The ROS/TXNIP/NLRP3 pathway mediates LPS-induced microglial inflammatory response.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction activated by microglia. The potential pathological changes of SAE are complex, and the cellular pathophysiological characteristics remains unclear. This study aims to explore the ROS/TXNIP/NLRP3 pathway mediated lipopolysaccharide (LPS)-induced inflammatory response in microglia. METHODS: BV-2 cells were pre-incubated with 10 µM N-acetyl-L-cysteine (NAC) for 2 h, which were then reacted with 1 µg/mL LPS for 24 h. Western blot assay examined the protein levels of IBA1, CD68, TXNIP, NLRP3, ASC, and Cleaved Caspase-1 in BV-2 cells. The contents of inflammatory factor were detected by ELISA assay. The co-immunoprecipitation assay examined the interaction between TXNIP and NLRP3. RESULTS: LPS was confirmed to promote the positive expressions of IBA1 and CD68 in BV-2 cells. The further experiments indicated that LPS enhanced ROS production and NLRP3 inflammasome activation in BV-2 cells. Moreover, we also found that NAC partially reversed the facilitation of LPS on the levels of ROS, IL-1ß, IL-18, TXNIP, NLRP3, ASC, and Cleaved Caspase-1 in BV-2 cells. NAC treatment also notably alleviated the interaction between TXNIP and NLRP3 in BV-2 cells. CONCLUSION: ROS inhibition mediated NLRP3 signaling inactivation by decreasing TXNIP expression.

EpilepsyGene: a genetic resource for genes and mutations related to epilepsy.

Epilepsy is one of the most prevalent chronic neurological disorders, afflicting about 3.5-6.5 per 1000 children and 10.8 per 1000 elderly people. With intensive effort made during the last two decades, numerous genes and mutations have been published to be associated with the disease. An organized resource integrating and annotating the ever-increasing genetic data will be imperative to acquire a global view of the cutting-edge in epilepsy research. Herein, we developed EpilepsyGene (http://61.152.91.49/EpilepsyGene). It contains cumulative to date 499 genes and 3931 variants associated with 331 clinical phenotypes collected from 818 publications. Furthermore, in-depth data mining was performed to gain insights into the understanding of the data, including functional annotation, gene prioritization, functional analysis of prioritized genes and overlap analysis focusing on the comorbidity. An intuitive web interface to search and browse the diversified genetic data was also developed to facilitate access to the data of interest. In general, EpilepsyGene is designed to be a central genetic database to provide the research community substantial convenience to uncover the genetic basis of epilepsy.

Mechanisms underlying palmitic acid-induced disruption of locomotor activity and sleep behavior in Drosophila.

The globally prevalent of sleep disorders is partly attributed to unhealthy dietary habits. This study investigated the underlying mechanisms of elevated palmitic acid (PA) intake on locomotor activity and sleep behavior in Drosophila. Our results indicate that exposure to PA significantly elevated Drosophila's daytime and nighttime locomotor activity while concurrently reducing overall sleep duration. Utilizing 16S rRNA sequencing, we observed substantial alterations in the composition of the gut microbiota induced by PA, notably, characterized by a significant reduction in Lactobacillus plantarum. Furthermore, PA significantly increased the levels of inflammatory factors Upd3 and Eiger in Drosophila intestines, and downregulated the expression of Gad and Tph, as well as 5-HT1A. Conversely, Gdh and Hdc were significantly upregulated in the PA group. Supplementation with L. plantarum or lactic acid significantly ameliorated PA-induced disruptions in both locomotor activity and sleep behavior. This supplementation also suppressed the expression of intestinal inflammatory factors, thus restoring impaired neurotransmitter-mediated sleep-wake regulation. Moreover, specific knockdown of intestinal epithelial Upd3 or Eiger similarly restored disrupted neurotransmitter expression, ultimately improving PA-induced disturbances in Drosophila locomotor activity and sleep behavior. These findings provide important insights into the intricate interplay between dietary components and essential behaviors, highlighting potential avenues for addressing health challenges associated with modern dietary habits.

Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1.

Cerebral adrenoleukodystrophy (CALD) is a fatal genetic disease characterized by rapid, devastating neurological decline, with a narrow curative treatment window in the early stage. Non-canonical splice-site (NCSS) variants can easily be missed during genomic DNA analyses, and only a few of them in ABCD1 have been explored. Here, we studied a Chinese patient with clinical features similar to those of early-stage CALD but with a negative molecular diagnosis and a sibling who had presumably died of CALD. Trio-based whole-exome sequencing (trio-WES) and RNA sequencing (RNA-Seq) revealed a novel hemizygote NCSS variant c.901-25_901-9 del in ABCD1 intron 1, resulting in a complex splicing pattern. The in vitro minigene assay revealed that the c.901-25_901-9 del construct contained two aberrant transcripts that caused skipping of exon 2 and a small 48-bp deletion on left of the same exon. We identified a novel NCSS variant, that extends the spectrum of the known ABCD1 variants, and demonstrated the pathogenicity of this gene variant. Our findings highlight the importance of combining RNA-Seq and WES techniques for prompt diagnosis of leukodystrophy with NCSS variants.

[An epidemiological survey of febrile convulsions among pupils in the Wenzhou region].

OBJECTIVE: To study the prevalence and clinical features of febrile convulsion (FC) among pupils in the Wenzhou region, Zhejiang Province, China. METHODS: Using a random stratified cluster sampling method, 6406 children under 12 years from two primary schools of urban areas and two primary schools of rural areas were surveyed. RESULTS: The prevalence of FC was 3.67% (235/6406). Most children (75.7%) experienced their first onset of FC at 6 months to 3 years of age (median: 16 months). The seizures were generalized (95.3%, 224/235), with a duration of less than 10 minutes (86.4%, 203/235). FC was developed into epilepsy in 13 children (5.5%) who all suffered from complex FC. Relapses were noted in 88 cases (37.4%), among whom 38 patients had only 1 recurrence and 50 patients had 2 or more relapses. EEG was performed in 200 cases, among whom 12(6.0%) showed abnormalities. CONCLUSIONS: The prevalence of FC is 3.67% among pupils in the Wenzhou region. The seizures are generalized, with a short duration. A part of complex FC can be developed into subsequent epilepsy.

Sulforaphane Attenuates Chronic Intermittent Hypoxia-Induced Brain Damage in Mice via Augmenting Nrf2 Nuclear Translocation and Autophagy.

Obstructive sleep apnea-hypopnea syndrome (OSAHS), typically characterized by chronic intermittent hypoxia (CIH), is associated with neurocognitive dysfunction in children. Sulforaphane (SFN), an activator of nuclear factor E2-related factor 2 (Nrf2), has been demonstrated to protect against oxidative stress in various diseases. However, the effect of SFN on OSAHS remains elusive. In this research, we investigated the neuroprotective role of SFN in CIH-induced cognitive dysfunction and underlying mechanisms of regulation of Nrf2 signaling pathway and autophagy. CIH exposures for 4 weeks in mice, modeling OSAHS, contributed to neurocognitive dysfunction, manifested as increased working memory errors (WMEs), reference memory errors (RMEs) and total memory errors (TEs) in the 8-arm radial maze test. The mice were intraperitoneally injected with SFN (0.5 mg/kg) 30 min before CIH exposure everyday. SFN treatment ameliorated neurocognitive dysfunction in CIH mice, which demonstrates less RME, WME, and TE. Also, SFN effectively alleviated apoptosis of hippocampal neurons following CIH by decreased TUNEL-positive cells, downregulated cleaved PARP, cleaved caspase 3, and upregulated Bcl-2. SFN protects hippocampal tissue from CIH-induced oxidative stress as evidenced by elevated superoxide dismutase (SOD) activities and reduced malondialdehyde (MDA). In addition, we found that SFN enhanced Nrf2 nuclear translocation to hold an antioxidative function on CIH-induced neuronal apoptosis in hippocampus. Meanwhile, SFN promoted autophagy activation, as shown by increased Beclin1, ATG5, and LC3II/LC3I. Overall, our findings indicated that SFN reduced the apoptosis of hippocampal neurons through antioxidant effect of Nrf2 and autophagy in CIH-induced brain damage, which highlights the potential of SFN as a novel therapy for OSAHS-related neurocognitive dysfunction.

Treatment of hyponatremia in children with acute bacterial meningitis.

Purpose: Few studies have evaluated hyponatremia management in children with bacterial meningitis (BM). Thus, we aimed to describe variations in clinical practice, the effectiveness of sodium management, and adverse outcomes in children with BM and hyponatremia. Methods: This retrospective cross-sectional study conducted at a tertiary institution analyzed participants' demographic, clinical, and sodium-altering treatment data. The sodium trigger for treatment was defined as pretreatment sodium level, with response and overcorrection defined as increments of ≥5 and >10 mmol/L after 24 h, respectively. Results: This study enrolled 364 children with BM (age: <16 years; 215 boys). Hyponatremia occurred in 62.1% of patients, among whom 25.7% received sodium-altering therapies; 91.4% of those individuals had moderate/severe hyponatremia. Monotherapy was the most common initial hyponatremia treatment. After 24 h of treatment initiation, 82.4% of the patients responded. Logistic regression analyses revealed that ΔNa24 <5 mmol/L [odds ratio (OR) 15.52, 95% CI 1.71-141.06, p = 0.015] and minimum Glasgow Coma Scale (GCS) score ≤ 8 (OR 11.09, 95% CI 1.16-105.73, p = 0.036) predicted dysnatremia at 48 h after treatment initiation. Although rare, persistent moderate/severe hyponatremia or hypernatremia at 48 h after treatment initiation was associated with a high mortality rate (57.1%). Conclusion: This study found that most cases of hyponatremia responded well to various treatments. It is important to identify and institute appropriate treatment early for moderate or severe hyponatremia or hypernatremia in children with BM. This study was limited by its non-randomized nature.

Indole-3-propionic Acid Attenuates HI-Related Blood-Brain Barrier Injury in Neonatal Rats by Modulating the PXR Signaling Pathway.

The blood-brain barrier (BBB) is an important physiological barrier of the human body contributing to maintaining brain homeostasis and normal function. Hypoxic-ischemic (HI)-related brain injury is one of the main causes of neonatal acute morbidity and chronic disability. The previous research of our group confirmed that there was serious BBB destruction during HI brain injury. However, at present, the protection strategy of BBB is very limited, and further research on the protection mechanism is warranted. Indole-3-propionic acid (IPA) is a bacterial metabolism with anti-inflammatory and antioxidant properties, having neuroprotective effects and protective effects on the mucosal barrier. However, the role of IPA in BBB is not clear. In this research, we demonstrated the protective effect of IPA on BBB disruption from HI brain injury and hypothesized that it involves the amelioration of inflammation, oxidative stress, and MMP activation, thereby inhibiting apoptosis of rat brain microvascular endothelial cells (rBMECs). We demonstrated that expression levels of several inflammatory markers, including iNOS, TNF-α, IL-6, and IL-1ß, were significantly increased from HI damage or OGD injury. However, IPA treatment inhibited the increase significantly. Moreover, we demonstrated that IPA reduced intracellular ROS levels and MMP activation in rBMECs from OGD injury. Further research on the underlying detailed molecular mechanisms suggested that IPA attenuates inflammation by inhibiting NF-κB signaling. Finally, we investigated the mechanism of the relationship between PXR activation and NF-κB inhibition. The results suggested overexpression of PXR in rBMECs could significantly counteract the decrease of junction proteins and downregulate the increased p-IκB-α and p-NF-κB from OGD injury. However, the protective effects of IPA were reversed by antagonists of the PXR. Taken together, IPA might mitigate HI-induced damage of the BBB and the protective effect may be exerted through modulating the PXR signaling pathway.

PRRT2 variants and effectiveness of various antiepileptic drugs in self-limited familial infantile epilepsy.

PURPOSE: Self-limited familial infantile epilepsy (SFIE) is largely associated with variants in proline-rich transmembrane protein 2 (PRRT2). However, the detailed phenotype-genotype correlations are unclear, along with the efficacy of various antiepileptic drugs in the treatment of this epilepsy syndrome. In this study, we analysed the PRRT2 variants associated with SFIE in Chinese patients, and the efficacy of different antiepileptic drugs prescribed during follow-up. METHODS: We retrospectively included 20 patients diagnosed with SFIE and reviewed their clinical characteristics, genetic variants, and treatment responses. RESULTS: Eighteen of the 20 (90%) patients harboured the common heterozygous variant of PRRT2 c.649dupC p.(Arg217fs). One patient had two heterozygous variants of PRRT2, c.640G>C p.(Ala214Pro) and c.955G>T p.(Val319Leu), and the other patient harboured a novel c.606delA (p.Pro203Hisfs) variant. Nine patients who had first-line treatment of oxcarbazepine (OXC) became seizure-free. However, initial treatment with levetiracetam (LEV) or sodium valproate (VPA) in eight and three patients, respectively, was not effective even after increasing the dosage, and seizure-free status was only achieved after changing the treatment to OXC. The treatment responses suggested a significant difference (P < 0.001) between OXC and other anti-epileptic drugs. CONCLUSION: OXC as a sodium channel blocker may have a better effect than LEV and VPA in the treatment of PRRT2-associated SFIE. PRRT2 variants may be used as a biomarker to help select antiepileptic drugs for SFIE.

Case Report: CNNM2 Mutations Cause Damaged Brain Development and Intractable Epilepsy in a Patient Without Hypomagnesemia.

A series of neurological manifestations such as intellectual disability and epilepsy are closely related to hypomagnesemia. Cyclin M2 (CNNM2) proteins, as a member of magnesium (Mg2+) transporters, were found along the basolateral membrane of distal renal tubules and involved in the reabsorption of Mg2+. Homozygous and heterozygous variants in CNNM2 reported so far were responsible for a variable degree of hypomagnesemia, several of which also showed varying degrees of neurological phenotypes such as intellectual disability and epilepsy. Here, we report a de novo heterozygous CNNM2 variant (c.2228C > T, p.Ser743Phe) in a Chinese patient, which is the variant located in the cyclic nucleotide monophosphate-binding homology (CNBH) domain of CNNM2 proteins. The patient presented with mild intellectual disability and refractory epilepsy but without hypomagnesemia. Thus, we reviewed the literature and analyzed the phenotypes related to CNNM2 variants, and then concluded that the number of variant alleles and the changed protein domains correlates with the severity of the disease, and speculated that the CNBH domain of CNNM2 possibly plays a limited role in Mg2+ transport but a significant role in brain development. Furthermore, it can be speculated that neurological phenotypes such as intellectual disability and seizures can be purely caused by CNNM2 variants.

Different experiences of two PRRT2-associated self-limited familial infantile epilepsy.

To analyze the clinical characteristics and PRRT2 gene mutation of self-limited familial infantile epilepsy and evaluate the treatment responses of different antiepileptic drugs in self-limited familial infantile epilepsy. We reviewed the clinical feature and genetic mutation results and treatment responses of two sibling sisters. They were detected with the PRRT2 gene mutation through Sanger sequencing. Elder sister was treated with oxcarbazepine oral suspension, while younger sister was treated with levetiracetam oral solution. The two sibling sisters exhibited PRRT2 heterozygous mutation inherited from their mother in c.649dupC p.(Arg217fs). Oxcarbazepine oral suspension had an immediate effect on the elder sister who was treated with it. However, levetiracetam oral solution had no effect on younger sister even though the dose was increased, but she got seizure-free after turning to oxcarbazepine oral suspension. Oxcarbazepine, which plays the mechanism of the sodium channel blockers, has a more significant effect than levetiracetam, which has no mechanism of the sodium channel blockers in self-limited familial infantile epilepsy. The PRRT2 gene of infantile epileptic patients with a family history of infantile convulsions or paroxysmal kinesigenic dyskinesia(PKD) could be detected by sanger sequencing and a biomarker to select antiepileptic drugs which play the mechanism of the sodium channel blockers could be utilized.

Hyponatremia in Children With Bacterial Meningitis.

Background: Hyponatremia has frequently been described as a common complication associated with bacterial meningitis, though its frequency and clinical course in children with bacterial meningitis are unclear. The present study aimed to investigate the frequency, clinical characteristics, and prognosis associated with pediatric hyponatremia due to bacterial meningitis. Methods: We performed a retrospective review of children with bacterial meningitis provided with standard care. One hundred seventy-five children were included. We documented all participants' symptoms and signs, laboratory and microbiological data, radiological findings, and complications that occurred during their hospital admission. Disease severity was determined using the maximum Pediatric Cerebral Performance Category (PCPC) and minimum Glasgow Coma Scale (GCS). Residual deficits were assessed using PCPC at discharge. Results: Hyponatremia (<135 mmol/L) was seen in 116 (66.4%) of the patients assessed and was classified as mild (130-135 mmol/L) in 77, moderate (125-129 mmol/L) in 26, and severe (<125 mmol/L) in 13. Hyponatremia was associated with a shorter duration of symptoms before admission, higher CSF white cell counts, and a longer duration of hospitalization. Moderate and severe hyponatremia were associated with an increase in convulsions, impaired consciousness, altered CSF protein levels, higher maximum PCPC scores, and lower minimum GCS scores. Severe hyponatremia was further associated with the development of systemic complications including shock, multiple organ dysfunction syndrome, respiratory failure requiring mechanical ventilation, and an increase in poor outcome (PCPC ≥ 2). Hyponatremia was not associated with the development of neurologic complications. Logistic regression analyses revealed that convulsions (OR 12.09, 95% CI 2.63-56.84) and blood glucose levels > 6.1 mmol/L (OR 8.28, 95% CI 1.65-41.60) predicted severe hyponatremia. Conclusion: Hyponatremia occurred in 66.4% of the assessed pediatric bacterial meningitis patients. Moderate and severe hyponatremia affected the severity of pediatric bacterial meningitis. Only severe hyponatremia affected the short-term prognosis of patients with pediatric bacterial meningitis. We recommend that patients with pediatric bacterial meningitis who exhibit convulsions and increased blood glucose levels should be checked for severe hyponatremia. Further studies are needed to evaluate the effectiveness of treatment of hyponatremia.

De Novo Germline Mutations in SEMA5A Associated With Infantile Spasms.

Infantile spasm (IS) is an early-onset epileptic encephalopathy that usually presents with hypsarrhythmia on an electroencephalogram with developmental impairment or regression. In this study, whole-exome sequencing was performed to detect potential pathogenic de novo mutations, and finally we identified a novel damaging de novo mutation in SEMA5A and a compound heterozygous mutation in CLTCL1 in three sporadic trios with IS. The expression profiling of SEMA5A in the human brain showed that it was mainly highly expressed in the cerebral cortex, during the early brain development stage (8 to 9 post-conception weeks and 0 to 5 months after birth). In addition, we identified a close protein-protein interaction network between SEMA5A and candidate genes associated with epilepsy, autism spectrum disorder (ASD) or intellectual disability. Gene enrichment and function analysis demonstrated that genes interacting with SEMA5A were significantly enriched in several brain regions across early fetal development, including the cortex, cerebellum, striatum and thalamus (q < 0.05), and were involved in axonal, neuronal and synapse-associated processes. Furthermore, SEMA5A and its interacting genes were associated with ASD, epilepsy syndrome and developmental disorders of mental health. Our results provide insightful information indicating that SEMA5A may contribute to the development of the brain and is associated with IS. However, further genetic studies are still needed to evaluate the role of SEMA5A in IS to definitively establish the role of SEMA5A in this disorder.

Management of Refractory Orofacial Dyskinesia Caused by Anti-N-methyl-d-aspartate Receptor Encephalitis Using Botulinum Toxin.

The use of botulinum neurotoxin serotype A (BoNT-A) injections for the treatment of orofacial dyskinesia secondary to anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is rarely reported. Here, we report a case of an urgent, successful management of severe orofacial dyskinesia in an 8-year-old girl with anti-NMDAR encephalitis using BoNT-A injection. The patient presented with de novo unilateral paroxysmal movement disorder progressing to generalized dystonia and repetitive orofacial dyskinesia. Diagnosis was confirmed by the presence of NMDAR antibodies in serum and cerebrospinal fluid. The orofacial dyskinesia worsened despite the aggressive use of first-line immunotherapy and second-line immunotherapy (rituximab), and resulted in a potentially fatal self-inflicted oral injury. We urgently attempted symptomatic management using BoNT-A injections in the masseter, and induced muscle paralysis using vecuronium. The patient's severe orofacial dyskinesia was controlled. We observed the effects of the BoNT-A injections and a tapering off of the effects of vecuronium 10 days after the treatment. The movement disorder had improved significantly 4 weeks after the first administration of rituximab. The injection of BoNT-A into the masseter may be an effective treatment for medically refractory orofacial dyskinesia in pediatric patients with anti-NMDAR encephalitis. We propose that the use of BoNT-A injections should be considered early to avoid self-inflicted oral injury due to severe refractory orofacial dyskinesia in patients with anti-NMDAR encephalitis.

Identification of De Novo DNMT3A Mutations That Cause West Syndrome by Using Whole-Exome Sequencing.

Epileptic encephalopathies (EEs) are a group of severe neurodevelopmental disorders with extreme genetic heterogeneity. Recent trio-based whole-exome sequencing (WES) studies have demonstrated that de novo mutations (DNMs) play prominent roles in severe EE. In this study, we searched for potential causal DNMs by using high-coverage WES of four unrelated Chinese parent-offspring trios affected by West syndrome. Through extensive bioinformatic analysis, we identified three novel DNMs in DNMT3A, CDKL5, and MAMDC2 in three trios and two compound heterozygous mutations in KMT2A in one trio. The DNMs in CDKL5 and DNMT3A were considered to be deleterious on the basis of the consensus of several genetic damage prediction tools. In addition, spatiotemporal expression patterns revealed a high level of DNMT3A expression during the early embryonic stage in nearly all brain regions. We also observed that certain high-confidence genes for epilepsy were shared among the co-expression and genetic interaction networks of DNMT3A, CDKL5, and KMT2A. Furthermore, all the candidate epilepsy genes in the co-expression network of DNMT3A were significantly enriched in the early developmental stages of the brain according to a rank-based enrichment test. In particular, we found that the DNMs of DNMT3A were shared among EE, autism spectrum disorder (ASD), and intellectual disability (ID) and mainly occurred in the functional domain of DNMT3A. Together, our findings support an association between DNMT3A mutations and EE susceptibility and suggest a shared molecular pathophysiology among EE and other neuropsychiatric disorders.

Basal ganglia calcification and novel compound heterozygous mutations in the PANK2 gene in a Chinese boy with classic Pantothenate kinase-associated neurodegeneration: A case report.

RATIONALE: Pantothenate kinase-associated neurodegeneration (PKAN) represents an autosomal recessive hereditary disease. In this report, a PANK2 gene mutation in a Chinese child was identified, as well as detections of PKAN among his family members. Our findings exposed a world-wide novel compound heterozygous mutation. PATIENT CONCERNS: We described a 6-year-old male patient with PKAN, exhibiting involuntary movement for a period of 1.5 years, as well as feeding difficulties for 2 weeks. DIAGNOSIS: Due to brain computed tomography and magnetic resonance imaging results, and patient behavior, the attending physician suspected a hereditary effect. INTERVENTIONS: The patient sample underwent high-throughput sequencing. Subsequently, his parents and sister were screened for the mutations identified in the patient genome. OUTCOMES: High-throughput sequencing revealed a novel complex heterozygous mutation of the PANK2 gene, which was detected in the second and fourth exons, c.A650G, and c.T1341G, respectively, resulting in amino acid alterations (p.D217G and p.D447E, respectively). The child's father was confirmed to possess a heterozygous c.A650G mutation, while his mother was heterozygous for the c.T1341G mutation. LESSONS: The key finding of the study encompassed the detection of a novel PANK2 gene mutation in a child of Chinese ethnicity with PKAN. The PANK2 gene c.A650G, as well as c.T1341G, mutations may be potential mutation hotspots in children with PKAN in Mainland China.

Oxcarbazepine oral suspension in young pediatric patients with partial seizures and/or generalized tonic-clonic seizures in routine clinical practice in China: a prospective observational study.

BACKGROUND: This study aimed to assess efficacy and safety of oxcarbazepine (OXC) oral suspension in pediatric patients aged 2-5 years with partial seizures (PS) and/or generalized tonic-clonic seizures (GTCS) in real-world clinical practice in China. METHODS: This 26-week, prospective, single-arm, multicenter, observational study recruited pediatric patients aged 2-5 years with PS or GTCS suitable for OXC oral suspension treatment based on physicians' judgments from 11 medical centers in China. Enrolled subjects started OXC oral suspension treatment as monotherapy or in combination with other antiepileptic drugs. Primary efficacy outcome was the percentage of pediatric subjects achieving ≥ 50% seizure frequency reduction at the end of the 26-week treatment. Secondary efficacy-related parameters and safety parameters such as adverse events (AEs) and serious AEs (SAEs) were also monitored during the 26-week treatment period. RESULTS: Six hundred and six pediatric patients were enrolled and 531 (87.6%) completed the study. After 26 weeks of treatment, 93.3% subjects achieved ≥ 50% seizure frequency reduction, and 81.8% achieved 100% seizure frequency reduction compared to baseline. Among different seizure types, OXC was effective in all subjects with simple PS and in > 90% of subject with other type of seizure present in the study. AEs were observed in 49 (8.1%) subjects. Only three subjects experienced SAE. Rash (n = 18, 2.97%) was the most common AE. Only 17 subjects discontinued due to AEs. CONCLUSION: This study, reporting the real-world data, further confirms the efficacy and good safety profile of OXC oral suspension in Chinese pediatric patients aged 2-5 years with PS and/or GTCS.

Unusual brain images of a boy with adolescent cerebral X-linked adrenoleukodystrophy presenting with exhibitionism: A CARE-compliant case report.

RATIONALE: The respective involvements of both the thalamus and exhibitionism in cerebral X-linked adrenoleukodystrophy (X-ALD) have not been reported. PATIENT CONCERNS: An 11-year-old boy initially presented with exhibitionism and progressive neurobehavioral symptoms. He subsequently developed transient urinary and fecal incontinence, and an unwillingness to eat or communicate. DIAGNOSES: We conducted contrast-enhanced brain magnetic resonance imaging (MRI), which revealed symmetrical altered signal intensities in bilateral frontal white matter, the basal ganglia, and dorsal thalami, as well as a peripheral rim of contrast enhancement. Diagnosis of adolescent cerebral X-ALD was confirmed on the basis of next generation genetic sequencing analysis. INTERVENTIONS: We initiated the patient on hormonal replacement therapy. OUTCOMES: We observed rapidly progressive neurologic deterioration in this patient, and the boy fell into a vegetative state 10 months after discharge. LESSONS: We recommend that physicians should not disregard X-ALD in patients with isolated psychiatric symptoms, including hypersexual behavior. The combination of detailed clinical evaluation, MRI, and next generation genetic sequencing can expedite the diagnostic process of atypical variant of X-ALD.

Whole-exome sequencing identifies a novel de novo mutation in DYNC1H1 in epileptic encephalopathies.

Epileptic encephalopathies (EE) are a group of severe childhood epilepsy disorders characterized by intractable seizures, cognitive impairment and neurological deficits. Recent whole-exome sequencing (WES) studies have implicated significant contribution of de novo mutations to EE. In this study, we utilized WES for identifying causal de novo mutations in 4 parent-offspring trios affected by West syndrome. As a result, we found two deleterious de novo mutations in DYNC1H1 and RTP1 in two trios. Expression profile analysis showed that DYNC1H1 and RTP1 are expressed in almost all brain regions and developmental stages. Interestingly, co-expression and genetic interaction network analyses suggested that DYNC1H1 and RTP1 are tightly associated with known epilepsy genes. Furthermore, we observed that the de novo mutations of DYNC1H1 were identified in several different neuropsychiatric disorders including EE, autism spectrum disorders and intellectual disabilities by previous studies, and these mutations primarily occurred in the functional domain of the protein. Taken together, these results demonstrate DYNC1H1 as a strong candidate and RTP1 as a potential candidate on the onset of EE. In addition, this work also proves WES as a powerful tool for the molecular genetic dissection of children affected by sporadic EE.

Oxcarbazepine oral suspension in pediatric patients with partial seizures and/or generalized tonic-clonic seizures: a multi-center, single arm, observational study in China.

BACKGROUND: To assess efficacy and safety of oxcarbazepine (OXC) oral suspension in pediatric patients aged 2-16 years with partial seizures (PS) and/or generalized tonic-clonic seizures (GTCS) in real-world clinical practice in China. METHODS: This 26-week, single arm, multicenter and observational study recruited patients aged 2-16 years with PS or GTCS suitable for OXC oral suspension treatment. Enrolled patients received OXC oral suspension treatment for 26 weeks. Primary endpoints included mean seizure frequency at the end of the treatment and mean seizure frequency reduction at the end of the treatment vs. baseline. Secondary efficacy-related endpoints and safety parameters were also assessed. RESULTS: Nine hundred and eighty-seven pediatric patients were enrolled and 912 (92.4%) completed the study. The mean seizure frequencies at baseline and the end of week 26 were 13.40±64.92 and 1.62±19.47 times/ month, respectively. The mean seizure frequency reduction was 10.03±63.67 times/month and the mean seizure frequency reduction percentage was 90.02%±5127.0% (P<0.0001). After 26 weeks of treatment, 82.36%, 7.24% and 3.86% of the patients became controlled, significantly improved and improved, respectively. Adverse events (AEs) were reported in 74 (7.65%) patients. Rash was the most common AE. The efficacy of OXC was not affected by seizure types, age or gender. CONCLUSIONS: This study confirms the efficacy and good safety profile of OXC oral suspension in Chinese pediatric patients aged 2-16 years with PS and/or GTCS.