Ayfer Ülgenalp

TLR Polymorphisms in FMF: Association of TLR-2 (Arg753Gln) and TLR-4 (Asp299Gly, Thre399Ile) Polymorphisms and Myeloid Cell TLR-2 and TLR-4 Expression with the Development of Secondary Amyloidosis in FMF

Amyloidosis is the major complication of familial Mediterranean fever (FMF). Toll-like receptors (TLR) are involved in the activation of an innate immune system TLR-2 and TLR-4 recognize lipoteichoic acid and lipopolysaccharides (LPS), respectively. While TLR-2 Arg753Gln polymorphism upregulates, TLR-4 Asp299Gly and Thre399Ile polymorphisms downregulate inflammation. We investigated the effect of these polymorphisms on the development of amyloidosis in FMF patients. We also investigated myeloid cell TLR-2 and TLR-4 expressions in these patients. We studied 26 FMF patients and 13 FMF patients with amyloidosis. TLR-2 Arg753Gln and TLR-4 Asp299Gly and Thr399Ile polymorphisms were analyzed with the polymerase chain reaction-restriction fragment length polymorphism method. Myeloid cell baseline TLR-2 and TLR-4 and LPS-induced TLR-4 expressions were evaluated. The TLR-2 and TLR-4 polymorphism rate was compared with the results of 100 healthy subjects in our previous study. In addition, 13 healthy controls were enrolled for leukocyte TLR-2 and TLR-4 expressions. Serum amyloid A (SAA) levels were measured in these 13 control cases and in FMF patients during attack-free periods. The frequency of TLR-2 Arg753Gln, TLR-4 Asp299Gly, and Thr399Ile polymorphisms in healthy controls in our previous study were 1%, 3%, and 2%, respectively. The frequency of these polymorphisms were not different in FMF patients (with or without amyloidosis) compared to the control group. Likewise, myeloid cell TLR-2 and TLR-4 expressions were not different among the controls and FMF patients. However, LPS-induced TLR-4 expression in granulocytes was more prominent in FMF patients. There was no correlation between TLR-2 and TLR-4 expressions and SAA levels. Neither myeloid cell TLR-2 and TLR-4 expressions nor TLR-3 Arg753Gln, TLR-4 Asp299Gly, and Thr399Ile polymorphisms seem to affect the development of secondary amyloidosis in FMF patients in our study population.

Lack of association of childhood partial epilepsy with brain derived neurotrophic factor gene.

Brain-derived factor (BDNF) is a member of neurotrophin family and is localized and upregulated in areas implicated in epileptogenesis. Several lines of evidence make the BDNF gene a plausible candidate gene for predisposition to epilepsy. In this study, we tested that BDNF might be involved in the etiology of childhood PE. To assess whether BDNF gene C270T polimorphism could be implicated in vulnerability to PE, we conducted a case-control association analysis (112 partial epileptic and 100 controls) in Turkish children. Epileptic children were divided into two groups: 1—idiopathic (n = 85) and 2—symptomathic epilepsy (n = 27). There was no significant difference in genotypic distribution and allelic frequencies of the BDNF gene C270T polimorphism between the PE and control groups. However, the BDNF gene TT genotype was more frequently seen in the epileptic children (15 versus 11 patients, resp.). Interestingly, in the epilepsy group, both two children with TT genotype have posttraumatic epilepsy. The data indicate a possible association with the 270T genotype of the BDNF gene with a posttraumatic epilepsy. To draw any conclusion, further studies using larger sample sizes should be carried out in various ethnic populations in childhood epilepsies.

Long-standing fever and Angelman syndrome: report of two cases.

Abstract:  An 8‐month‐old girl and a 20‐month‐old boy who presented with motor and developmental delay and long‐standing fever are presented. The patients were diagnosed as Angelman syndrome with fluorescence in situ hybridization (FISH) analysis. Despite extensive clinical and laboratory examinations, no inflammatory or infectious origin for the fever was found. It was considered that the long‐standing fever observed in these cases was due to hypothalamic dysfunction for thermoregulation.

Plasminogen activator inhibitor-1 and angiotensin converting enzyme gene polymorphisms in Turkish asthmatic children.

BACKGROUND Polymorphisms of plasminogen activator inhibitor-1 (PAI-1) and angiotensin-converting enzyme (ACE) genes have been implicated in susceptibility to asthma. In this study, we aimed to investigate whether there was any association between childhood asthma and polymorphisms of the PAI-1 and ACE genes. METHODS Two hundred and three Turkish children aged 5-15 years, including 102 asthmatic patients and 101 healthy control subjects were included in this study. The asthma group was divided into two groups as follows: Group I: Asthmatic children with positive family history for atopy (n=53), Group II: Asthmatic children without any family history for atopy (n=49). One hundred and twenty-eight atopic family members were also included in the study. The insertion/deletion (I/D) polymorphism of the ACE and PAI-1 4G/5G gene polymorphisms was carried out by polymerase chain reaction. RESULTS The prevalence of the PAI-1 4G allele was significantly greater in asthmatic children compared to control group (p<0.05, OR: 1.64 (1.11-2.43)) but there was no significant relation between ACE I/D genotypes and childhood asthma. No significant difference was detected between Groups I and II in terms of these ACE and PAI-1 genotypes and allele frequencies. No significant relationship was found between both gene polymorphisms and total serum IgE and skin prick test results. CONCLUSION It has been established that PAI-1 4G allele may be a genetic risk factor for childhood asthma but ACE gene I/D polymorphisms do not play a role in the development of asthma in the sample of Turkish children.

Role of Apolipoprotein E in Febrile Convulsion

Apolipoprotein E is consistently associated with the progression of some common human neurodegenerative diseases, e.g., epilepsy. We hypothesized that genetic variations in the apolipoprotein E gene have implications for susceptibility to, and prognoses in, febrile convulsion, which plays an apparent role in the development of epilepsy. We used the polymerase chain reaction and restriction enzyme digestion to characterize variations of the apolipoprotein E gene. Sixty-nine patients with febrile convulsion (simple/complex) and a corresponding cohort of healthy patients (n = 75) were used. There was no significant difference in genotypic distribution and allelic frequencies of the apolipoprotein E gene between the febrile convulsion and control groups. Comparing subpopulations of the febrile convulsion group (patients with simple and complex febrile convulsion), we noted that no patients with the epsilon3/epsilon4 genotype had complex febrile convulsions. The apolipoprotein E epsilon3/epsilon4 genotype was more frequently seen in the simple febrile than in the complicated febrile convulsion group (9 versus 0 patients, respectively). The data indicate an association with the epsilon3/epsilon4 genotype of the apolipoprotein E gene with a milder phenotype. Although apolipoprotein E4 is not a vulnerability factor regarding febrile convulsions, it seems effective in regard to prognoses.

Myalgia as a symptom of familial Mediterranean fever in children.

We read the article entitled Familial Mediterranean fever gene mutation frequencies and genotype–phenotype correlations in the Aegean region of Turkey prepared by Ozalkaya et al. [1]. The results will be more rational while describing the characteristics of an inherited disease in a certain geographic region, if the data obtained from all or near all of the patients in that region is given. As being another center in the Aegean Region, serving children with familial Mediterranean fever (FMF), we compared our results with those of the above study and aimed to evaluate their consistency. There were 172 patients (M/F: 89/83) being followed up in our center with the diagnosis of FMF based on Tel Hashomer criteria. The mean ages at the onset of symptoms and at the time of diagnosis were months (1–292) and 115 § 63 months (2–612), respectively. Clinical features of the patients are shown in Table 1. MEFV gene analysis including 12 most frequent mutations seen in Turkish people was performed in 84 patients. The results are shown in Table 2. Most frequent mutation was M694V that was present in 60 (71.4%) patients. Three cases with amyloidosis had MEVF gene analysis; two cases were homozygous and one case was heterozygous for M694V mutation. There were 6 patients with none of the twelve mutations screened. The data of our cases from the same geographic region including the mean age of the patients at the diagnosis and at onset of the symptom, frequency of symptoms except for myalgia and genotypes of the patients were found similar to those described in the study of Ozalkaya et al. Although from the same region, myalgia was signiWcantly more frequent among our patients than those in the study of Ozalkaya et al. They categorized their patients due to reliability of diagnosis as deWnitive, probable and suspicious FMF groups. Myalgia frequency was reported to be 9, 7.8 and 2.4% in these subgroups, respectively, the diVerence among the groups being not statistically signiWcant. The rate of myalgia in their group was 6.1% in total, while 20.3% of our patients had myalgia [2–4]. Those patients with protracted febrile myalgia presented to our clinic mostly during the spring months, and their ASO levels were high [2, 3]. Most cases with myalgia were homozygous or compound heterozygous for M694V mutation, while only one case was homozygous for E148Q [2, 5]. One of the patients with myalgia had also amyloidosis and osteopoikilosis and he was transplanted for end stage renal disease [6].

A 12-Year-Old Girl with Bilateral Coats Disease and ABCA4 Gene Mutation

A 12-year-old girl with bilateral stage 2B Coats disease was screened meticulously for a possible underlying systemic disease as she was female and the disease was bilateral. Full systemic workout turned out to be unremarkable. However, an ABCA4 gene mutation was found in the genetic analysis. NDP and TINF2 gene mutations were not present. She was successfully treated with a bilateral, single intravitreal injection of dexamethasone implant and a single session of indirect laser photocoagulation with a relatively good anatomic and functional result. To the best of our knowledge, the present case is the only reported case of Coats disease with an ABCA4 gene mutation.

Prevalence of Mediterranean FeVer Gene Mutations in Turkish Cypriot Population

Objectives This study aims to determine the carrier frequency and the most common mutations of the Mediterranean FeVer (MEFV) gene in healthy Cypriot population of Turkish origin. Patients and methods A total of 296 healthy participants (102 males, 194 females; median age 30 years; range 1 to 81 years) were evaluated. The exon 2, 3, 5 and 10 of MEFV genes were amplified by polymerase chain reaction. Results The participants demonstrated an extremely high carrier rate (12.5%). Most commonly detected mutations were E148Q and A74S, with rates of 7.3% and 2.8%, respectively. Conclusion Mediterranean FeVer gene mutation types and carrier rates in Turkish Cypriot population are different than other Mediterranean populations in the region. MEFV mutation carriage is frequent in North Cyprus and familial Mediterranean fever might be one of the causes for end stage renal disease in Turkish Cypriots.

Glutathione S-Transferase Gene Polymorphisms in Children with Down Syndrome and Their Mothers

Abstract To elucidate the genetic factors causing clinical differences in the children with Down syndrome and evaluate possible maternal risk factors, the researchers have investigated GSTM1, GSTT1, GSTP1 gene polymorphisms. Four groups were defined: group I (n = 52), children with Down syndrome; group II (n = 70), healthy children; group III (n = 52), mothers of the children with Down syndrome; and group IV (n = 69), mothers of the healthy children. Genomic DNA was extracted from the white blood cells and GenID ® GmbH kit used for GST M1, T1 and P1 gene amplification to determine polymorphisms. The researchers did not detect any significant difference in the allele frequencies between groups I and II, nor groups III and IV. The data indicated no relationship between detected GST polymorphisms, neither with Down syndrome nor with the risk of having an infant with Down syndrome.

Risk factors for subclinical inflammation in children with familial mediterranean fever

Familial Mediterranean fever (FMF) is the most common autosomal-recessive inherited inflammatory disease characterized by attacks of painful inflammation. Some patients with FMF have subclinical inflammation persisting between the attacks. Persistent inflammation may lead to amyloidosis and other complications of chronic inflammation.