CNS disorders such as perinatal asphyxia, infections, drug exposure or trauma; genetic analysis for GAG deletion of DYT-1 gene may be performed even if dystonia starts at a very young age or it spreads to involve oromandibular muscles.