Background:The COVID-19 pandemic has disrupted early childhood environments globally, raising concerns about its potential impacts on neurodevelopment. Although early childhood is a critical developmental period, large-scale evidence from South Korea - where strict social distancing and unique caregiving structures were in place - remains limited. We aim to evaluate age- and domain-specific neurodevelopmental outcomes among children aged 0-5 years before and during the pandemic, focusing on differences by age and sex. Methods:We analysed children aged 0-5 years using data from a national health screening programme and a pre-post comparison design with repeated cross-sectional data. We compared the pre-pandemic (July 2018-March 2020) and pandemic (April 2020-December 2021) periods. We categorised children into infants (9-12 months), toddlers (18-36 months), and preschoolers (42-71 months). We measured developmental outcomes using the Korean Developmental Screening Test across six domains: gross motor, fine motor, cognition, language, social skills, and self-help. We conducted multivariable logistic regression and difference-in-differences analyses. Results:We analysed 6 253 076 assessments from 2 797 459 children. Peer-level developmental status declined significantly during the pandemic across all age groups, with the most pronounced decrease among toddlers (adjusted odds ratio (aOR) = 0.92; 95% confidence interval (CI) = 0.91-0.92), followed by infants and preschoolers. The language domain experienced the greatest decline (aOR = 0.87; 95% CI = 0.86-0.88), whereas the gross motor domain showed significant improvement (aOR = 1.13; 95% CI = 1.11-1.15). Boys were more adversely affected than girls, particularly in gross motor and social skill domains. Conclusions:The COVID-19 pandemic led to significant developmental declines among young children, particularly in language and social domains and among toddlers. Boys were more adversely affected than girls, especially in language and socioemotional skills, highlighting sex-related vulnerabilities. Prioritising early screening and interventions targeting these key domains, alongside sex-sensitive strategies and caregiver support, will be essential to mitigate developmental disruptions during future pandemics.

Lennox-Gastaut syndrome (LGS) is a rare and severe developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, mandatory tonic seizures, cognitive and behavioral impairment, and distinctive electroencephalographic features, including slow spike-wave discharges and generalized paroxysmal fast activity. Despite decades of therapeutic advances, LGS remains associated with profound lifelong disability and the absence of a single disease-defining molecular mechanism. Recent advances in genetics, neurophysiology, and network neuroscience have reframed LGS as a convergent network encephalopathy, in which diverse genetic, structural, metabolic, immune, and acquired insults funnel into shared molecular hubs, leading to thalamocortical network dysfunction. This framework helps explain the limited efficacy of purely syndrome-based treatments. This review synthesizes current evidence on electroclinical phenotyping, molecular and network pathogenesis, and contemporary diagnostic workflows and proposes a molecule-to-precision-therapy framework for LGS. We critically appraise pharmacologic, dietary, surgical, and neuromodulatory therapies, emphasizing drop seizures as a major driver of morbidity. Among available treatments, cannabidiol shows the most consistent and clinically meaningful efficacy for drop seizures, with benefits extending beyond seizure counts to seizure-free days and caregiver-relevant outcomes. Finally, we highlight key gaps and future directions, including etiology-stratified trials, network-guided interventions, and outcome measures that capture long-term developmental and quality-of-life impacts.

Background: Identifying the genetic cause of hereditary kidney disease is essential for appropriate management. However, pediatric patients often present with nonspecific renal symptoms such as proteinuria, hematuria, or both, making accurate diagnosis difficult. Mitochondrial diseases are also an important but underrecognized etiology of hereditary kidney disorders. This study aimed to assess the diagnostic utility of whole-exome sequencing (WES) combined with mitochondrial DNA (mtDNA) analysis and to describe the clinical and genetic features of pediatric patients presenting with isolated proteinuria, combined hematuria and proteinuria, or hematuria with a relevant family history. Methods: DNA was extracted from peripheral blood leukocytes of 77 pediatric patients with hematuria and/or proteinuria with or without family history. WES and mtDNA analyses were conducted to identify underlying genetic etiologies. Results: The overall molecular diagnostic yield was 54.5% (42/77) with COL4A-related nephropathy (29 cases) being the most prevalent diagnosis. Notably, one patient with no systemic symptoms except for renal manifestations was identified with the m.3243A>G variant in MT-TL1, which is associated with the MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) syndrome. This patient’s initial and predominant presentation was gross and microscopic hematuria, diverging from typical MELAS-associated kidney disease. Conclusion: WES proved valuable in diagnosing hereditary kidney diseases in pediatric patients with nonspecific urinalysis findings. Incorporating mtDNA analysis further improved diagnostic yield and enabled identification of atypical presentations of mitochondrial disorders, such as MELAS, even when renal symptoms were isolated.

Drug-resistant epilepsy (DRE) affects 20–30% of patients with epilepsy who fail to achieve seizure control with antiseizure medications, posing a significant therapeutic challenge. In this narrative review, we examine the clinical efficacy and safety of the classic ketogenic diet (cKD) and its variants, including the modified Atkins diet (MAD), medium-chain triglyceride diet (MCTD), and low glycemic index treatment (LGIT), in patients with genetically confirmed drug-resistant epilepsy. These diets induce a metabolic shift from glucose to ketones, enhance mitochondrial function, modulate neurotransmitter balance, and exert anti-inflammatory effects. However, genetic factors strongly influence the efficacy and safety of the cKD, with absolute indications including glucose transporter type 1 deficiency syndrome (GLUT1DS) and pyruvate dehydrogenase complex deficiency (PDCD). Preferred adjunctive applications of the KD include genetic epilepsies, such as SCN1A-related Dravet syndrome, TSC1/TSC2-related tuberous sclerosis complex, and UBE3A-related Angelman syndrome. However, because of the risk of metabolic decompensation, the cKD is contraindicated in patients with pathogenic variants of pyruvate carboxylase and SLC22A5. Recent advancements in precision medicine suggest that genetic and microbiome profiling may refine patient selection and optimize KD-based dietary interventions. Genome-wide association studies and multiomics approaches have identified key metabolic pathways influencing the response to the cKD, and these pave the way for individualized treatment strategies. Future research should integrate genomic, metabolomic, and microbiome data to develop biomarker-driven dietary protocols with improved efficacy and safety. As dietary therapies continue to evolve, a personalized medical approach is essential to maximize their clinical utility for genetic epilepsy and refractory epilepsy syndromes.

This study presents the first reported case of a Korean patient with Alpha-1,3-Mannosyltransferase-Congenital Disorder of Glycosylation (ALG3-CDG), characterized by a novel maternally inherited missense mutation and a previously reported paternally inherited nonsense mutation. The patient exhibited typical ALG3-CDG manifestations, including developmental delays, epilepsy, and multisystem involvement, alongside a diagnosis of Lennox-Gastaut Syndrome (LGS). Cannabidiol therapy, combined with dietary management, led to seizure freedom for over 13 months, significant EEG improvement, and enhanced developmental outcomes. This case underscores the potential of cannabidiol as a promising treatment strategy for patients with ALG3-CDG and refractory epilepsy, broadening therapeutic perspectives for this rare disorder.

Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder characterized by progressive motor function loss and skeletal muscular atrophy. Nusinersen, an antisense oligonucleotide, is the first FDA-approved therapy to achieve a significant milestone in SMA management. However, its high molecular weight requires intrathecal administration, posing challenges for clinical implementation. This study aimed to identify factors associated with postprocedural pain following repeated CT-guided transforaminal nusinersen injection in non-ambulatory patients with SMA. This single-center retrospective study evaluated 34 patients who underwent a total of 290 procedures. Postprocedural pain occurred in 49.3% of cases. Factors influencing postprocedural pain included needle angle with vertical and horizontal lines, prophylactic pain control, and number of CT scans (p < 0.05). In patients experiencing postprocedural pain, the needle angle with vertical and horizontal lines emerged as significant variables, with a beta coefficient (standard error) of 0.034 (0.011) (p < 0.05). Needle angle was an important predictor of postprocedural pain.

Background/Objectives: Pediatric chronic migraine (CM) is a debilitating condition with challenging management due to diagnostic complexities and a lack of evidence-based treatment. Calcitonin gene-related peptide (CGRP)-targeted therapies have transformed adult CM management, but their use in pediatric populations is underexplored. This study evaluated the safety and efficacy of CGRP-targeted therapies combined with structured lifestyle modifications in Korean pediatric patients with CM. Methods: This retrospective study examined 10 pediatric CM patients treated at Gangnam Severance Hospital from 2021 to 2024. Inclusion criteria were as follows: (1) Pediatric Migraine Disability Assessment Scale (PedMIDAS) score ≥ 30, (2) >2 failed preventive therapies, and (3) ≥8 migraine days per month. Patients received CGRP monoclonal antibodies or antagonists, alongside sleep, dietary, and exercise interventions. Changes in migraine burden, neuropsychological outcomes, and adherence to lifestyle interventions were assessed over 12 months. Results: Migraine frequency significantly decreased from a median of 26.5 to 14 days per month (p < 0.001); PedMIDAS scores declined from 58.5 to 48.0 (p = 0.037); and acute analgesic use was reduced from 14 to 5 days per month (p < 0.001). Adherence to lifestyle interventions improved significantly (p < 0.001). No serious adverse events were reported, and minor side effects, such as injection site pain and dizziness, were self-limiting. Conclusions: CGRP-targeted therapies, combined with structured lifestyle modifications, safely and effectively reduce migraine burden in pediatric CM patients. These therapies have facilitated sustainable improvements in management and support their integration into comprehensive pediatric CM care. This study highlights the importance of integrating pharmacologic and lifestyle-based approaches for holistic pediatric migraine management.

Mitochondrial diseases (MDs) are genetic disorders with diverse phenotypes that affect high-energy-demand organs, notably the central nervous system and muscles. Epilepsy is a common comorbidity, affecting 40%-60% of patients with MDs and significantly reducing their quality of life. This review discusses the different treatment modalities for epilepsy in patients with MDs. Advances in genetic sequencing have identified specific mutations in mitochondrial and nuclear DNA, enabling more precise diagnoses and tailored therapeutic strategies. Anti-seizure medications and dietary interventions, such as ketogenic diets and their variants, have been effective in reducing seizures and improving mitochondrial function. Emerging treatments include gene therapy, mitochondrial transplantation, and antioxidants such as EPI-743, which protect mitochondrial integrity and improve neurological function. Additionally, therapies that promote mitochondrial biogenesis, such as bezafibrate and epicatechin, are being explored for their potential to enhance mitochondrial proliferation and energy production. Gene therapy aims to correct genetic defects underlying MDs. Techniques like mitochondrial gene replacement and using viral vectors to deliver functional genes have shown promise in preclinical studies. Mitochondrial transplantation, an emerging experimental technique, involves transferring healthy mitochondria into cells with dysfunctional mitochondria. This technique has been demonstrated to restore mitochondrial function and energy metabolism in preclinical models. Patient-derived induced pluripotent stem cells can model specific mitochondrial dysfunctions in vitro, allowing for the testing of various treatments tailored to individual genetic and biochemical profiles. The future of mitochondrial medicine is promising, with the development of more targeted and personalized therapeutic strategies offering hope for improved management and prognosis of mitochondrial epilepsy.

Cannabidiol (CBD) has transitioned from anecdotal use to an evidence-based adjunctive therapy for Lennox–Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. This review integrates knowledge on CBD’s pharmacology, pharmacokinetics, and clinical implementation, with focus on metabolism, therapeutic drug monitoring (TDM), and clinically relevant interactions with antiseizure medications. CBD exerts CB1/CB2-independent mechanisms—prominently GPR55 antagonism, TRP-channel desensitization, and adenosine-mediated network dampening—supporting efficacy across heterogeneous seizure phenotypes. Its pharmacokinetic profile is characterized by low and variable oral bioavailability, a pronounced food effect, extensive tissue distribution, and phase I/II biotransformation to the active 7-hydroxy-CBD and abundant 7-carboxy-CBD, resulting in substantial inter-individual variability and liability for drug–drug interactions. Clinically salient interactions include CYP2C19-mediated elevation of N-desmethylclobazam and increased transaminases in valproate co-therapy. We summarize emerging TDM practices—standardized fed-state trough sampling with paired measurement of CBD and 7-hydroxy-CBD—and discuss how preliminary interpretive ranges can support dose optimization, adherence assessment, and safety surveillance. Practical recommendations emphasize interaction-aware titration within evidence-based dose bands, liver function monitoring, and standardized documentation of formulation and sampling conditions. Future work should align pharmacogenomics with TDM, refine bioavailability through advanced delivery systems, and tighten analytical and product-quality standards to consolidate CBD as a precision-ready component of modern epilepsy care.

Asparagine synthetase deficiency (ASNSD, OMIM #615574) is a rare neurometabolic disease with an autosomal recessive inheritance pattern. Initially reported in 2013 by Ruzzo and colleagues, gene sequencing is required for the diagnosis and patients from diverse ethnic origins have been reported [ [1] Ruzzo E.K. Capo-Chichi J.M. Ben-Zeev B. Chitayat D. Mao H. Pappas A.L. et al. Deficiency of asparagine synthetase causes congenital microcephaly and a progressive form of encephalopathy. Neuron. 2013; 80: 429-441 Abstract Full Text Full Text PDF PubMed Google Scholar ]. ASNSD results in congenital microcephaly, global developmental delay, severe epilepsy, progressive brain atrophy and ventriculomegaly with mortality as high as 70 % during early infancy [ [2] Alfadhel M., El-Hattab A.W. Asparagine synthetase deficiency. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, et al., editors. GeneReviews((R)). Seattle (WA) 1993. Google Scholar ]. Here, we report the first case of a Korean/Vietnamese male child with ASNSD caused by novel compound heterozygous mutations inherited from a Korean father and a Vietnamese mother. Frequent electroencephalography (EEG) recordings revealed various seizure phenotypes from epileptic spasms, migrating focal epilepsy to generalized tonic seizures. This case report further expands the genetic and clinical spectrum of ASNSD.

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a complex mitochondrial disorder characterized by a wide range of systemic manifestations. Key clinical features include recurrent stroke-like episodes, seizures, lactic acidosis, muscle weakness, exercise intolerance, sensorineural hearing loss, diabetes, and progressive neurological decline. MELAS is most commonly associated with mutations in mitochondrial DNA, particularly the m.3243A>G mutation in the MT-TL1 gene, which encodes tRNALeu (CUR). These mutations impair mitochondrial protein synthesis, leading to defective oxidative phosphorylation and energy failure at the cellular level. The clinical presentation and severity vary widely among patients, but the syndrome often results in significant morbidity and reduced life expectancy because of progressive neurological deterioration. Current management is largely focused on conservative care, including anti-seizure medications, arginine or citrulline supplementation, high-dose taurine, and dietary therapies. However, these therapies do not address the underlying genetic mutations, leaving many patients with substantial disease burden. Emerging experimental treatments, such as gene therapy and mitochondrial replacement techniques, aim to correct the underlying genetic defects and offer potential curative strategies. Further research is essential to understand the pathophysiology of MELAS, optimize current therapies, and develop novel treatments that may significantly improve patient outcomes and extend survival.

Background: With the outbreak of COVID-19, school closures and quarantines following social distancing have brought significant changes to children's lifestyles. Therefore, we aimed to compare the population-adjusted incidence of febrile seizures(FS) and epilepsy before and after the COVID-19 outbreak in Korea and to assess the effects of the COVID-19 outbreak on the incidence by region and age group.Methods: A retrospective cohort study was conducted using nationwide claims data and covid data from January 2019 to December 2020. The incidence of diseases and difference in incidence before (Jan 20 to Dec 30, 2019) and after (Jan 20 to Dec 30, 2020) the COVID-19 outbreak was measured using rate ratio. An Interrupted time series analysis was used to identify the effect of COVID-19 on trends of FS and epilepsy. Subgroup analysis by age, sex, insurance, and risk of coronavirus by area were conducted. Results: Following the onset of the pandemic, the number of newly diagnosed FS cases decreased sharply by 69 % (24,182 to 7238), whereas the incidence of epilepsy, increased to 1.02 times (30,286-29,312), when adjusted in proportion to the population. Notably, a greater decrease in the incidence of FS were found in the regions with high-risk of coronavirus. A result of segmented regression analysis proved the decrease was significant and made immediately after the pandemic started(p < 0.001). In contrast to the incidence of FS, that of epilepsy did not exhibit a significant month-to-month change during the baseline period, immediately after the pandemic started, and during the pandemic.Conclusions: The COVID-19 outbreak and resulting social distancing measures reduced the incidence of febrile seizure immediately rather than gradually. Unlike in the case of acute febrile seizure, the COVID-19 pandemic had no effect on the incidence of chronic epilepsy.(c) 2023 The Author(s). Published by Elsevier Ltd on behalf of King Saud Bin Abdulaziz University for Health Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/li-censes/by-nc-nd/4.0/).

Purpose Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by arylsulfatase A deficiency, which leads to progressive demyelination in both the central and peripheral nervous systems, resulting in significant gross motor deterioration. This study aimed to analyze data concerning neuroimaging and clinical phenotypes of MLD patients, categorized by disease subtype. Methods Patients diagnosed with MLD based on arylsulfatase A enzymatic activity, demyelination observed in brain magnetic resonance images, and/or pathogenic mutations were included in this study. The medical charts of 10 patients with confirmed MLD were retrospectively reviewed. We used a simplified magnetic resonance imaging (MRI) scoring system and clinical status, including survival. We analyzed the correlations between the scores of specific neuroimaging lesions and clinical status in two groups, categorized as late-infantile and juvenile types based on the age at symptom onset. Results We detected a positive relationship between clinical function deterioration and MRI score (rho=0.59, P=0.002) in patients with MLD. This correlation was stronger in the late-infantile type (rho=0.700, P=0.003) than in the juvenile type (rho=0.513, P=0.029). A strong relationship was also noted in patients with high signal intensities in the pons and basal ganglia, and cerebellar atrophy, but not in those with lesions in the midbrain. MLD with a high MRI score was associated with poor clinical function. Conclusion The identified correlations between modified MRI scores and clinical function scales may help predict the prognosis of patients with MLD, thereby aiding in the identification of treatment options and enhancing the quality of life for these patients.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a multi-system disorder mostly caused by mutations in mitochondrial DNA [1]. The pathogenic variant m.3243A>G accounts for more than 80% of cases of MELAS syndrome. The clinical manifestations of MELAS are highly diverse and include seizures, dementia, stroke-like episodes, migraines, depression, sensorineural hearing loss, muscle weakness, cardiomyopathy

BackgroundLennox–Gastaut syndrome (LGS), a severe developmental epileptic encephalopathy, has various underlying causes. Mitochondrial respiratory chain complex I (MRC I) deficiency is an important cause of metabolic disorders such as mitochondrial dysfunction that can compromise brain function, thereby causing intractable epilepsy, including LGS. Thus, it can be expected that the presence or absence of MRC I deficiency may affect the treatment outcome of patients with LGS.ObjectivesIn this retrospective study, we aimed to investigate differences in the epilepsy characteristics and treatment outcomes between patients with LGS with and without MRC I deficiency.MethodsWe retrospectively reviewed the medical records of 92 patients with LGS. We divided 68 patients with LGS according to the presence (n = 30) or absence (n = 38) of MRC I deficiency and compared their epilepsy characteristics.ResultsGeneralized tonic and drop seizures were significantly worse in patients with LGS and MRC I deficiency than in those without MRC I deficiency group at the 1-year follow-up (p < 0.001) and final follow-up 1 (p < 0.001). Patients with LGS and MRC I deficiency had significantly fewer electroencephalogram (EEG) improvements compared to those without MRC I deficiency at the 1-year follow-up (p = 0.031). Additionally, in the final follow-up period, patients with LGS and MRC I deficiency had significantly less improvement in EEG findings compared to patients without MRC I deficiency (p < 0.001).ConclusionThe overall treatment prognosis—in terms of improvement in traumatic generalized tonic seizure, drop seizure, and EEG findings—is worse in patients with LGS and MRC I deficiency than that in patients with LGS but without MRC I deficiency. Additional and targeted treatment is required to treat LGS with MRC I deficiency.

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited multisystemic disorder caused by mutations in mitochondrial DNA that result in cellular energy deficiency. MELAS affects the most metabolically active organs, including the brain, skeletal muscles, cochlea, retina, heart, kidneys, and pancreas. As a result, about 85% of carriers of m.3243A > G, the most common mutation in MELAS, develop diabetes by the age of 70. Although metformin is the most widely prescribed drug for diabetes, its usefulness in mitochondrial dysfunction remains controversial. Here, we present the case of a 32-year-old Korean patient diagnosed with MELAS who presented with exacerbated stroke-like episodes and lactic acidosis triggered by metformin.