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    Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia
    (Oxford Univ Press, 2024) Ousingsawat, Jiraporn; Talbi, Khaoula; Gomez-Martin, Hilario; Koy, Anne; Fernandez-Jaen, Alberto; Tekgul, Hasan; Serdaroglu, Esra
    Anoctamin 3 (ANO3) belongs to a family of transmembrane proteins that form phospholipid scramblases and ion channels. A large number of ANO3 variants were identified as the cause of craniocervical dystonia, but the underlying pathogenic mechanisms remain obscure. It was suggested that ANO3 variants may dysregulate intracellular Ca2+ signalling, as variants in other Ca2+ regulating proteins like hippocalcin were also identified as a cause of dystonia. In this study, we conducted a comprehensive evaluation of the clinical, radiological and molecular characteristics of four individuals from four families who carried heterozygous variants in ANO3. The median age at follow-up was 6.6 years (ranging from 3.8 to 8.7 years). Three individuals presented with hypotonia and motor developmental delay. Two patients exhibited generalized progressive dystonia, while one patient presented with paroxysmal dystonia. Additionally, another patient exhibited early dyskinetic encephalopathy. One patient underwent bipallidal deep brain stimulation (DBS) and showed a mild but noteworthy response, while another patient is currently being considered for DBS treatment. Neuroimaging analysis of brain MRI studies did not reveal any specific abnormalities. The molecular spectrum included two novel ANO3 variants (V561L and S116L) and two previously reported ANO3 variants (A599D and S651N). As anoctamins are suggested to affect intracellular Ca2+ signals, we compared Ca2+ signalling and activation of ion channels in cells expressing wild-type ANO3 and cells expressing anoctamin variants. Novel V561L and S116L variants were compared with previously reported A599D and S651N variants and with wild-type ANO3 expressed in fibroblasts isolated from patients or when overexpressed in HEK293 cells. We identified ANO3 as a Ca2+-activated phospholipid scramblase that also conducts ions. Impaired Ca2+ signalling and compromised activation of Ca2+-dependent K+ channels were detected in cells expressing ANO3 variants. In the brain striatal cells of affected patients, impaired activation of KCa3.1 channels due to compromised Ca2+ signals may lead to depolarized membrane voltage and neuronal hyperexcitability and may also lead to reduced cellular viability, as shown in the present study. In conclusion, our study reveals the association between ANO3 variants and paroxysmal dystonia, representing the first reported link between these variants and this specific dystonic phenotype. We demonstrate that ANO3 functions as a Ca2+-activated phospholipid scramblase and ion channel; cells expressing ANO3 variants exhibit impaired Ca2+ signalling and compromised activation of Ca2+-dependent K+ channels. These findings provide a mechanism for the observed clinical manifestations and highlight the importance of ANO3 for neuronal excitability and cellular viability.
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    The effectiveness and tolerability of clobazam in the pediatric population: Adjunctive therapy and monotherapy in a large-cohort multicenter study
    (Elsevier, 2022) Kamasak, Tulay; Serdaroglu, Esra; Yilmaz, Ozlem; Kilic, Betuel Aydin; Polat, Burcin G.; Erdogan, Irmak; Sen, A. Derda Yucel
    Objective: To evaluate the effectiveness and tolerability of clobazam therapy in the pediatric population in terms of seizure semiology, epileptic syndromes, and etiological subgroups.Methods: A retrospective cohort study was conducted consisting of 1710 epileptic children from eight centers in seven geographic regions of Turkey. The initial efficacy of clobazam therapy was evaluated after three months of treatment. The long-term effectiveness of the drug, overall seizure outcomes, and overall therapeutic outcomes were evaluated during 12 months of therapy. Results: Analysis of initial efficacy after the first three months of clobazam therapy showed that 320 (18.7 %) patients were seizure-free, 683 (39.9 %) had > 50 % seizure reductions, and 297 (17.4 %) had < 50 % seizure reductions. A positive response (seizure-free and >50 % seizure reduction) was determined for focal-onset (62.3 %) seizures, epileptic spasms (61.5 %), and generalized onset seisures (57.4). The highest positive response rate among the epileptic syndromes was for self-limited epilepsy with centrotemporal spikes (SeLECTS). The highest negative response rate was for developmental and/or epileptic encephalopathies (DEEs). Magnetic resonance imaging (MRI) revealed a structural etiological diagnosis in 25.8 % of the cohort. A higher positive response rate was observed at MRI in patients with sequelae lesions than in those with congenital lesions. The seizure recurrence rate was higher in the patient group with epilepsy with genetic and metabolic causes, in individuals with more than one seizure type, and in those using three or more antiseizure drugs.Conclusions: This cohort study provides additional evidence that clobazam is an effective and well-tolerable drug with a high seizure-free rate (18.7 %), a significant seizure reduction rate (57.3 %), and with excellent overall therapeutic outcomes with a low seizure relapse rate and considerable reversible benefits in the pediatric population.
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    Evaluation of seizure semiology, genetics, magnetic resonance imaging, and electroencephalogram findings in children with Rett syndrome: A multicenter retrospective study
    (Elsevier, 2024) Yildiz, Nihal; Serdaroglu, Esra; Kart, Pinar Ozkan; Besen, Seyda; Kanmaz, Seda; Toprak, Dilara Ece; Kilic, Betul
    Objectives: This study aimed to evaluate seizure semiology, electroencephalogram (EEG), magnetic resonance imaging (MRI), and genetic findings, as well as treatment choices in Rett syndrome (RTT). Methods: A retrospective analysis was conducted on one hundred and twenty cases diagnosed with RTT with a genetic mutation. Data were obtained from nine participating centers. Results: In this study, 93.3 % of patients were female, with typical RTT found in 70 % of cases. Genetic etiology revealed MECP2, FoxG1, and CDKL5 in 93.8 %, 2.7 %, and 1.8 % of cases, respectively. Atypical RTT clinics were observed in 50 % of male cases, with the first EEG being normal in atypical RTT cases (p = 0.01). Generalized tonic-clonic and myoclonic epilepsy were the most common seizure semiologies, while absence and focal epilepsy were less prevalent. Valproate, levetiracetam, lamotrigine, and clobazam were the most commonly used antiepileptic drugs, affecting the severity and frequency of seizures (p = 0.015, p = <0.001, p = 0.022, and p = <0.001, respectively). No significant differences were observed in EEG findings. The initiation of anti-seizure medications significantly altered seizure characteristics (Table 4). A ketogenic diet and vagal nerve stimulation (VNS) correlated with a 50 % improvement in cognitive function, while steroid treatment showed a 60 % improvement. Remarkably, seizures were substantially reduced after VNS application. Conclusion: This study underscores the importance of genetic diagnosis in RTT cases with a clinical diagnosis. These preliminary results will be further validated with the inclusion of clinically diagnosed RTT cases in our ongoing study.
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    A Multicenter Study of Self-Limited Epilepsy With Centrotemporal Spikes: Effectiveness of Antiseizure Medication With Respect to Spike-Wave Index
    (Elsevier Science Inc, 2024) Dilber, Beril; Serdaroglu, Esra; Kanmaz, Seda; Kilic, Betuel; Ipek, Rojan; Menderes, Deniz Kargin; Yildiz, Nihal
    Background: There is no certain validated electroencephalographic (EEG) parameters for outcome prediction in children with self-limited epilepsy with centrotemporal spikes. To assess the effectiveness of antiseizure medication (ASM) for seizure outcome with respect to the spike-wave index (SWI) on serial EEG recordings. Methods: In this multicenter study, the study cohort consisted of 604 children with self-limited epilepsy with centrotemporal spikes. A data set of epilepsy centers follow-up between 2010 and 2022. The cohort was divided into 4 groups as those receiving 3 different monotherapy (carbamazepine [CBZ]/valproic acid [VPA]/levetiracetam [LEV]) and dual therapy. SWI analysis was performed with the percent of spikes in the 2-minute epoch in the 5th 6th minutes of the nonrapid eye movement sleep EEG record. The study group were also categorized according to seizure burden with seizure frequency (I) >2 seizures and (II) >5 seizures. Seizure outcome was evaluated based on the reduction in seizure frequency over 6-month periods: (1) 50% reduction and (2) seizure-free (complete response). Results: ASM monotherapy was achieved in 74.5% children with VPA, CBZ, and LEV with similar rates of 85.8%, 85.7%, and 77.9%. Dual therapy was need in the 25.5% of children with SeLECT. More dual therapy was administered in children aged below 5 years with a rate of 46.2%. Earlier seizure-free achievement time was seen in children with LEV monotherapy with more complete-response rate (86.7%) compared the VPA and CBZ. Conclusions: We also determined that the children on dual therapy had more SWI clearance in the subsequent EEG recordings. The ROC curve analyses were performed to predict initial drug selection with using the SWI% might be used for the prediction of ASM type and drug selection in children. (c) 2023 Elsevier Inc. All rights reserved.
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    Trends in the choice of antiseizure medications in juvenile myoclonic epilepsy: A retrospective multi-center study from Turkey between 2010 and 2020
    (W B Saunders Co Ltd, 2022) Kilic, Betul; Serdaroglu, Esra; Polat, Burcin Gonullu; Ince, Tugce; Esenulku, Gulnur; Topcu, Yasemin; Serdaroglu, Ayse
    Purpose:Valproic acid (VPA) is frequently used and effective in juvenile myoclonic epilepsy (JME). Recently, levetiracetam (LEV) has been suggested as a monotherapy in JME. This study aimed to evaluate antiseizure medication (ASM) use in patients with JME. Methods: Treatment choices in a total of 257 patients (age range 8-18 years, 152 girls, 105 boys) with JME diagnosed and treated between 2010 and 2020 were evaluated retrospectively. Seizure remission was defined as complete seizure control for at least 12 months. Results: Across the study period and entire patient group, VPA was most commonly chosen as the initial ASM (50.9%), followed by LEV (44.4%), and lamotrigine (4.7%). VPA was also the most frequent first choice in the subgroup of boys (73.3%), while LEV was the commonest first choice in girls (57.9%). The sex difference regarding the ASM of the first choice was statistically significant (p<0.001). While VPA was the most frequent initial ASM in the first 5 years of the study period (2010-2015,n = 66, 64%), LEV had taken over as the most popular first ASM in the last 5 years (n = 83, 53.9%, p = 0.005). The most frequent reasons for discontinuation were inefficacy for LEV and adverse effects for VPA (p= 0.001). During follow-up, 237 patients (92.2%) were seizure-free for at least 12 months, and 159 (61.9%) were also in electmgraphic remission. Seizure remission occurred earlier than electroencephalographic remission (p<0.001). Conclusion: This study revealed that LEV has become the most frequently chosen initial ASM in the treatment of JME. Although LEV appears to have a better adverse effect profile, VPA seems more likely to be effective in achieving seizure control.