Semra Hız Kurul

CASK-related disorders comprise two main phenotypes: severe microcephaly with pontocerebellar hypoplasia (MICPCH), typically caused by truncating variants, and milder X-linked intellectual disability (XLID), usually associated with missense variants. We aimed to characterize this molecular spectrum within an underrepresented national cohort. We evaluated 18 affected individuals from 16 unrelated families with CASK variants identified through exome or genome sequencing. Clinical, neurodevelopmental and neuroimaging findings were systematically reviewed. Selected missense variants were evaluated by in silico prediction tools and structural modeling. We identified 16 distinct CASK variants, 11 of which are novel, including frameshift, stop-gain, splice-site, and missense variants, as well as one large deletion. Consistent with known genotype-phenotype correlations, null alleles resulted in the severe MICPCH phenotype, while presumed hypomorphic alleles were associated with XLID. However, unlike previous reports, our MICPCH patients exhibited a higher frequency of dysmorphic facial features (86%), skeletal anomalies (57%) and sensorineural hearing loss (43%). Furthermore, contrary to the literature suggesting a milder epilepsy in females due to X-inactivation, 63% of our female patients with MICPCH presented with recurrent seizures. This cohort broadens both the molecular and phenotypic spectrum of CASK-related disorders. Findings reinforce that truncating variants predominantly cause MICPCH, while missense variants can lead to various outcomes depending on domain-level structural impact. We demonstrate that the CASK phenotypic spectrum is broader than previously recognized, frequently involving distinctive facial dysmorphism, skeletal defects and hearing impairment, suggesting that CASK plays a critical role not only in synaptic function but also in wider developmental processes.

Objectives: Very low birth weight (VLBW) infants are at disproportionately high risk for neonatal seizures, yet optimal first-line antiseizure medication (ASM) strategies in this vulnerable population remain a matter of debate. Over the past decade, levetiracetam (LEV) has emerged as a promising alternative to phenobarbital (PB), driven by growing concerns over PB’s limited efficacy and potential neurotoxic effects. Methods: This retrospective cohort study analyzed medical records of VLBW infants treated for seizures at our Neonatal Intensive Care Unit from 2013 to 2023. We compared the efficacy and safety of LEV and PB as initial antiepileptic treatments. Data on gestational age, birth weight, type of seizures, electroencephalogram findings, and treatment outcomes were meticulously collected and analyzed. Results: The study included 103 VLBW infants (mean gestational age 26.17±2.31 weeks); 27 received LEV and 76 received PB. Baseline demographic and clinical characteristics were comparable between the two groups. Although the LEV group had a higher proportion of infants with severe intraventricular hemorrhage and necrotizing enterocolitis indicating a potentially more critical baseline, these differences were not statistically significant. The primary outcome revealed that significantly fewer infants in the LEV group were unresponsive to initial treatment compared to the PB group (14.8 vs. 56.6 %; p<0.001). Furthermore, lower gestational age was identified as a significant risk factor for PB unresponsiveness. Conclusions: This study supports that LEV is more successful in clinical seizure control compared to PB as the first choice in ASM selection in VLBW. If our study results are supported by randomized controlled prospective studies, LEV, with its potentially fewer side effects, could be included in clinical algorithms as the first-choice ASM especially for VLBW.

Objective: This study aimed to evaluate the neurological and systemic outcomes of amantadine treatment in the acute phase of severe traumatic brain injury (TBI) in children. In addition, the potential factors associated with functional outcomes were analyzed. Methods: This retrospective cohort study analyzed data of pediatric patients with severe TBI. Amantadine treatment was administered to all patients who presented after 2022. The treatment protocol was initiated on the third day of hospitalization, at a daily dose of 6 mg/kg, and at 100 mg twice daily for older children. The Functional Status Scale (FSS) was used to assess mental status, vision, hearing, communication, motor abilities, respiration, and feeding both at discharge from intensive care unit (ICU) and again 6 months after the incident of TBI. Results: In this study, 60 patients had a median age of 14.5 years (IQR 8; range 2-17 years), while 32 patients received amantadine treatment. The length of median ICU stay and hospital stay were 11 and 20 days, respectively. At the 6-month follow-up, there was a significant improvement in FSS scores compared to those estimated at ICU discharge (P < .001), but no significant difference was observed between the amantadine and non-amantadine groups in terms of functional recovery, and inotrope requirement was identified as an independent risk factor for poor neurological outcome. Conclusion: Administration of amantadine did not provide a significant functional benefit. However, craniectomy was performed less frequently for patients who received amantadine. Amantadine treatment was well tolerated with a favorable safety profile.

Introduction: Tuberous sclerosis complex (TSC) is a genetic disorder primarily caused by pathogenic variants in the TSC1 or TSC2 genes and is inherited in an autosomal dominant manner with variable phenotypic expression. A substantial proportion of cases arise from de novo mutations, and the clinical spectrum is highly heterogeneous. Molecular genetic diagnosis is essential not only for establishing a definitive diagnosis but also for enabling genotype–phenotype correlations, family screening, genetic counseling, and targeted therapeutic approaches. This review aims to summarize the genetic characteristics of TSC and current molecular diagnostic strategies to guide clinical practice. Conclusion: Genetic variants in TSC are distributed throughout the genes, with point mutations being the most common. Mutations in TSC2 are generally associated with a more severe clinical phenotype, whereas TSC1 mutations tend to present with milder manifestations. Mosaicism, particularly in patients with mild clinical features, may be overlooked by conventional testing methods and therefore requires careful evaluation. Next-generation sequencing is the first-line diagnostic approach, complemented by MLPA and chromosomal microarray analysis for detecting large deletions or duplications. Whole-exome and whole-genome sequencing are valuable for identifying complex or intronic variants. Molecular diagnosis plays a critical role in prognostic assessment and in the development of personalized treatment strategies. Keywords: Tuberous Sclerosis Complex, TSC1, TSC2, genetic variants, molecular diagnosis, mosaicism, genotype–phenotype correlation

Background: Ataxia‐telangiectasia (AT) is a rare disorder leading to multisystem involvement due to impaired DNA repair. Recent advances in targeted therapies highlight the importance of early diagnosis. This study aimed to evaluate clinical, radiological, and genetic variability in patients with AT and examine genotype–phenotype associations and diagnostic timing. Methods: A retrospective study was conducted on genetically confirmed AT patients followed in four pediatric neurology centers in Türkiye over a 12‐year period. Results: A total of 21 patients with AT were included; the median age at symptom onset was 26 months, and the median age at diagnosis was 60 months, with a diagnostic delay of 21 months. Ocular telangiectasia was present in all patients. Ataxia, oculomotor apraxia, and dysarthria were other common features. Involuntary movements and strabismus were each observed in 52.4%. Cerebellar atrophy was noted in 57.1%, and decreased immunoglobulin levels in 95.2%. No significant differences in the frequency of clinical findings were observed between early and late diagnosis groups, except that recurrent respiratory tract infections were significantly more common in the early‐diagnosis group ( p = 0.035). Conclusion: In this study, clinical variability and key clinical features of AT were identified. AT should be suspected and immunoglobulin levels assessed in patients with neurological symptoms and recurrent infections. Improving recognition of AT may contribute to earlier diagnosis and better outcomes.

Intellectual disability (ID) and epilepsy are often comorbid, but the pathways that lead to epilepsy in individuals with ID remain unclear. This study aims to explore the molecular pathways linked to epilepsy development in ID, providing insights into shared genetic mechanisms. Definitive ID-related genes were extracted from the SysNDD database, and their association with epilepsy pathways was assessed using gene set overrepresentation analysis. Enrichment was performed using Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Disease Ontology (DO) terms. Pathways were classified based on their relevance to epilepsy, and the involvement of specific genes was analyzed. Approximately 75% of ID-related genes were associated with epilepsy. Enriched pathways in ID-related epilepsy genes included neurotransmitter signaling, ion channel regulation, and metabolic pathways such as “nicotine addiction” and “thermogenesis.” Key genes like GRIN2A, CACNA1A, and PIGB were found to be involved in multiple pathways, suggesting their potential as therapeutic targets. DO and GO terms indicated shared and distinct mechanisms between ID and epilepsy, with significant overlap in pathways such as “intellectual disability.” We performed overrepresentation analyses on curated gene sets; the results are descriptive and hypothesis-generating rather than causal. These insights provide potential targets for therapeutic interventions and highlight the need for further research into the genetic underpinnings of epilepsy in this population.

This pilot study aimed to assess the dual-task performance and balance ability in children and adolescents with Juvenile Myoclonic Epilepsy (JME). Additionally, it sought to investigate the impact of dual-task conditions on functional performance and explore relationship between balance ability and dual-task performance. Ten children and adolescents with JME (mean age 16.90 ± 1.20 years) were evaluated. Static and dynamic balance were assessed using the Balance Master System, with modified Clinical Test of Sensory Interaction on Balance (mCTSIB) and Limit of Stability tests measuring static and dynamic balance, respectively. The mCTSIB and TUG tests were performed under single- and dual-task (motor-motor, cognitive-motor) conditions. No significant differences were found in mCTSIB test between single-task and dual-task conditions (p > 0.05). However, TUG completion time increased under cognitive-motor dual-task conditions (p < 0.05). There was no significant correlation between balance and dual-task performance (p > 0.05). This exploratory pilot study, conducted without a control group, suggests that children with JME may face difficulties with tasks requiring both cognitive and motor functions, as cognitive-motor dual tasks significantly increased task completion time. Lower scores in certain balance measures suggest a potential risk of balance impairment. These findings underscore the importance of integrating both cognitive-motor dual-task and balance assessments into rehabilitation programs for children with JME.

Although post-stroke epilepsy (PSE) is a prevalent complication in children, optimal management remains challenging. This study evaluated the impact of different treatment modalities and antiseizure medications (ASM) on the development and management of pediatric PSE following arterial ischemic stroke. We conducted a retrospective cohort analysis over 20 years, examining pediatric patients who experienced seizures during the course of arterial ischemic stroke. Exclusions included neonatal stroke, hemorrhagic stroke, and sinovenous thrombosis. Cut-off point of seven days were accepted as early seizures and PSE. Treatments included acute stroke therapies such as intravenous tissue plasminogen activator, mechanical thrombectomy, anti-edema therapies, and antithrombotic treatments. Medications for seizure control were categorized as acute seizure management agents (benzodiazepines and phenytoin), which are not used for long-term post-stroke epilepsy control, and long-term antiseizure medications (levetiracetam and carbamazepine) for PSE management. Among 153 patients, 99 were male, with a median age of 23 months. PSE was diagnosed in 59.5% of the cohort. Cardiac disorders were the primary etiology (32.7%). Hyperacute treatments and anti-edema therapies showed no significant impact on PSE development. Benzodiazepines and phenytoin also did not affect PSE rates. Levetiracetam was associated with a higher PSE rate (66.7%) compared to carbamazepine (45.1%) (p = 0.010). Carbamazepine demonstrated superior seizure freedom at 6 and 24 months (p = 0.024 and p = 0.014, respectively). Seizure control was achieved in 19.8% of PSE patients through dose titration, with carbamazepine showing higher efficacy (p = 0.037). ASM discontinuation rates were higher with carbamazepine (95.7%) compared to levetiracetam (79.4%). Acute stroke therapies, anti-edema, and antithrombotic treatments did not lower the PSE development. Benzodiazepines and phenytoin were not effective in preventing PSE. Carbamazepine may be more effective than levetiracetam in managing pediatric PSE, providing better seizure control and higher ASM discontinuation rates. Further research is needed to confirm these findings.