Shared Biological Pathways and Processes in Patients with Intellectual Disability: A Multicenter Study.

BACKGROUND: Although the underlying genetic causes of intellectual disability (ID) continue to be rapidly identified, the biological pathways and processes that could be targets for a potential molecular therapy are not yet known. This study aimed to identify ID-related shared pathways and processes utilizing enrichment analyses. METHODS: In this multicenter study, causative genes of patients with ID were used as input for Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. RESULTS: Genetic test results of 720 patients from 27 centers were obtained. Patients with chromosomal deletion/duplication, non-ID genes, novel genes, and results with changes in more than one gene were excluded. A total of 558 patients with 341 different causative genes were included in the study. Pathway-based enrichment analysis of the ID-related genes via ClusterProfiler revealed 18 shared pathways, with lysine degradation and nicotine addiction being the most common. The most common of the 25 overrepresented DO terms was ID. The most frequently overrepresented GO biological process, cellular component, and molecular function terms were regulation of membrane potential, ion channel complex, and voltage-gated ion channel activity/voltage-gated channel activity, respectively. CONCLUSION: Lysine degradation, nicotine addiction, and thyroid hormone signaling pathways are well-suited to be research areas for the discovery of new targeted therapies in ID patients.

Dysembryoplastic neuroepithelial tumors of childhood: Ege University experience.

BACKGROUND: Dysembryoplastic neuroepithelial tumors (DNETs) are rare, low-grade tumors of the central nervous system (CNS) of childhood. It is an important cause of intractable epilepsy, and it is surgically curable. We aimed to review our institutional experience with DNET in children. METHODS: Medical records of children aged less than 18 years of age diagnosed with DNET between 2009 and 2020 at Ege University Hospital were reviewed. Clinical features of the patients including age, gender, initial symptoms, duration of symptoms, medical treatments, age at the time of surgery, tumor location, degree of surgical resection, and outcome of the patients were documented. RESULTS: We reviewed the records of 17 patients with DNETs. Twelve of them were male (70%), 5 of them female (30%). The median age was 11 years (19 months-17 years). The major symptom was a seizure in all of the patients. Thirteen patients presented with complex partial seizures, whereas 2 had a simple partial seizure, and 2 generalized tonic-clonic seizures. Seven patients had drug resistant epilepsy and had received at least two anti-epileptic drugs before surgery. The median duration of symptoms was 6.6 months (0-48 months). In surgery, total surgical resection was performed in 15 patients, and 2 patients underwent partial resection. From these 15 patients, seven patients underwent lesionectomy of the tumor while the other eight patients had extended lesionectomy. The mean follow-up time was 107 months (54-144 months), the seizure control was achieved in 14 patients (82.4%) after surgery, but 3 patients experienced tumor recurrence in the follow-up. CONCLUSION: In DNETs, the complete total resection of the lesion is generally associated with seizure-free outcomes. In the patients with partial resection and lesionectomy, MRI follow-up is recommended for recurrence.

The Utility of Genetic Testing in Infantile Epileptic Spasms Syndrome: A Step-Based Approach in the Next-Generation Sequencing Era.

BACKGROUND: To evaluate the utility of genetic testing for etiology-specific diagnosis (ESD) in infantile epileptic spasms syndrome (IESS) with a step-based diagnostic approach in the next-generation sequencing (NGS) era. METHODS: The study cohort consisted of 314 patients with IESS, followed by the Pediatric Neurology Division of Ege University Hospital between 2005 and 2021. The ESD was evaluated using a step-based approach: step I (clinical phenomenology), step II (neuroimaging), step III (metabolic screening), and step IV (genetic testing). The diagnostic utility of genetic testing was evaluated to compare the early-NGS period (2005 to 2013, n = 183) and the NGS era (2014 to 2021, n = 131). RESULTS: An ESD was established in 221 of 314 (70.4%) infants with IESS: structural, 40.8%; genetic, 17.2%; metabolic, 8.3%; immune-infectious, 4.1%. The diagnostic yield of genetic testing increased from 8.9% to 41.7% in the cohort during the four follow-up periods. The rate of unknown etiology decreased from 34.9% to 22.1% during the follow-up periods. The genetic ESD was established as 27.4% with genetic testing in the NGS era. The genetic testing in the NGS era increased dramatically in subgroups with unknown and structural etiologies. The diagnostic yields of the epilepsy panels increased from 7.6% to 19.2%. However, the diagnostic yield of whole exome sequencing remained at similar levels during the early-NGS period at 54.5% and in the NGS era at 59%. CONCLUSIONS: The more genetic ESD (27.4%) was defined for IESS in the NGS era with the implication of precision therapy (37.7%).

What are the predominant predictors of seizure relapse following discontinuation of anti-seizure medication in epileptic children?

OBJECTIVE: The aim of the study was to identify the predominant predictors of seizure relapse following discontinuation of ASM in epileptic children. METHODS: The study cohort consisted of 403 epileptic children who had a withdrawal process of ASM (monotherapy: 344; dual therapy or polytherapy: 59) after at least a 2-year seizure-free period. Patients were categorized if they had a well-defined epileptic syndrome. Epileptic children with ongoing ketogenic diet, vagal nerve stimulation, or surgery were excluded from the cohort due to the additional withdrawal process related to other therapy modalities. RESULTS: The cohort's seizure relapse rate was 12.7% (51/403). The highest rates of seizure relapse were defined for genetic etiology at 25% and structural etiology at 14.9%. An epilepsy syndrome was defined in 183 of 403 children (45.4%). There was no difference in the seizure relapse rate between the subgroups of well-defined epileptic syndromes; 13.8% for self-limited focal epileptic syndromes, 11.7% for developmental and epileptic encephalopathies, and 7.1% for generalized epileptic syndromes. Five predictors were defined as the most powerful predictors of seizure relapse in univariate analysis: age at epilepsy diagnosis >2 years (hazard ratio [HR]: 1.480; 95% confidence interval [CI]: 1.134-1.933), defined etiology (HR: 1.304; 95% CI: 1.003-1.696), focal seizure (HR: 1.499; 95% CI: 1.209-1.859), ≤3 months duration of the withdrawal process (HR: 1.654; 95% CI: 1.322-2.070), and a history of neonatal encephalopathy with or without seizures (HR: 3.140; 95% CI: 2.393-4.122). In multivariate analysis, the main predictor of seizure relapse was a history of neonatal encephalopathy with or without seizures (HR: 2.823; 95% CI: 2.067-3.854). SIGNIFICANCE: The duration of seizure freedom before discontinuation of ASM was not a predominant risk factor for seizure relapse: 2-3 years versus >3 years. The predictive values of five predictors of seizure relapse rate should be evaluated for patients with different epilepsy subgroups.

Assessment of Prognostic Factors and Validity of Scoring Models in Childhood Autoimmune Encephalitis.

OBJECTIVE: The aim of this study is to evaluate the prognostic factors in a single-center pediatric cohort with autoimmune encephalitis. MATERIALS AND METHODS: The study group consisted of 23 pediatric autoimmune encephalitis patients (seropositive autoimmune encephalitis: 15, seronegative autoimmune encephalitis: 8). Five group prognostic parameters were evaluated: clinical manifestations, elect roenc ephal ograp hy features, magnetic resonance imaging characteristics, biomarkers, and treatment modalities. Three scoring models were applied: the Antibody Prevalence in Epilepsy and Response to Immunotherapy in Epilepsy for predicting autoimmune-related epilepsy in the whole cohort and the anti-N-methyl-d-aspartate receptor Encephalitis 1-Year Functional Status score for overall outcome in patients with anti-N-methyl-d-aspartate receptor encephalitis. RESULTS: The initial clinical spectrum of the disease was similar in the seronegative and seropositive groups. Almost half of the patients (48%) recovered without any complications with first-line immunotherapy. The patients with movement disorders in the acute phase of the disease needed more likely second-line immunotherapy (P = .039). The presence of status epilepticus at admission was significantly associated with adverse outcomes and the development of autoimmune-related epilepsy (P = .019). Autoimmune-related epilepsy was defined in an equal proportion of patients (91.5%) with 2 immune epilepsy scores (Antibody Prevalence in Epilepsy and Response to Immunotherapy in Epilepsy). The N-methyl-d-aspartate receptor Encephalitis 1-Year Functional Status score and the modified Rankin score assessed for the first-year prognosis were strongly correlated among the patients with anti-N-methyl-d-aspartate receptor encephalitis (P = .03, Spearmen's rho = 0.751). CONCLUSIONS: The presence of status epilepticus was the most important prognostic factor in the patients with the adverse outcome. The studied scoring models (Anti-N-methyl-d-aspartate receptor Encephalitis 1-Year Functional Status, Antibody Prevalence in Epilepsy, and Response to Immunotherapy in Epilepsy) have also been proven to be applicable to the pediatric age group for predicting overall outcome and autoimmune-related epilepsy.