Purpose Cannabidiol (CBD) is a promising treatment option for pediatric drug-resistant epilepsy (DRE). The aim of this study was to assess the tolerability and safety of CBD in a single-center retrospective cohort based on real-world clinical experience. Methods This study included 71 pediatric patients (median age, 8.9 years; interquartile range [IQR], 6.2 to 14.0) with Lennox–Gastaut syndrome who received purified CBD (Epidiolex, GW Pharmaceuticals) between March 2019 and July 2024. All patients had previously failed treatment with more than five anti-seizure medications (ASMs). Responder rate (≥50% seizure frequency reduction), retention rate, adverse effects (AEs), and predictors of favorable treatment response were analyzed over a median follow-up of 21.3 months (IQR, 2.8 to 38.5). Results The initial responder rate during the first 3 months was 45.1%, which increased to 70.8% at 18 months and 63.0% at 24 months. The retention rate at 24 months was 52.4% (33/71). Seven patients (9.9%) achieved seizure freedom beyond 24 months of CBD therapy, and five of these patients were able to reduce their concomitant ASM burden. AEs were observed in 39.4% (28/71) of patients, with the most frequent being somnolence (20 cases) and increased seizure frequency (six cases); 92.9% of AEs occurred within the first 3 months of treatment. No serious AEs requiring treatment discontinuation were identified. Conclusion In this real-world study, CBD demonstrated potential as an adjunctive therapy with manageable AEs. These findings highlight that CBD can reduce seizure frequency while maintaining tolerability in pediatric patients with DRE.

DNM1L-associated encephalopathy is a neurological disorder with a broad spectrum of symptoms associated with mutations in the DNM1L gene. Treatment primarily aims to alleviate symptoms, which is mostly ineffective as the underlying neuropathology is not well understood. Moreover, the progression and reversibility of the molecular pathology across the key developmental and postnatal stages have not been well characterized, which is crucial for identifying the therapeutic window and formulating effective treatment strategies. Here we demonstrated that the expression of DNM1L variants in developing mouse brains caused severe neuronal loss pronounced at the early postnatal stage. Using a human stem cell model with chemogenetic control of DNM1L, we elucidated the neurodevelopmental stage-specific reversibility of transcriptional changes caused by DNM1L dysfunction. Noticeably, more than 75% of the transcriptional landscape associated with pathology can be restored even in differentiated neurons. We validate that a feasible therapeutic strategy targeting one of the reversible pathways, mitochondrial biogenesis, prevents neurodegeneration, suggesting the potential for effective postnatal clinical intervention in DNM1L-associated disorders.

Purpose This study evaluates a patient-centered photography project aimed to enhance phenotypic characterization, assess caregiver quality of life, and foster public awareness for undiagnosed rare diseases. Methods Twenty patients with complex, undiagnosed conditions at Seoul National University Hospital were enrolled. Photography sessions captured natural facial expressions and typical body postures in everyday context. Caregivers completed the WHOQOL-BREF questionnaire. The resulting images were used in expert diagnostic forums and shared through public media. Results The cohort exhibited high medical complexity and early symptom onset with a median of 2 weeks. Caregivers reported significantly reduced QOL, with the physical domain and psychological domain scoring lower than caregivers of known neurodevelopmental disorders or chronic diseases. Qualitatively, families valued the sessions as meaningful emotional milestones beyond clinical documentation. Following the project, 17 news articles were generated, enhancing social inclusion and public understanding of the diagnostic odyssey. In addition, four patients received new diagnoses of genetic diseases, including RNU2-2 and RNU5B-1. Conclusion Patient-centered professional photography serves as a high-impact, low-risk intervention in rare disease care. By capturing real-life phenotypes, it facilitates expert collaboration and hypothesis generation while providing essential psychosocial support to families. This integrated approach extends the impact of undiagnosed disease programs beyond traditional genomics, addressing the emotional, identity-related, and societal dimensions of living with a rare condition.

Global developmental delay (GDD) and intellectual disability (ID) are frequently caused by genetic factors, yet many patients remain undiagnosed even after whole exome sequencing (WES). This study aimed to apply Optical Genome Mapping (OGM) and Illumina Complete Long Reads (ICLR) in pediatric patients with unexplained GDD/ID after WES and propose a practical diagnostic strategy for clinical implementation. We conducted OGM and ICLR on 87 pediatric patients with unexplained GDD/ID despite prior WES. Discordant cases underwent further validation using gap-PCR or PacBio long-read sequencing. A minigene assay was also performed to confirm the pathogenicity of an intronic variant. Of the 87 patients, 6 were found to carry pathogenic or likely pathogenic variants, including 4 structural variants (SVs) and 2 single nucleotide variants (SNVs). OGM and ICLR provided additional diagnostic yields of 4.71% and 6.98%. OGM was effective in detecting complex rearrangements, whereas ICLR performed well in cases with overlapping structural variants. For all SV burden, ICLR detected 8 SVs (mean 0.09 ± 0.33 per sample), and OGM identified 8 SVs (mean 0.09 ± 0.29 per sample), showing comparable results. This study demonstrates the complementary utility of ICLR and OGM in detecting diverse classes of pathogenic variants in GDD/ID. ICLR was advantageous for detecting non-coding SNVs, as well as for providing accurate breakpoint resolution in SVs, while OGM was effective for complex rearrangements and repetitive regions. These findings support a stepwise diagnostic strategy in which ICLR may be considered as an early second-tier test for WES-negative GDD/ID cases.

Neurodevelopmental disorders (NDDs) affect 2-4% of the population, are predominantly genetic and remain unsolved in ~50% of individuals. We show that rare biallelic variants in RNU2-2 are enriched and over-transmitted in individuals with unresolved NDDs. We define a recessive RNU2-2 syndrome, delineate its unique genetic architecture and show that it manifests clinically as a severe developmental and epileptic encephalopathy. We find that candidate biallelic variants are significantly correlated with reduced U2-2 abundance, implicating compromised transcript stability as a probable pathomechanism. We identify a decreased ratio of U2-2 to its paralog U2-1 as a potential diagnostic biomarker for this condition. We show that the recessive RNU2-2 syndrome is genetically, clinically and mechanistically distinct from the dominant RNU2-2 disorder. Within our cohort, the recessive RNU2-2 syndrome emerges as by far the most frequent recessive NDD, greatly disproportionate to the small genomic footprint of this non-protein-coding gene.

Short tandem repeat (STR) expansion is a major genetic mechanism underlying numerous neurogenetic disorders. However, traditional PCR amplification and short-read next-generation sequencing-based methods often fail to detect large-scale, complex expansions and to capture methylation information. Thus, this study aimed to modify an amplification-free nanopore Cas9-targeted sequencing (nCATS) platform to achieve uniform coverage across 56 currently defined STR loci using a single test with genomic DNA from patient-derived blood cells and to develop a dedicated analysis algorithm, STRiker, capable of identifying internal motif contexts and de novo repeat structures. Ultimately, this study identified pathogenic repeat expansions in 12 of 37 patients (32.4%) with cerebellar ataxia who remained genetically undiagnosed despite extensive prior genetic testing, in FGF14 (n = 4), ATXN8OS, NOP56, RFC1 (n = 2 each), and PRNP and NOTCH2NLC (n = 1 each). Additionally, family-based cascade screening revealed six relatives with repeat expansions in five families. These results demonstrate a broader diversity of pathogenic repeat structures, particularly in FGF14, and illustrate that CpG methylation can mitigate the pathogenic effects of repeat expansions. This nCATS-STRiker workflow offers a powerful strategy for improving the diagnosis of STR-related neurogenetic diseases, such as cerebellar ataxia and other diseases.

BACKGROUND:Focal cerebral arteriopathy-inflammatory type (FCA-i) is a leading cause of pediatric arterial ischemic stroke, but diagnostic challenges persist, particularly in East Asian populations where moyamoya disease (MMD) prevalence is high. The focal cerebral arteriopathy severity score quantifies arteriopathy severity but has not been validated in East Asian cohorts. We aimed to validate the focal cerebral arteriopathy severity score in Korean pediatric patients with FCA-i and compare temporal progression patterns with unilateral MMD. METHODS:We conducted a retrospective cohort study of children with arterial ischemic stroke presenting to Seoul National University Hospital between January 2002 and December 2024. Patients were classified according to the Childhood Arterial Ischemic Stroke Standardized Classification and Diagnostic Evaluation criteria. The focal cerebral arteriopathy severity score was applied to serial magnetic resonance angiograms at baseline, peak severity, and final follow-up. RESULTS:Among 216 children with arterial ischemic stroke, 132 patients (61.1%) demonstrated arteriopathy, including 49 with FCA-i (median age, 8.6 [interquartile range (IQR), 6.4-11.3] years; 55% male), 60 with MMD (median age, 5.7 [IQR, 3.1-9.2] years; 43% male), and 13 with arterial dissection (median age, 7.0 [IQR, 3.1-10.4] years; 62% male). In FCA-i patients, the severity score correlated significantly with baseline infarct burden (ρ=0.42; P=0.0069) and exhibited characteristic monophasic evolution with early peak at 2 months followed by gradual recovery reaching lowest values at 11 months. Patients with unilateral MMD demonstrated consistently higher severity scores at all timepoints compared with FCA-i (baseline: 6.0 versus 2.0; final: 8.0 versus 3.0; P<0.001) without radiographic recovery. A baseline severity score ≥8.0 predicted contralateral progression in unilateral MMD with an area under the curve of 0.962 (sensitivity, 0.83; specificity, 0.91). CONCLUSIONS:The focal cerebral arteriopathy severity score demonstrates validity as a dynamic biomarker for monitoring FCA-i in Korean pediatric patients, exhibiting characteristic monophasic recovery patterns that distinguish it from progressive unilateral MMD.

SUPT16H encodes a subunit of the FACT (FAcilitates Chromatin Transcription) complex, a histone chaperone essential for maintaining chromatin integrity during transcription, replication, and DNA repair. Pathogenic de novo SUPT16H missense variants have previously been linked to neurodevelopmental disorders in eight individuals. Here, we expand the genotypic and phenotypic spectrum by identifying 24 additional individuals harboring ultrarare heterozygous missense or truncating variants, who share overlapping clinical features including intellectual disability, autism spectrum disorder, hypotonia, and characteristic craniofacial dysmorphism. To elucidate the underlying mechanisms, we generated a supt16h knockout zebrafish model using CRISPR/Cas9. The supt16h loss-of-function (LOF) model recapitulated key patient phenotypes such as developmental delay, craniofacial anomalies, and hypotonia. Structural and functional analyses of selected SUPT16H variants demonstrated differential rescue of developmental defects in supt16h-deficient embryos, indicating variant-specific LOF effects in vivo. The presence of non-neural manifestations, including facial and ear anomalies, suggested a role for SUPT16H in neural crest development. Consistently, supt16h loss impaired neural crest cell migration and differentiation and triggered p53-dependent apoptosis in the central nervous system (CNS) and neural crest-derived pharyngeal arches. Notably, supt16h deficiency impaired oligodendrocyte specification in the CNS and perturbed differentiation of neural crest-derived Schwann cells in the peripheral nervous system, providing a plausible basis for hypotonia. These findings uncover a previously unrecognized role of SUPT16H in neural crest development, linking chromatin regulation to neural crest-derived lineage specification and differentiation, thereby defining SUPT16H deficiency as a neurocristopathy that broadens the clinical and mechanistic landscape of SUPT16H-associated disorders.

BACKGROUND:Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an inflammatory demyelinating disorder in children. While serum myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) is a recognized biomarker, the role of cerebrospinal fluid (CSF) MOG-IgG remains unclear, particularly in Asian pediatric populations. This study aimed to assess the diagnostic and prognostic significance of CSF MOG-IgG in pediatric MOGAD patients in Asia. METHODS:In this retrospective multicenter study, 63 pediatric MOGAD patients were identified based on clinical and radiological features and underwent paired serum and CSF MOG-IgG testing between 2000 and 2023 at two Korean institutions using a flow-cytometry-based assay. RESULTS:MOG-IgG was detected in both serum and CSF in 44 (70%) patients, serum only in 17 (27%), and CSF only in 2 (3%). Most patients (65.1%) had a monophasic course, and both CSF-only cases remained monophasic during follow-up. CSF-positive patients exhibited significantly higher CSF white blood cell counts (P = 0.011) and more favorable long-term outcomes, as indicated by lower final Expanded Disability Status Scale scores (P < 0.001). CONCLUSIONS:This study highlights the clinical characteristics of CSF MOG-IgG in Asian pediatric MOGAD patients, suggesting a possible monophasic course in CSF-only cases and potential ethnic variations, though confirmation in larger prospective cohorts is warranted.

Short-read sequencing (SRS)-based disease-targeted NGS gene panels have revolutionized rare disease diagnostics but often leave autosomal recessive cases unsolved when only one pathogenic allele is detected. Missing variants may reside in deep intronic regions or involve structural variants (SVs) undetectable by SRS. To improve diagnostic yield, we implemented a cost-effective target capture-based long-read sequencing (LRS) assay covering 56 genes and retrospectively analyzed 78 patients suspected of autosomal recessive disorders who remained undiagnosed after SRS. Functional validation using reverse transcription PCR (RT-PCR) and minigene assays was performed to further determine pathogenicity. Target capture-based LRS solved 25.6% (20/78) of cases by identifying 10 SVs, 3 deep intronic variants experimentally confirmed to cause aberrant splicing, and 7 cases in which haplotype phasing confirmed that variants were in trans with the known pathogenic variant, leading to reclassification of the VUS as likely pathogenic. This study demonstrates that target capture-based LRS effectively detects diverse types of variants missed by SRS. Integrating this assay into stepwise diagnostic workflows offers a practical and cost-effective strategy to enhance diagnostic yield in autosomal recessive diseases. However, because this cohort was retrospectively defined based on a prior single-allele detection by SRS, this 25.6% (20/78) diagnostic yield reflects performance within a highly enriched population and should not be directly extrapolated to unselected rare disease cohorts.

The E3 ubiquitin ligase WWP1 orchestrates multiple cellular functions, yet the neurodevelopmental role and pathological implications of its dysregulation remain poorly defined, in contrast to its established oncogenic effects. Here, we demonstrate that hyperactive WWP1 induces neurodevelopmental abnormalities characterized by impaired neuronal migration and caspase-dependent cell death in the developing mouse brain and human neural progenitor cell models. Mechanistically, WWP1 gain-of-function (GOF) mutation disrupts cell adhesion, leading to anoikis, detachment-induced cell death. Pathway-level screening identifies TGFβ1 ligand treatment to restore cell survival in both neural progenitor cultures and embryonic mouse brains. Conversely, TGFβ pathway inhibition phenocopies WWP1-induced apoptosis, establishing that WWP1 hyperactivity promotes cell death via TGFβ pathway downregulation. Transcriptomic profiling of the WWP1 GOF cellular models confirms the downregulation of cell adhesion and TGFβ signaling pathway signatures, highlighting the necessity of balanced WWP1 activity during neurodevelopment. In addition, we identified a de novo WWP1 variant in a patient with developmental and epileptic encephalopathy. Biochemical and in vivo functional analyses characterize the variant as GOF, supporting the clinical relevance of WWP1 dysregulation in neurodevelopmental disorders. Together, these findings reveal WWP1 as a critical regulator of neuronal survival and adhesion, with its dysregulation disrupting key developmental processes in the human brain.

Objectives Anti-signal recognition particle (SRP) myositis is a rare subset of immune-mediated necrotizing myopathy (IMNM). It is characterized by proximal muscle weakness, markedly elevated serum creatine kinase (CK) levels, and poor response to conventional therapies. Evidence for optimal management remains limited, particularly regarding the long-term outcomes of rituximab treatment. Method We retrospectively reviewed anti-SRP myositis patients who received rituximab at Seoul National University Hospital. Diagnosis was based on clinical features, elevated CK levels, and positivity for anti-SRP antibodies. Demographic, clinical, laboratory, radiological, histopathological, and treatment data were collected. Results Five patients, aged between 4 and 71 years, exhibited proximal muscle weakness, elevated CK levels, and variable disease severity. Rituximab induction followed by maintenance therapy led to a significant improvement in muscle strength and normalization of CK and aldolase levels. In patients with mild or subclinical phenotypes, aldolase elevations often preceded clinical relapses. Relapses during follow-up were managed with rituximab re-administration, which restored muscle strength and biochemical markers. MRI, EMG, and muscle biopsy findings were consistent with myopathic changes. Conclusions This case series highlights the heterogeneity in age, disease severity, and clinical course of anti-SRP myositis and the efficacy of rituximab in refractory and relapsing cases. Multimodal monitoring, including CK, aldolase, CD19+ B-cell counts, and clinical assessment, is essential for the early detection of relapses. Our findings support rituximab as a valuable component of individualized treatment strategies for anti-SRP myositis, though larger studies are warranted to establish standardized protocols and clarify long-term outcomes.

Background and ObjectivesArboleda-Tham syndrome (ARTHS) is a rare autosomal dominant neurodevelopmental disorder caused by pathogenic variants in the lysine acetyltransferase 6A (KAT6A) gene, characterized by global developmental delay, severe speech impairment, craniofacial dysmorphism, and congenital heart defects (CHDs).MethodsWe retrospectively reviewed data from 14 patients with molecularly confirmed KAT6A variants evaluated at the pediatric neurology center of Seoul National University Children's Hospital between 2018 and 2024. Clinical, genetic, neuroimaging, and laboratory data were systematically analyzed to evaluate the phenotypic spectrum associated with ARTHS.ResultsFourteen patients were identified, 79% of whom were male, with ages ranging from 2 to 14 years at the time of their last visit. Thirteen patients (93%) harbored late-truncating variants. Global developmental delay was universal, with marked speech impairment; most patients remained minimally verbal beyond age 5. Craniofacial dysmorphisms were observed in 11 patients (79%) and CHDs in 6 of the 10 assessed (60%). Notably, 3 of 11 patients (27%) exhibited hematologic abnormalities, ranging from transient neonatal neutropenia to severe aplastic anemia requiring hematopoietic stem cell transplantation. Brain imaging revealed type 1 Chiari malformation and white matter hyperintensities in 2 of the 10 assessed (20%), suggesting a broader neuroanatomic involvement. Radioulnar synostosis was observed in 1 patient, suggesting a possible expansion of the skeletal phenotype in ARTHS.DiscussionOur study broadens the recognized clinical features of ARTHS by reporting diverse neuroimaging findings, skeletal anomalies including radioulnar synostosis, and hematologic manifestations such as transient neonatal neutropenia and severe aplastic anemia. These findings reinforce the need for multidisciplinary surveillance in ARTHS and suggest potential avenues for further investigation into the role of KAT6A in hematopoiesis, neurodevelopment, and skeletal formation.

Pathogenic variants in human KCTD3 are associated with severe neurodevelopmental disorders characterized by early-onset seizures, developmental delay, hypotonia, and cerebellar hypoplasia, but the underlying mechanisms remain unclear. Here we show that KCTD3 regulates neuronal structural organization through DAAM1, a protein involved in actin cytoskeleton assembly. In Kctd3-deficient neurons, DAAM1 protein levels are reduced, the axon initial segment is abnormally organized, and neurite growth and growth cone morphology are impaired. These defects are rescued by DAAM1 overexpression. Systemic Kctd3 depletion also disrupts axon initial segment organization and motor axon innervation at neuromuscular junctions, leading to motor dysfunction and growth impairment in mice. These findings identify a KCTD3-DAAM1 pathway required for neuronal structural development and provide a framework for understanding how KCTD3 deficiency contributes to neurodevelopmental disorders.

Background Rare diseases inflict severe psychosocial and economic burdens on patients and their families, with difficulties often faced in accessing specialized medical services due to geographical and physical barriers. Although telemedicine has gained attention as a potential strategy for improving access to healthcare, limited research has empirically validated its effectiveness for patients with rare diseases and their families. This study aimed to apply a telemedicine platform developed for patients with rare diseases and their caregivers and evaluate its effectiveness compared with conventional in-person care. Methods This study utilized a non-randomized controlled design and included 79 participants, specifically patients with rare diseases and their caregivers. The intervention group received telemedicine care and a control group received conventional in-person care. The telemedicine platform comprised features for writing a care diary, reviewing pre-consultation summaries based on artificial intelligence (AI), and conducting multi-party video consultations. The intervention period spanned approximately one year. The primary endpoints were quality of life and depression, while treatment satisfaction and cost-effectiveness indicators were also measured. Factors hindering the intervention process were systematically categorized. Results The study included 38 participants in the intervention group and 41 in the control group. There was no significant group-by-time interaction effect for quality of life (F = 0.04, p = 0.847) and depression (F = 0.03, p = 0.864). Satisfaction was significantly higher in the intervention group (t = 5.07, p < 0.001). The total annual cost per patient was significantly lower in the intervention group (median: 0 [IQR 0–57487] vs. 240000 [IQR 99600–470010] Korean Won, p < 0.001). We identified technical, administrative, and institutional factors hindering implementation, such as unstable video connections, errors in electronic prescriptions, and inconsistencies in administrative processing. Conclusion The telemedicine platform for patients with rare diseases and their caregivers did not show evidence of a difference in quality of life or depression compared with in-person care, while significantly improving treatment satisfaction and reducing healthcare costs. A systematic analysis of operational barriers provides practical evidence for the sustainable implementation of telemedicine care. Future research should employ multicenter non-inferiority designs with pre-specified equivalence margins, longer follow-up periods, and comprehensive economic evaluations incorporating non-monetary outcomes. Trial registration This study was prospectively registered with the Clinical Research Information Service (CRIS registration number KCT0011719).

Molybdenum cofactor deficiency (MoCD) is a rare autosomal recessive neurodegenerative disorder that often mimics hypoxic-ischemic encephalopathy (HIE) in neonates, leading to delayed diagnosis. Here, a term female neonate developed refractory seizures on day 3 of life with persistent hypouricemia. Magnetic resonance imaging revealed diffuse cortical and subcortical diffusion restriction, basal ganglia and thalamic involvement, white matter injury, and cerebellar hypoplasia, which were initially misinterpreted as HIE in the absence of a sentinel hypoxic-ischemic event. Serial neuroimaging showed rapidly progressive leukomalacia, and trio-based whole-genome sequencing ultimately identified a homozygous likely pathogenic variant in the MOCS2 gene, c.265T>C, p.*89Glnext*3. Both parents were confirmed as heterozygous carriers, establishing a diagnosis of MoCD type B and representing the first genetically confirmed case in South Korea. Despite aggressive anti-seizure therapy, dietary protein restriction, and supportive care, the patient exhibited severe global developmental delay and spasticity at 12 months of age, underscoring the poor prognosis of early-onset MoCD and the need to consider this entity in neonates with HIE-like encephalopathy, negative standard metabolic workup, and unexplained hypouricemia.

BACKGROUND:Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome frequently involving the central nervous system (CNS) and associated with poor outcomes. Neurological manifestations may precede or obscure systemic features, resulting in diagnostic challenges. METHODS:We retrospectively reviewed pediatric patients with HLH treated at Seoul National University Children's Hospital between 2000 and 2024. CNS involvement was defined by neurological symptoms and abnormal cerebrospinal fluid (CSF) findings and/or brain imaging abnormalities. Clinical features, neuroimaging findings, CSF profiles, genetic testing results, treatment, and outcomes were analyzed. RESULTS:Among 136 screened patients with HLH, 20 met criteria for CNS involvement. Neurological symptoms were the initial manifestation in 6 of 20 patients (30%), and seizures were the most common symptom (14/20, 70%). Brain imaging abnormalities were observed in all patients who underwent neuroimaging (19/19), typically demonstrating multifocal parenchymal lesions with bilateral or multilobar involvement. CSF abnormalities were present in 13 of 18 patients (72%) but were nonspecific. More than half of the patients (11/20, 55%) were initially evaluated under alternative diagnostic considerations, contributing to delayed recognition of HLH. Genetic testing identified causative variants in 6 of 12 tested patients (50%), most commonly in UNC13D or STXBP2. Among the 19 patients with follow-up data, 7 (37%) survived. CONCLUSIONS:Pediatric HLH with CNS involvement shows heterogeneous and often misleading initial presentations. Neurological-predominant manifestations may contribute to delayed recognition of HLH. Careful longitudinal assessment and consideration of genetic evaluation may facilitate earlier diagnosis in selected patients.