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.

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.

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.

Evolutionary Patterns of the Chloroplast Genome in Vanilloid Orchids (Vanilloideae, Orchidaceae).

The Vanilloideae (vanilloids) is one of five subfamilies of Orchidaceae and is composed of fourteen genera and approximately 245 species. In this study, the six new chloroplast genomes (plastomes) of vanilloids (two Lecanorchis, two Pogonia, and two Vanilla species) were decoded, and then the evolutionary patterns of plastomes were compared to all available vanilloid plastomes. Pogonia japonica has the longest plastome, with 158,200 bp in genome size. In contrast, Lecanorchis japonica has the shortest plastome with 70,498 bp in genome size. The vanilloid plastomes have regular quadripartite structures, but the small single copy (SSC) region was drastically reduced. Two different tribes of Vanilloideae (Pogonieae and Vanilleae) showed different levels of SSC reductions. In addition, various gene losses were observed among the vanilloid plastomes. The photosynthetic vanilloids (Pogonia and Vanilla) showed signs of stage 1 degradation and had lost most of their ndh genes. The other three species (one Cyrotsia and two Lecanorchis), however, had stage 3 or stage 4 degradation and had lost almost all the genes in their plastomes, except for some housekeeping genes. The Vanilloideae were located between the Apostasioideae and Cypripedioideae in the maximum likelihood tree. A total of ten rearrangements were found among ten Vanilloideae plastomes when compared to the basal Apostasioideae plastomes. The four sub-regions of the single copy (SC) region shifted into an inverted repeat (IR) region, and the other four sub-regions of the IR region shifted into the SC regions. Both the synonymous (dS) and nonsynonymous (dN) substitution rates of IR in-cooperated SC sub-regions were decelerated, while the substitution rates of SC in-cooperated IR sub-regions were accelerated. A total of 20 protein-coding genes remained in mycoheterotrophic vanilloids. Almost all these protein genes show accelerated base substitution rates compared to the photosynthetic vanilloids. Two of the twenty genes in the mycoheterotrophic species faced strong "relaxed selection" pressure (p-value < 0.05).

Inhibition of Melanogenesis by Essential Oils from the Citrus Cultivars Peels.

Citrus is one of the most popular and widely grown fruit crops in the world. However, the bioactivity of only certain species of citrus cultivars is studied. In this study, the effects of essential oils from 21 citrus cultivars on melanogenesis were investigated in an effort to identify active anti-melanogenesis constituents. The essential oils from the peels of 21 citrus cultivars obtained by hydro-distillation were analyzed using gas chromatography-mass spectrometry. Mouse melanoma B16BL6 cells were used in all assays conducted in this study. The tyrosinase activity and melanin content were determined using the lysate of α-Melanocyte-stimulated B16BL6 cells. In addition, the melanogenic gene expression was determined by quantitative reverse transcription-polymerase chain reaction. Overall, the essential oils of (Citrus unshiu X Citrus sinensis) X Citrus reticulata, Citrus reticulata, and ((Citrus unshiu X Citrus sinensis) X Citrus reticulata) X Citrus reticulata provided the best bioactivity and comprised five distinct constituents compared to other essential oils such as limonene, farnesene, ß-elemene, terpinen-4-ol, and sabinene. The anti-melanogenesis activities of the five individual compounds were evaluated. Among the five essential oils, ß-elemene, farnesene, and limonene showed dominating properties. The experimental results indicated that (Citrus unshiu X Citrus sinensis) X Citrus reticulata, Citrus reticulata, and ((Citrus unshiu X Citrus sinensis) X Citrus reticulata) X Citrus reticulara are potential candidates with anti-melanogenesis activity for use as cosmetics and pharmaceutical agents against skin hyperpigmentation.

Ancient Horizontal Gene Transfers from Plastome to Mitogenome of a Nonphotosynthetic Orchid, Gastrodia pubilabiata (Epidendroideae, Orchidaceae).

Gastrodia pubilabiata is a nonphotosynthetic and mycoheterotrophic orchid belonging to subfamily Epidendroideae. Compared to other typical angiosperm species, the plastome of G. pubilabiata is dramatically reduced in size to only 30,698 base pairs (bp). This reduction has led to the loss of most photosynthesis-related genes and some housekeeping genes in the plastome, which now only contains 19 protein coding genes, three tRNAs, and three rRNAs. In contrast, the typical orchid species contains 79 protein coding genes, 30 tRNAs, and four rRNAs. This study decoded the entire mitogenome of G. pubilabiata, which consisted of 44 contigs with a total length of 867,349 bp. Its mitogenome contained 38 protein coding genes, nine tRNAs, and three rRNAs. The gene content of G. pubilabiata mitogenome is similar to the typical plant mitogenomes even though the mitogenome size is twice as large as the typical ones. To determine possible gene transfer events between the plastome and the mitogenome individual BLASTN searches were conducted, using all available orchid plastome sequences and flowering plant mitogenome sequences. Plastid rRNA fragments were found at a high frequency in the mitogenome. Seven plastid protein coding gene fragments (ndhC, ndhJ, ndhK, psaA, psbF, rpoB, and rps4) were also identified in the mitogenome of G. pubilabiata. Phylogenetic trees using these seven plastid protein coding gene fragments suggested that horizontal gene transfer (HGT) from plastome to mitogenome occurred before losses of photosynthesis related genes, leading to the lineage of G. pubilabiata. Compared to species phylogeny of the lineage of orchid, it was estimated that HGT might have occurred approximately 30 million years ago.

Vagus nerve stimulation modulates hippocampal inflammation caused by continuous stress in rats.

BACKGROUND: Previous studies have shown that vagus nerve stimulation (VNS) can attenuate inflammatory responses in peripheral tissues and also improve some neurological disorders and cognitive function in the brain. However, it is not clear how VNS is involved in neuropathological processes in brain tissues. Here, we investigated the regulatory effects of VNS on the production of proinflammatory cytokines in the hippocampus of an animal model of continuous stress (CS). METHODS: CS was induced by placing rats in cages immersed with water, and acute or chronic electrical stimulation was applied to the cervical vagus nerve of CS animals. Protein levels in the gastric and hippocampal tissues were measured by western blotting and protein signals analyzed by immunofluorescence staining. von Frey test and forced swimming test were performed to assess pain sensitivity and depressive-like behavior in rats, respectively. RESULTS: Levels of TNF-α, IL-1ß, and IL-6 in the gastric and hippocampal tissues were significantly increased in CS animals compared to the untreated control and downregulated by acute VNS (aVNS). Iba-1-labeled microglial cells in the hippocampus of CS animals revealed morphological features of activated inflammatory cells and then changed to a normal shape by VNS. VNS elevated hippocampal expression of α7 nicotinic acetylcholine receptors (α7 nAChR) in CS animals, and pharmacological blockade of α7 nAChR increased the production of TNF-α, IL-1ß, and IL-6, thus suppressing cholinergic anti-inflammatory activity that was mediated by VNS. Chronic VNS (cVNS) down-regulated the hippocampal production of active form of caspase 3 and 5-HT1A receptors and also decreased levels of TNF-α, IL-1ß, and IL-6 in the gastric and hippocampal tissues of CS animals. Pain sensitivity and depressive-like behavior, which were increased by CS, were improved by cVNS. CONCLUSIONS: Our data suggest that VNS may be involved in modulating pathophysiological processes caused by CS in the brain.

Real-Time Monitoring of Gas-Phase and Dissolved CO2 Using a Mixed-Matrix Composite Integrated Fiber Optic Sensor for Carbon Storage Application.

Novel chemical sensors that improve detection and quantification of CO2 are critical to ensuring safe and cost-effective monitoring of carbon storage sites. Fiber optic (FO)-based chemical sensor systems are promising field-deployable systems for real-time monitoring of CO2 in geological formations for long-range distributed sensing. In this work, a mixed-matrix composite integrated FO sensor system was developed with a purely optical readout that reliably operates as a detector for gas-phase and dissolved CO2. A mixed-matrix composite sensor coating consisting of plasmonic nanocrystals and hydrophobic zeolite embedded in a polymer matrix was integrated on the FO sensor. The mixed-matrix composite FO sensor showed excellent reversibility/stability in a high humidity environment and sensitivity to gas-phase CO2 over a large concentration range. This remarkable sensing performance was enabled by using plasmonic nanocrystals to significantly enhance the sensitivity and a hydrophobic zeolite to effectively mitigate interference from water vapor. The sensor exhibited the ability to sense CO2 in the presence of other geologically relevant gases, which is of importance for applications in geological formations. A prototype FO sensor configuration, which possesses a robust sensing capability for monitoring dissolved CO2 in natural water, was demonstrated. Reproducibility was confirmed over many cycles, both in a laboratory setting and in the field. More importantly, we demonstrated on-line monitoring capabilities with a wireless telemetry system, which transferred the data from the field to a website. The combination of outstanding CO2 sensing properties and facile coating processability makes this mixed-matrix composite FO sensor a good candidate for practical carbon storage applications.

Clinico-radiological characteristics of anti-myelin oligodendrocyte glycoprotein antibody-associated autoimmune encephalitis in children.

AIM: To investigate the clinical characteristics and prevalence of paediatric anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated autoimmune encephalitis. METHOD: A total of 94 paediatric patients (46 males, 48 females, median age 9 years 5 months, range: 8 months-17 years 8 months) with autoimmune encephalitis were recruited at Seoul National University Children's Hospital. We evaluated autoantibody status and identified patients with anti-MOG antibody-associated autoimmune encephalitis. Retrospective reviews of medical records were performed to describe clinical presentations, laboratory findings, treatments, and outcomes. RESULTS: Eight patients (five males, three females, median age 11 years 9 months) with anti-MOG antibody-associated encephalitis were identified (8.5% of those with autoimmune encephalitis), one of whom was copositive for anti-N-methyl-d-aspartate receptor (NMDAR) antibodies. Anti-NMDAR antibodies were identified in 23 patients (23 out of 94, 24.5%). Unilateral or bilateral cortical involvement was identified in five patients. Focal contrast enhancement was also identified in three of the five patients with cortical lesions. All patients showed favourable response to immunotherapy with a Modified Rankin Scale ≤2 at the last follow-up. Relapse was found in one patient and clinico-radiological remission was achieved with cyclic intravenous immunoglobulin therapy. INTERPRETATION: Anti-MOG antibody-associated encephalitis accounts for a significant proportion of clinically defined paediatric patients with autoimmune encephalitis. Anti-MOG antibody-associated encephalitis should be included in the clinical spectrum of anti-MOG-associated diseases.

Genetic diagnosis of infantile-onset epilepsy in the clinic: Application of whole-exome sequencing following epilepsy gene panel testing.

This study aimed to evaluate the clinical utility of whole-exome sequencing in a group of infantile-onset epilepsy patients who tested negative for epilepsy using a gene panel test. Whole-exome sequencing was performed on 59 patients who tested negative on customized epilepsy gene panel testing. We identified eight pathogenic or likely pathogenic sequence variants in eight different genes (FARS2, YWHAG, KCNC1, DYRK1A, SMC1A, PIGA, OGT, and FGF12), one pathogenic structural variant (8.6 Mb-sized deletion on chromosome X [140 994 419-149 630 805]), and three putative low-frequency mosaic variants from three different genes (GABBR2, MTOR, and CUX1). Subsequent whole-exome sequencing revealed an additional 8% of diagnostic yield with genetic confirmation of epilepsy in 55.4% (62/112) of our cohort. Three genes (YWHAG, KCNC1, and FGF12) were identified as epilepsy-causing genes after the original gene panel was designed. The others were initially linked with mitochondrial encephalopathy or different neurodevelopmental disorders, although an epilepsy phenotype was listed as one of the clinical features. Application of whole-exome sequencing following epilepsy gene panel testing provided 8% of additional diagnostic yield in an infantile-onset epilepsy cohort. Whole-exome sequencing could provide an opportunity to reanalyze newly recognized epilepsy-linked genes without updating the gene panel design.

Impact of mobile health application on data collection and self-management of epilepsy.

Recent advances in mobile health have enabled health data collection, which includes seizure and medication tracking and epilepsy self-management. We developed a mobile epilepsy management application, integrated with a hospital electronic health record (EHR). In this prospective clinical trial, we assessed whether the mobile application provides quality healthcare data compared to conventional clinic visits, and enhances epilepsy self-management for patients with epilepsy. The study population includes patients with epilepsy (ages 15 years and older) and caregivers for children with epilepsy. Participants were provided access to the application for 90 days. We compared healthcare data collected from the mobile application with data obtained from clinic visits. The healthcare data included seizure records, seizure triggering factors, medication adherence rate, profiles of adverse events resulting from anti-seizure medication (ASM), and comorbidity screenings. In addition, we conducted baseline and follow-up questionnaires after the 90-day period to evaluate how this mobile application improved epilepsy knowledge and self-efficacy in seizure management. Data of 99 participants (18 patients with epilepsy and 81 caregivers) were analyzed. Among 24 individuals who had seizures, we obtained detailed seizure records from 13 individuals through clinic visits and for 18 from the application. Aside from the 6 individuals who reported their medication adherence during clinic visitation, half of the study participants had adherence rates of over 70%, as monitored through the application. However, the adherence rates were not reliable due to high variability. Twenty-three individuals reported 59 adverse reactions on the application, whereas 21 individuals reported 24 adverse reactions during clinic visits. We collected comorbidity data from 4 individuals during clinic visits. In comparison, 64 participants underwent comorbidity self-screening on the application, and 2 of them were referred to neuropsychiatric services. Compared to rare/non-users, app users demonstrated significant improvement in epilepsy knowledge score (p < 0.001) and self-efficacy score (p = 0.038). In conclusion, mobile health technology would help patients and caregivers to record their healthcare data and aid in self-management. Mobile health technology would provide an influential clinical validity in epilepsy care when users engage and actively maintain records on the application.

Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes.

Leigh syndrome (LS), the most common childhood mitochondrial disorder, has characteristic clinical and neuroradiologic features. Mutations in more than 75 genes have been identified in both the mitochondrial and nuclear genome, implicating a high degree of genetic heterogeneity in LS. To profile these genetic signatures and understand the pathophysiology of LS, we recruited 64 patients from 62 families who were clinically diagnosed with LS at Seoul National University Children's Hospital. Mitochondrial genetic analysis followed by whole-exome sequencing was performed on 61 patients. Pathogenic variants in mitochondrial DNA were identified in 18 families and nuclear DNA mutations in 22. The following 17 genes analyzed in 40 families were found to have genetic complexity: MTATP6, MTND1, MTND3, MTND5, MTND6, MTTK, NDUFS1, NDUFV1, NDUFAF6, SURF1, SLC19A3, ECHS1, PNPT1, IARS2, NARS2, VPS13D, and NAXE. Two treatable cases had biotin-thiamine responsive basal ganglia disease, and another three were identified as having defects in the newly recognized genes (VPS13D or NAXE). Variants in the nuclear genes that encoded mitochondrial aminoacyl tRNA synthetases were present in 27.3% of cases. Our findings expand the genetic and clinical spectrum of LS, showing genetic heterogeneity and highlighting treatable cases and those with novel genetic causes.

Plastome evolution and phylogeny of subtribe Aeridinae (Vandeae, Orchidaceae).

Subtribe Aeridinae (Vandeae, Epidendroideae, Orchidaceae) consists of 83 genera and 2,345 species. The present study completely decoded the plastomes and nuclear ribosomal (nr) RNA gene clusters of seven species of Aeridinae belonging to Gastrochilus, Neofinetia, Pelatantheria, and Thrixspermum and compared them with existing data to investigate their genome evolution and phylogeny. Although no large structural variations were observed among the Aeridinae plastomes, 14 small inversions (SI) were found in Orchidaceae for the first time. Therefore, the evolutionary trends and usefulness of SI as molecular identification markers were evaluated. Since all 11 ndh genes in the Aeridinae plastome were lost or pseudogenized, the evolutionary trends of ndh genes are discussed at the tribe and family levels. In the maximum likelihood tree reconstructed from 83 plastome genes, the five Orchidaceae subfamilies were shown to have diverged in the following order: Apostasioideae, Vanilloideae, Cypripedioideae, Orchioideae, Epidendroideaeae. Divergence times for major lineages were found to be more recent, 5-10 Mya, than previous studies, which only used two or three genes. Vandeae, which includes Aeridinae, formed a sister group with Cymbidieae and Epidendreae. The Vandeae, Cymbidieae, and Epidendreae lineages were inferred to have diverged at 25.31 Mya; thus, numerous speciation events within Aeridineae occurred since then. Furthermore, the present study reconstructed a phylogenetic tree from 422 nrITS sequences belonging to Aerdinae and allied taxa and uses it to discuss the phylogenetic positions and species identities of five endangered species.

Analysis of antiseizure drug-related adverse reactions from the electronic health record using the common data model.

OBJECTIVE: Antiseizure drugs (ASDs) are known to cause a wide range of adverse drug reactions (ADRs). Recently, electronic health care data using the common data model (CDM) have been introduced and commonly adopted in pharmacovigilance research. We aimed to analyze ASD-related ADRs using CDM and to assess the feasibility of CDM analysis in monitoring ADR in a single tertiary hospital. METHODS: We selected five ASDs: oxcarbazepine (OXC), lamotrigine (LTG), levetiracetam (LEV), valproic acid (VPA), and topiramate (TPM). Patients diagnosed with epilepsy and exposed to monotherapy with one of the ASDs before age 18 years were included. We measured four ADR outcomes: (1) hematologic abnormality, (2) hyponatremia, (3) elevation of liver enzymes, and (4) subclinical hypothyroidism. We performed a subgroup analysis to exclude the effects of concomitant medications. RESULTS: From the database, 1344 patients were included for the study. Of the 1344 patients, 436 were receiving OXC, 293 were receiving LTG, 275 were receiving LEV, 180 were receiving VPA, and 160 were receiving TPM. Thrombocytopenia developed in 14.1% of patients taking VPA. Hyponatremia occurred in 10.5% of patients taking OXC. Variable ranges of liver enzyme elevation were detected in 19.3% of patients taking VPA. Subclinical hypothyroidism occurred in approximately 21.5% to 28% of patients with ASD monotherapy, which did not significantly differ according to the type of ASD. In a subgroup analysis, we observed similar ADR tendencies, but with less thrombocytopenia in the TPM group. SIGNIFICANCE: The incidence and trends of ADRs that were evaluated by CDM were similar to the previous literature. CDM can be a useful tool for analyzing ASD-related ADRs in a multicenter study. The strengths and limitations of CDM should be carefully addressed.

Serum α-synuclein and IL-1ß are increased and correlated with measures of disease severity in children with epilepsy: potential prognostic biomarkers?

BACKGROUND: The search for noninvasive biomarkers of neuroinflammation and neurodegeneration has focused on various neurological disorders, including epilepsy. We sought to determine whether α-synuclein and cytokines are correlated with the degree of neuroinflammation and/or neurodegeneration in children with epilepsy and with acquired demyelinating disorders of the central nervous system (CNS), as a prototype of autoimmune neuroinflammatory disorders. METHODS: We analyzed serum and exosome levels of α-synuclein and serum proinflammatory and anti-inflammatory cytokines among 115 children with epilepsy and 10 acquired demyelinating disorders of the CNS and compared to 146 controls. Patients were enrolled prospectively and blood was obtained from patients within 48 h after acute afebrile seizure attacks or relapse of neurological symptoms. Acquired demyelinating disorders of the CNS include acute disseminated encephalomyelitis, multiple sclerosis, neuromyelitis optica spectrum disorders, and transverse myelitis. The controls were healthy age-matched children. The serum exosomes were extracted with ExoQuick exosome precipitation solution. Serum α-synuclein levels and serum levels of cytokines including IFN-ß, IFN-γ, IL-1ß, IL-6, IL-10 and TNF-α were measured using single and multiplex ELISA kits. Data were analyzed and compared with measures of disease severity, such as age at disease onset, duration of disease, and numbers of antiepileptic drug in use. RESULTS: Serum α-synuclein levels were significantly increased in patients with epilepsy and acquired demyelinating disorders of the CNS compared to controls (both, p < 0.05) and showed correlation with measures of disease severity both in epilepsy (p < 0.05, r = 0.2132) and in acquired demyelinating disorders of the CNS (p < 0.05, r = 0.5892). Exosome α-synuclein showed a significant correlation with serum α-synuclein (p < 0.0001, r = 0.5915). Serum IL-1ß levels were correlated only with the numbers of antiepileptic drug used in children with epilepsy (p < 0.001, r = 0.3428), suggesting drug resistant epilepsy. CONCLUSIONS: This is the first study in children demonstrating that serum α-synuclein levels were significantly increased in children with epilepsy and with acquired demyelinating disorders of the CNS and correlated with measures of disease severity. Serum IL-1ß levels showed significant correlation only with drug resistance in children with epilepsy. Thus, these data support that serum levels of α-synuclein and IL-1ß are potential prognostic biomarkers for disease severity in children with epilepsy. CNS, central nervous system.

Importance of early diagnosis in LMNA-related muscular dystrophy for cardiac surveillance.

INTRODUCTION: The identification of LMNA-related muscular dystrophy is important because it poses life-threatening cardiac complications. However, diagnosis of LMNA-related muscular dystrophy based on clinical features is challenging. METHODS: We reviewed the clinical phenotypes of 14 children with LMNA variants, focusing on the cardiac function and genotypes. RESULTS: Most patients presented with motor developmental delay or gait abnormalities. Eight (57%) patients had prominent neck extensor weakness or contractures. All patients showed ankle contractures at an early stage. Regular cardiac surveillance allowed for the detection of dysrhythmias in 57% of patients at a mean age of 14 years (range, 5-26). All patients had missense variants; however, there were no clear phenotype-genotype correlations. DISCUSSION: Early diagnosis of LMNA-related muscular dystrophy provides an opportunity for cardiac surveillance, potentially leading to the prevention of cardiac mortality in children.

Satellite lesions of DNET: implications for seizure and tumor control after resection.

PURPOSE: Dysembryoplastic neuroepithelial tumors (DNETs) are a common cause of chronic drug-resistant epilepsy and are known for their favorable surgical outcomes. Nevertheless, the seizure recurrence-free rate is not as favorable if tumorous nodules are present near the main mass. We call these small tumorous nodules in the vicinity of the main mass satellite lesions (SLs). We analyzed tumor and seizure control in the presence and following the subsequent removal of SLs. METHODS: We retrospectively reviewed the medical records, radiological data, and surgical procedures to obtain the outcomes of children who underwent resection surgery for DNET. The analyses were designed to address the associations among the demographic, tumor and seizure-related variables. A Cox proportional hazard model was used for the univariate and multivariate analyses. RESULTS: In total, 39 consecutive patients were included (26 males and 13 females). SLs were found in 22 patients (56%). The year-to-year analysis of patients with Engel class I was approximately 80% during the follow-up period. However, the actual seizure recurrence-free survival (RFS) rate was 82, 73 and 70% at the first, second and fifth year, respectively. The patients who initially presented with SLs had 46% seizure recurrence rates, while those without SL had 18% seizure recurrence rates. CONCLUSIONS: As the seizure-RFS rate significantly declines over time, a more accurate seizure-free rate analysis using survival curves could be important for determining the outcome of DNET surgery. A thorough review identifying satellite lesions preoperatively and using intraoperative neuronavigation, electrocorticography (ECoG) or intraoperative ultrasonography is warranted to accomplish the wide resection of tumors with accompanying satellite lesions.

GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy.

OBJECTIVE: Rett syndrome (RTT) and epileptic encephalopathy (EE) are devastating neurodevelopmental disorders with distinct diagnostic criteria. However, highly heterogeneous and overlapping clinical features often allocate patients into the boundary of the two conditions, complicating accurate diagnosis and appropriate medical interventions. Therefore, we investigated the specific molecular mechanism that allows an understanding of the pathogenesis and relationship of these two conditions. METHODS: We screened novel genetic factors from 34 RTT-like patients without MECP2 mutations, which account for ∼90% of RTT cases, by whole-exome sequencing. The biological function of the discovered variants was assessed in cell culture and Xenopus tropicalis models. RESULTS: We identified a recurring de novo variant in GABAB receptor R2 (GABBR2) that reduces the receptor function, whereas different GABBR2 variants in EE patients possess a more profound effect in reducing receptor activity and are more responsive to agonist rescue in an animal model. INTERPRETATION: GABBR2 is a genetic factor that determines RTT- or EE-like phenotype expression depending on the variant positions. GABBR2-mediated γ-aminobutyric acid signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. Ann Neurol 2017;82:466-478.

Collagen VI-related myopathy: Expanding the clinical and genetic spectrum.

INTRODUCTION: We aimed to analyze the clinical and genetic characteristics of collagen VI-related myopathy. METHODS: We analyzed the clinical course and mutation spectrum in patients with collagen VI gene mutations among our congenital muscular dystrophy cohort. RESULTS: Among 24 patients with mutations in collagen VI coding genes, 13 (54.2%) were categorized as Ullrich type, and 11 (45.8%) as non-Ullrich type. Congenital orthopedic problems were similarly observed in both types, yet multiple joint contractures were found only in the Ullrich type. Clinical courses and pathology findings varied between patients. Mutations in COL6A1, COL6A2, and COL6A3 were found in 15 (65%), 3 (13%), and 5 (22%) patients, respectively, without genotype-phenotype association. Five novel variants were detected. DISCUSSION: We verified clinical heterogeneity of collagen VI-related myopathy, which emphasizes the importance of genetic testing. Genotype-phenotype association or early predictors for progression were not identified. Multiple joint contractures predict rapid deterioration. Muscle Nerve 58: 381-388, 2018.

Flexible nanograss with highest combination of transparency and haze for optoelectronic plastic substrates.

Transparent polymer substrates have recently received increased attention for various flexible optoelectronic devices. Optoelectronic applications such as solar cells and light emitting-diodes would benefit from substrates with both high transparency and high haze, which increase how much light scatters into or out of the underlying photoactive layers. In this letter, we demonstrate a new flexible nanograss plastic substrate that displays the highest combination of transparency and haze in the literature for polyethylene terephthalate (PET). As opposed to other nanostructures that increase haze at the expense of transparency, our nanograss demonstrates the potential to improve both haze and transparency. Furthermore, the monolithic nanograss may be fabricated in a facile scalable maskless reactive ion etching process without the need for additional lithography or synthesis of nanostructures. Our 9 µm height nanograss sample exhibits a transparency and haze of 92.4% and 89.4%, respectively, and our 34 µm height nanograss displays a transparency and haze of 91.0% and 97.1%, respectively. We also performed durability experiments that demonstrate these nanostructured PET substrates are robust from bending and show similar transmission and haze values after 5000 cycles of bending.