Etiological involvement of KCND1 variants in an X-linked neurodevelopmental disorder with variable expressivity.

Utilizing trio whole-exome sequencing and a gene matching approach, we identified a cohort of 18 male individuals from 17 families with hemizygous variants in KCND1, including two de novo missense variants, three maternally inherited protein-truncating variants, and 12 maternally inherited missense variants. Affected subjects present with a neurodevelopmental disorder characterized by diverse neurological abnormalities, mostly delays in different developmental domains, but also distinct neuropsychiatric signs and epilepsy. Heterozygous carrier mothers are clinically unaffected. KCND1 encodes the α-subunit of Kv4.1 voltage-gated potassium channels. All variant-associated amino acid substitutions affect either the cytoplasmic N- or C-terminus of the channel protein except for two occurring in transmembrane segments 1 and 4. Kv4.1 channels were functionally characterized in the absence and presence of auxiliary ß subunits. Variant-specific alterations of biophysical channel properties were diverse and varied in magnitude. Genetic data analysis in combination with our functional assessment shows that Kv4.1 channel dysfunction is involved in the pathogenesis of an X-linked neurodevelopmental disorder frequently associated with a variable neuropsychiatric clinical phenotype.

Prevalence and Characterization of NOTCH2NLC GGC Repeat Expansions in Koreans: From a Hospital Cohort Analysis to a Population-Wide Study.

Background and Objectives: GGC repeat expansions in the NOTCH2NLC gene are associated with a broad spectrum of progressive neurologic disorders, notably, neuronal intranuclear inclusion disease (NIID). We aimed to investigate the population-wide prevalence and clinical manifestations of NOTCH2NLC-related disorders in Koreans. Methods: We conducted a study using 2 different cohorts from the Korean population. Patients with available brain MRI scans from Seoul National University Hospital (SNUH) were thoroughly reviewed, and NIID-suspected patients presenting the zigzag edging signs underwent genetic evaluation for NOTCH2NLC repeats by Cas9-mediated nanopore sequencing. In addition, we analyzed whole-genome sequencing data from 3,887 individuals in the Korea Biobank cohort to estimate the distribution of the repeat counts in Koreans and to identify putative patients with expanded alleles and neurologic phenotypes. Results: In the SNUH cohort, among 90 adult-onset leukoencephalopathy patients with unknown etiologies, we found 20 patients with zigzag edging signs. Except for 2 diagnosed with fragile X-associated tremor/ataxia syndrome and 2 with unavailable samples, all 16 patients (17.8%) were diagnosed with NIID (repeat range: 87-217). By analyzing the Korea Biobank cohort, we estimated the distribution of repeat counts and threshold (>64) for Koreans, identifying 6 potential patients with NIID. Furthermore, long-read sequencing enabled the elucidation of transmission and epigenetic patterns of NOTCH2NLC repeats within a family affected by pediatric-onset NIID. Discussion: This study presents the population-wide distribution of NOTCH2NLC repeats and the estimated prevalence of NIID in Koreans, providing valuable insights into the association between repeat counts and disease manifestations in diverse neurologic disorders.

Severe Neurological Manifestation Associated With Coronavirus Disease 2019 in Children During the Omicron Variant-Predominant Period.

BACKGROUND: The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to be more infectious and less severe than the other variants. Despite the increasing number of symptomatic patients, severe neurological complications in children with the Omicron variant have been reported rarely, unlike with wild-type or Delta variants. This study aimed to investigate severe neurological complications in children with Omicron variant infection. METHODS: We conducted a retrospective study of 17 pediatric patients with severe neurological manifestations associated with coronavirus disease 2019 in Korea during the Omicron variant prevalence, from January 1 to April 30, 2022. RESULTS: Among the 17 patients, 11 had pre-existing neurological disabilities and nine met the criteria for multisystem inflammatory syndrome in children (MIS-C). Four of the five vaccine-eligible patients (12 years and older) were unvaccinated. Severe neurological manifestations included acute necrotizing encephalopathy, acute fulminant cerebral edema, acute disseminated encephalomyelitis, basal ganglia encephalitis, unclassified severe encephalopathy/encephalitis, and refractory status dystonicus. Patients with MIS-C and underlying neurological disabilities had longer median hospital and intensive care unit stays compared with those without these conditions. Five patients survived with new neurological deficits at the one-year follow-up, and three died, all of whom had underlying neurological disabilities. CONCLUSIONS: This study shows that severe neurological complications in pediatric patients with the Omicron variant of SARS-CoV-2 occur infrequently but may lead to significant morbidity and mortality, especially among those with pre-existing neurological disabilities and unvaccinated individuals. Continued efforts are necessary to prevent and manage such complications in these vulnerable populations.

SYNGAP1-related developmental and epileptic encephalopathy: Genotypic and phenotypic characteristics and longitudinal insights.

The clinical and genetic characteristics of SYNGAP1 mutations in Korean pediatric patients are not well understood. We retrospectively analyzed 13 individuals with SYNGAP1 mutations from a longitudinal aspect. Clinical data, genetic profiles, and electroencephalography (EEG) patterns were examined. Genotypic analyses included gene panels and whole-exome sequencing. All patients exhibited global developmental delay from early infancy, with motor development eventually reaching independent ambulation by 3 years of age. Language developmental delay varied significantly from nonverbal to simple sentences, which plateaued in all patients. Patients with the best language outcomes typically managed 2-3-word sentences, corresponding to a developmental age of 2-3 years. Epilepsy developed in 77% of patients, with onset consistently following developmental delays at a median age of 31 months. Longitudinal EEG data revealed a shift from occipital to frontal epileptiform discharges with age, suggesting a correlation with synaptic maturation. These findings suggest that the critical developmental plateau occurs between the ages of 2 and 5 years and is potentially influenced by epilepsy. By analyzing longitudinal data, our study contributes to a deeper understanding of SYNGAP1-related DEE, provides potential EEG biomarkers, and underlines the importance of early diagnosis and intervention to address this complex disorder.

Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies.

CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Computational simulation of the 3D protein structure suggests the position of the identified variants to be implicated in penetrance and phenotype expression. CELSR3 immunolocalization in human embryonic urinary tract and transient suppression and rescue experiments of Celsr3 in fluorescent zebrafish reporter lines further support an embryonic role of CELSR3 in CNS and urinary tract formation.

Diagnostic uplift through the implementation of short tandem repeat analysis using exome sequencing.

To date, approximately 50 short tandem repeat (STR) disorders have been identified; yet, clinical laboratories rarely conduct STR analysis on exomes. To assess its diagnostic value, we analyzed STRs in 6099 exomes from 2510 families with mostly suspected neurogenetic disorders. We employed ExpansionHunter and REViewer to detect pathogenic repeat expansions, confirming them using orthogonal methods. Genotype-phenotype correlations led to the diagnosis of thirteen individuals in seven previously undiagnosed families, identifying three autosomal dominant disorders: dentatorubral-pallidoluysian atrophy (n = 3), spinocerebellar ataxia type 7 (n = 2), and myotonic dystrophy type 1 (n = 2), resulting in a diagnostic gain of 0.28% (7/2510). Additionally, we found expanded ATXN1 alleles (≥39 repeats) with varying patterns of CAT interruptions in twelve individuals, accounting for approximately 0.19% in the Korean population. Our study underscores the importance of integrating STR analysis into exome sequencing pipeline, broadening the application of exome sequencing for STR assessments.

Clinical Characteristics of Diabetes in People with Mitochondrial DNA 3243A>G Mutation in Korea.

Maternally inherited diabetes and deafness (MIDD) is a rare mitochondrial disorder primarily resulting from m.3243A>G mutation. The clinical characteristics of MIDD exhibit significant heterogeneity. Our study aims to delineate these characteristics and determine the potential correlation with m.3243A>G heteroplasmy levels. This retrospective, descriptive study encompassed patients with confirmed m.3243A>G mutation and diabetes mellitus at Seoul National University Hospital. Our cohort comprises 40 patients with MIDD, with a mean age at study enrollment of 33.3±12.9 years and an average % of heteroplasmy of 30.0%± 14.6% in the peripheral blood. The most prevalent comorbidity was hearing loss (90%), followed by albuminuria (61%), seizure (38%), and stroke (33%). We observed a significant negative correlation between % of heteroplasmy and age at diabetes diagnosis. These clinical features can aid in the suspicion of MIDD and further consideration of genetic testing for m.3243A>G mutation.

Interaction of interictal epileptiform activity with sleep spindles is associated with cognitive deficits and adverse surgical outcome in pediatric focal epilepsy.

OBJECTIVE: Temporal coordination between oscillations enables intercortical communication and is implicated in cognition. Focal epileptic activity can affect distributed neural networks and interfere with these interactions. Refractory pediatric epilepsies are often accompanied by substantial cognitive comorbidity, but mechanisms and predictors remain mostly unknown. Here, we investigate oscillatory coupling across large-scale networks in the developing brain. METHODS: We analyzed large-scale intracranial electroencephalographic recordings in children with medically refractory epilepsy undergoing presurgical workup (n = 25, aged 3-21 years). Interictal epileptiform discharges (IEDs), pathologic high-frequency oscillations (HFOs), and sleep spindles were detected. Spatiotemporal metrics of oscillatory coupling were determined and correlated with age, cognitive function, and postsurgical outcome. RESULTS: Children with epilepsy demonstrated significant temporal coupling of both IEDs and HFOs to sleep spindles in discrete brain regions. HFOs were associated with stronger coupling patterns than IEDs. These interactions involved tissue beyond the clinically identified epileptogenic zone and were ubiquitous across cortical regions. Increased spatial extent of coupling was most prominent in older children. Poor neurocognitive function was significantly correlated with high IED-spindle coupling strength and spatial extent; children with strong pathologic interactions additionally had decreased likelihood of postoperative seizure freedom. SIGNIFICANCE: Our findings identify pathologic large-scale oscillatory coupling patterns in the immature brain. These results suggest that such intercortical interactions could predict risk for adverse neurocognitive and surgical outcomes, with the potential to serve as novel therapeutic targets to restore physiologic development.

A Case of Multiple Mitochondrial Dysfunctions Syndrome 4 with Novel ISCA2 Variants, Mimicking Post-Infectious Encephalitis.

ISCA2 loss of function leads to leukodystrophy and developmental regression (multiple mitochondrial dysfunctions syndrome 4 (MMDS4)). We present a first Korean case of MMDS4 presenting with rapid developmental regression and leukodystrophy after febrile episode, mimicking post-infectious encephalitis. The patient had displayed normal development until 12 months of age. At 13 months of age, one month after experiencing a post-vaccination fever, she quickly progressed to being unable to sit unassisted nor speak any words. Analysis of the cerebrospinal fluid (CSF) revealed lympho-dominant pleocytosis. Amino acid analysis of both the serum and CSF demonstrated elevated glycine exclusively in the CSF. Diffuse leukodystrophy was noted in the brain magnetic resonance image. Whole exome sequencing revealed compound heterozygous ISCA2 variants of c.166T>G, p.C56G and c.422A>C, p.Q141P. No evidence of mitochondrial disease other than bilateral optic atrophy was noted. In cases of early onset rapid developmental regression with leukodystrophy, MMDS4 should be considered.

Expansion of clinico-genetic spectrum of PRDX3 disease: a literature review with two additional cases.

Graphical Abstract.

Impact of nusinersen on the health-related quality of life and caregiver burden of patients with spinal muscular atrophy with symptom onset after age 6 months.

INTRODUCTION/AIMS: Novel disease-modifying approaches for spinal muscular atrophy (SMA) have highlighted the patient's perspective on functional changes over time. In this study, we evaluated the impact of nusinersen on the health-related quality of life (HRQoL) of patients with later-onset SMA and the caregiver burden. METHODS: We assessed the changes in HRQoL using the Pediatric Quality of Life Inventory 4.0 Generic Core Scale (PedsQL GCS) and the Pediatric Quality of Life Inventory 3.0 Neuromuscular Module (PedsQL NMM) during 26 months of treatment. Caregiver burden was assessed using the Assessment of Caregiver Experience with Neuromuscular Disease. We also assessed motor function using the Hammersmith Functional Motor Scale-Expanded (HFMSE) and the Revised Upper Limb Module score. RESULTS: Twenty-four patients and their caregivers were included. The median age of patients at treatment onset was 148.8 (6.8 to 269.4) months. A significant improvement was observed in psychosocial health in proxy-reported PedsQL (P = .023). However, the physical health scores of the PedsQL GCS and About my neuromuscular disorder subscores of the PedsQL NMM did not change, although there was a significant increase in HFMSE scores. Regarding the caregiver burden, the financial burden was reduced, whereas time burden increased. A higher HFMSE score was associated with better self-reported PedsQL GCS total scores (P < .001). DISCUSSION: Our results provide insights into the multifaceted implications of disease-modifying therapies for SMA through patient-reported outcome measures (PROMs). PROMs should be taken into consideration to assess the clinical significance of the functional changes identified by clinician-reported scales.

Epilepsy phenotype and gene ontology analysis of the 129 genes in a large neurodevelopmental disorders cohort.

Objective: Although pediatric epilepsy is an independent disease entity, it is often observed in pediatric neurodevelopmental disorders (NDDs) as a major or minor clinical feature, which might provide diagnostic clues. This study aimed to identify the clinical and genetic characteristics of patients with epilepsy in an NDD cohort and demonstrate the importance of genetic testing. Methods: We retrospectively analyzed the detailed clinical differences of pediatric NDD patients with epilepsy according to their genetic etiology. Among 1,213 patients with NDDs, 477 were genetically diagnosed by exome sequencing, and 168 had epilepsy and causative variants in 129 genes. Causative genes were classified into two groups: (i) the "epilepsy-genes" group resulting in epilepsy as the main phenotype listed in OMIM, Epi25, and ClinGen (67 patients) and (ii) the "NDD-genes" group not included in the "epilepsy-genes" group (101 patients). Results: Patients in the "epilepsy-genes" group started having seizures, often characterized by epilepsy syndrome, at a younger age. However, overall clinical features, including treatment responses and all neurologic manifestations, showed no significant differences between the two groups. Gene ontology analysis revealed the close interactions of epilepsy genes associated with ion channels and neurotransmitters. Conclusion: We demonstrated a similar clinical presentation of different gene groups regarding biological/molecular processes in a large NDDs cohort with epilepsy. Phenotype-driven genetic analysis should cover a broad scope, and further studies are required to elucidate integrated pathomechanisms.

The Korean Genetic Diagnosis Program for Rare Disease Phase II: outcomes of a 6-year national project.

The Korean Genetic Diagnosis Program for Rare Disease (KGDP) enrolled 1890 patients with rare diseases between March 2017 and October 2022. Children and adolescents accounted for the majority of the patients, and systemic disease was the most common presenting symptom. The exome-based virtual disease-specific multigene panel was the most frequently used analytical method, with an overall diagnostic yield of 33.3%. A total of 629 positive cases were diagnosed, involving 297 genes. All 297 genes identified in these cases were confirmed to be known genes listed in the OMIM database. The nationwide KGDP network and its cooperation with the Korean Undiagnosed Diseases Program (KUDP) provide a more comprehensive genetic analysis of undiagnosed cases. The partnership between the KGDP and KUDP has the potential to improve the diagnosis and treatment options for patients. In conclusion, KGDP serves as the primary access point or gateway to KUDP.

Broad spectrum of phenotype and genotype in Korean α-dystroglycan related muscular dystrophy presenting to a tertiary pediatric neuromuscular center.

α-Dystroglycanopathies are a clinically and genetically heterogeneous group of muscular dystrophies associated with the defective glycosylation of α-dystroglycan (α-DG). Eighteen genes associated with α-dystroglycanopathies have been identified, and the relative prevalence of genetic subtypes varies with ethnicity. Here, we investigated the clinical and genetic characteristics of α-DG-related muscular dystrophy in the Korean pediatric population. We analyzed the clinical characteristics and variant profiles of 42 patients with α-DG-related muscular dystrophies diagnosed by either reduced glycosylation of α-DG and/or genetic confirmation. Genotype-phenotype correlations were explored by a retrospective medical record review. The muscle-eye-brain disease/Fukuyama congenital muscular dystrophy was the most common phenotype (28/42, 66.7%). Homozygous or compound heterozygous variants were detected in 37 patients belonging to 34 unrelated families (37/42; 88.1%). Pathogenic variants were identified in FKTN (n = 24), POMGNT1 (n = 4), GMPPB (n = 4), FKRP (n = 2), POMT1 (n = 2), and ISPD (n = 1). Compound heterozygous retrotransposal insertions and deep-intronic variants in FKTN were the most common genotypes and were associated with severe phenotypes. This study suggests that α-DG-related muscular dystrophy has a wide range of genotypes and phenotypes according to ethnicity. A stratified genetic test according to ethnicity should be considered to diagnose α-DG-related muscular dystrophy.

A case of pediatric anti-leucine-rich glioma inactivated 1 encephalitis with faciobrachial dystonic seizure.

BACKGROUND: Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis is a rare type of autoimmune encephalitis. A characteristic faciobrachial dystonic seizure (FBDS) is also frequently associated with this disease. Although primarily reported in the adult population, reports of its occurrence in the pediatric population are rare. Here, we describe a case of a 6-year-old girl diagnosed with anti-LGI1 encephalitis that presented with cognitive decline and FBDS. CASE PRESENTATION: The girl was referred to a pediatric neurology department for uncontrolled seizures and dyskinesia. She initially presented with a memory deficit, abnormal movement of the limbs and trunk, and ataxia. Her cerebrospinal fluid exam was unremarkable, but her brain MRI showed focal T2 high signal intensity in the left anterior putamen and right caudate nucleus. In addition, there were refractory episodes of brief tonic or dystonic movement of the face and arms that were suggestive of FBDS. She was initially treated with intravenous methylprednisolone and phenobarbital, then given another pulse of methylprednisolone and intravenous immunoglobulin as her symptoms persisted. Tests for neuronal autoantibodies revealed the presence of anti-LGI1 antibodies. Subsequent human leukocyte antigen (HLA) typing resulted in the identification of HLA-DRB1 DR7(*07:01 g) DR9(*09:01 g). Screening for thymoma and other neoplasms showed no signs of a tumor. She was treated with rituximab, tocilizumab, and antiseizure medications, including oxcarbazepine, valproic acid, and lamotrigine. Her FBDS and cognitive symptoms showed substantial improvements. CONCLUSION: While it is known that anti-LGI1 encephalitis responds well to immunotherapy, our patient showed an incomplete response, requiring further therapy. This is the first report of a pediatric patient with anti-LGI1 encephalitis treated with tocilizumab.

Outcomes of the second withdrawal of anti-seizure medication in patients with pediatric-onset epilepsy.

Withdrawal of anti-seizure medication (ASM) is challenging, especially in patients with recurrent seizures. Only limited evidence exists regarding the success rate and recurrence risk factors after withdrawal of ASM for a second time in patients with pediatric-onset epilepsy. In this observational study, we evaluated 104 patients with recurrent pediatric-onset epilepsy who had ASM withdrawn for a second time. The success rate was 41.3% after the second withdrawal of ASM. The absence of a self-limiting epilepsy syndrome, shorter seizure-free intervals before the second withdrawal of ASM, and relapse during tapering after the initial withdrawal of ASM were negative factors significantly associated with the success of ASM withdrawal for a second time. Even after a second seizure recurrence, all patients eventually became seizure-free after restarting their previous ASM (78.7%) or readjusting the ASM (21.3%). Our findings that 40% of patients with recurrent pediatric-onset epilepsy could achieve long-term seizure freedom and that all patients with a second seizure recurrence remained seizure-free suggest that ASM may be withdrawn for a second time after carefully stratifying clinical risk.

Prevalence and founder effect of DRC1 exon 1-4 deletion in Korean patients with primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder affecting ciliary structure and function. PCD exhibiting dynein regulatory complex subunit 1 (DRC1) exon 1-4 deletion has been reported in several Japanese PCD patients; however, no large scale studies have been performed. Here, we aimed to determine the prevalence and founder effect of this variant in the Korean population. Using an in-house copy number variation tool, we screened for DRC1 exon 1-4 deletion in 20 patients with PCD and exome data of 1435 patients in the Seoul National University Hospital repository. In cases of suspected DRC1 deletion, confirmatory gap-PCR was performed. In a PCD cohort, three of 20 (15%) patients were positive for DRC1 exon 1-4 deletion (NM_145038.5(DRC1): c.1-3952_540 + 1331del27748-bp) while pathogenic variants were found in CCDC39 (N = 1), DNAAF6 (N = 1), DNAH9 (N = 1). In the 1,435-sample exome data, seven patients (0.49%) were confirmed to have DRC1 exon 1-4 deletion. A chimeric sequence including the junction was searched from the 1000 Genomes Project data repository. One Japanese patient (0.96%) was found to have the same DRC1 exon 1-4 deletion, which was absent in other populations. This study demonstrated that the DRC1 exon 1-4 deletion is a founder mutation based on haplotype analysis. In summary, the prevalence of PCD based on DRC1 exon 1-4 deletion is particularly high in Korean and Japanese populations, which is attributed to the founder effect. Genetic testing for DRC1 exon 1-4 deletion should be considered as an initial screening tool for Korean and Japanese patients with PCD.

Rapid Targeted Sequencing Using Dried Blood Spot Samples for Patients With Suspected Actionable Genetic Diseases.

Background: New genome sequencing technologies with enhanced diagnostic efficiency have emerged. Rapid and timely diagnosis of treatable rare genetic diseases can alter their medical management and clinical course. However, multiple factors, including ethical issues, must be considered. We designed a targeted sequencing platform to avoid ethical issues and reduce the turnaround time. Methods: We designed an automated sequencing platform using dried blood spot samples and a NEOseq_ACTION panel comprising 254 genes associated with Mendelian diseases having curable or manageable treatment options. Retrospective validation was performed using data from 24 genetically and biochemically confirmed patients. Prospective validation was performed using data from 111 patients with suspected actionable genetic diseases. Results: In prospective clinical validation, 13.5% patients presented with medically actionable diseases, including short- or medium-chain acyl-CoA dehydrogenase deficiencies (N=6), hyperphenylalaninemia (N=2), mucopolysaccharidosis type IVA (N=1), alpha thalassemia (N=1), 3-methylcrotonyl-CoA carboxylase 2 deficiency (N=1), propionic acidemia (N=1), glycogen storage disease, type IX(a) (N=1), congenital myasthenic syndrome (N=1), and citrullinemia, type II (N=1). Using the automated analytic pipeline, the turnaround time from blood collection to result reporting was <4 days. Conclusions: This pilot study evaluated the possibility of rapid and timely diagnosis of treatable rare genetic diseases using a panel designed by a multidisciplinary team. The automated analytic pipeline maximized the clinical utility of rapid targeted sequencing for medically actionable genes, providing a strategy for appropriate and timely treatment of rare genetic diseases.