Importance Global developmental delay (GDD) is characterized by a complex etiology, diverse phenotypes, and high individual heterogeneity, presenting challenges for early clinical etiologic diagnosis. Cognitive impairment is the core symptom, and despite the pivotal role of genetic factors in GDD development, the understanding of them remains limited. Objectives To assess the utility of genetic detection in patients with GDD and to examine the potential molecular pathogenesis of GDD to identify targets for early intervention. Design, Setting, and Participants This multicenter, prospective cohort study enrolled patients aged 12 to 60 months with GDD from 6 centers in China from July 4, 2020, to August 31, 2023. Participants underwent trio whole exome sequencing (trio-WES) coupled with copy number variation sequencing (CNV-seq). Bioinformatics analysis was used to unravel pathogenesis and identify therapeutic targets. Main Outcomes and Measures The main outcomes of this study involved enhancing the rate of positive genetic diagnosis for GDD, broadening the scope of genetic testing indications, and investigating the underlying pathogenesis. The classification of children into levels of cognitive impairment was based on the developmental quotient assessed using the Gesell scale. Results The study encompassed 434 patients with GDD (262 [60%] male; mean [SD] age, 25.75 [13.24] months) with diverse degrees of cognitive impairment: mild (98 [23%]), moderate (141 [32%]), severe (122 [28%]), and profound (73 [17%]). The combined use of trio-WES and CNV-seq resulted in a 61% positive detection rate. Craniofacial abnormalities (odds ratio [OR], 2.27; 95% CI, 1.45-3.56), moderate or severe cognitive impairment (OR, 1.69; 95% CI, 1.05-2.70), and age between 12 and 24 months (OR, 1.57; 95% CI, 1.05-2.35) were associated with a higher risk of carrying genetic variants. Additionally, bioinformatics analysis suggested that genetic variants may induce alterations in brain development and function, which may give rise to cognitive impairment. Moreover, an association was found between the dopaminergic pathway and cognitive impairment. Conclusions and Relevance In this cohort study of patients with GDD, combining trio-WES with CNV-seq was a demonstrable, instrumental strategy for advancing the diagnosis of GDD. The close association among genetic variations, brain development, and clinical phenotypes contributed valuable insights into the pathogenesis of GDD. Notably, the dopaminergic pathway emerged as a promising focal point for potential targets in future precision medical interventions for GDD.

Objective: In this study, we aimed to evaluate the effects of pediatric epilepsy on family burden, parental anxiety, depression states, and quality of life of both parents and children.Methods: The study was undertaken between March and December 2021 using an online questionnaire that included the Family Burden Scale of Disease, the 7-item Generalized Anxiety Disorder scale, the 9 item Patient Health Questionnaire, the WHO Quality of Life Scale (WHOQOL-BREF), and the PedsQL 4.0 Generic Core Scales (parent-proxy report).Results: A total of 288 parents of children aged 2-18 years were included. Overall, 94.8% of the participating families experienced high levels of disease burden, 67.0% of parents suffered from anxiety states, 57.0% suffered from depression states, and 56.2% of children with epilepsy suffered from comorbid neuropsychiatric symptoms. The mean WHOQOL-BREF score for parental quality of life was 53.7 & PLUSMN; 12.8, while the median PedsQL score for children's quality of life was 65.4 (49.6-81.7). Parental depression states contributed the most to family burden and parental quality of life, whereas comorbidities of epilepsy contributed the most to children's quality of life. Seizure frequency significantly influenced parental anxiety states, and family burden was the most significant predictor of parental depression states.Conclusion: Heavy disease burden, anxiety states, and depression states are prevalent in families with children suffering from epilepsy, and most have a poor quality of life. There is a need for greater focus on the quality of life of this patient population and their caregivers, as well as increased resources to help combat anxiety, depression, and poor quality of life.& COPY; 2023 Published by Elsevier Inc.

Abstract Background ASXL2 encodes proteins involved in epigenetic regulation and the assembly of transcription factors at specific genomic loci. Germline de novo truncating variants in ASXL2 have been implicated in Shashi‐Pena syndrome, which results in features of developmental delay (DD), glabellar nevus flammeus, hypotonia, and cardiac disorders. However, the variants are rare, and the clinical spectrum may be incomplete. Methods The clinical data such as brain MRI were collect. The whole exome sequencing was performed for genetic etiology analysis. Results Here, we report a patient with DD, hypotonia, early atrial septal defect, and abnormal white matter signal. She presented with Shashi–Pena syndrome with a truncated variant in ASXL2 (NM_018263.6, c.2142_2152del, p.Ser714Argfs*5). She died of a digestive tract infection when she was 1 year and 6 months old. Conclusions Our study further expanded the spectrum of phenotypes and genetic variations of the syndrome, and we believe that it is necessary to screen the ASXL2 gene in patients with DD and cardiac and bone disorders.

Objectives: In this study, we aimed to evaluate the efficacy and tolerability of ketogenic diet (KD) in Chinese children with drug-resistant epilepsy (DRE) due to structural etiology. Methods: We retrospectively analyzed data from 23 pediatric patients with DRE due to structural etiology who were treated with KD at Department of Neurology, between May 2014 and December 2020. Based on etiological classifications, the patients were divided into a neonatal brain injury (Group 1), an intracranial infection group (Group2) and a group that showed malformations of cortical development (MCDs) (Group 3). Results: The 23 patients remained on the KD for a mean duration of 15.3 +/- 9.7 months. The response rates for the control of seizures were 60.9% (14/23), 52.2 % (12/23), 47.8% (11/23) at 3, 6 and 12 months, respectively. Subjective improvements in cognition were observed in 87.0% (20/23) of the children during follow-up. Reductions in the frequency of seizures of > 50% were more commonly achieved by patients in group 1 (75.0%, 9/ 12) compared to the patients in groups 2 (60.0%, 3/5) and 3 (33.4%, 2/6). Further analysis of the patients in Group 1 showed that children with a history of hypoxic ischemic encephalopathy (HIE) (100.0%, 6/6) had the highest rate of > 50% seizure reduction. The main reasons for the discontinuation of the KD were due to lack of efficacy and poor compliance. Most of the side effects associated with the KD diet were minor and easily corrected by appropriately adjusting the diet. Only 1 patient discontinued the diet due to severe refusal to eat. Conclusions: KD is an effective and safe treatment for Chinese children with DRE due to structural etiology. Better efficacy of seizure control was observed in patients with a history of neonatal brain injury. Patients with DRE secondary to HIE may be particularly responsive to the KD therapy, and so KD should be considered earlier in those patients.

Background To date, the repeated breakout of the novel coronavirus disease 2019 (COVID-19) pandemic across many regions in China has caused continuous physical and mental harm to health care workers. This study investigates the psychological burden of the pandemic and its associated risk factors among Chinese healthcare workers (HCWs) during a single wave of COVID-19. Methods For this cross-sectional web-based survey conducted from January 16, 2022 to February 5, 2022, a total of 412 HCWs from Northwestern China were recruited. Their socio-demographic data and COVID-19 related survey variables were then collected using online self-rating questionnaires. In addition, the Chinese versions of well-validated instruments, including the 12-item General Health Questionnaire for psychiatric morbidity, the Generalized Anxiety Disorder Scale-7 for anxiety, the Patient Health Questionnaire-9 for depression and the Insomnia Severity Index-7 for insomnia, were used to assess the participants' mental health status. Multivariate logistic regression analysis was eventually performed to identify the risk factors associated with the psychological outcomes. Results Of the 388 participants who were included in the final study (94.17% response rate), the prevalence of anxiety, depression, and insomnia symptoms were 25.3% (95% CI: 20.9-29.6%), 40.7% (95% CI: 35.8-45.6%), and 30.9% (95% CI: 26.3-35.5%), respectively. Multivariate logistic regression analysis revealed that being a woman and having a perceived need for psychological support were risk factors for all psychological outcomes, while poor disease cognition and perceived susceptibility were risk factors for anxiety. Poor disease cognition and being unvaccinated against COVID-19 were risk factors for depression, with the latter also being an independent risk factor for insomnia. Conclusion This study has identified a relatively lower prevalence rate of psychological disorders among Chinese HCWs during a single wave, deeper into the COVID-19 pandemic. Female HCWs, and those who had a perceived need for psychological support, had poor disease cognition, were perceived as susceptible to COVID-19 and had not been vaccinated against COVID-19 deserve more attention.

OBJECTIVES:We analyzed the clinical features and outcomes of children with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis in Northwestern China. METHODS:We retrospectively recruited 33 pediatric patients with anti-NMDAR encephalitis in Northwestern China from December 2013 to April 2020. The demographics, clinical features, treatments, and outcomes were reviewed. RESULTS:33 patients with anti-NMDAR encephalitis were enrolled in this study (a median age of 6.8 years, 20 females and 13 males). The initial symptoms included seizures (42.4%), psychiatric symptoms (39.4%), speech dysfunction (12.1%), and paralysis (6.1%). During the course of the disease, 31 patients (93.9%) presented with psychiatric symptoms, 29 patients (87.9%) presented with speech dysfunction, 25 patients (75.8%) presented with movement disorders and 24 patients (72.7%) presented with sleep disorders followed by seizures, consciousness disturbance, autonomic nervous dysfunction, paralysis, and hypoventilation. 12 patients (36.4%) had abnormal cerebrospinal fluid (CSF) findings, 10 patients (30.3%) exhibited abnormal brain magnetic resonance imaging (MRI) results, and 29 patients (87.9%) showed abnormal Electroencephalography (EEG) findings. None of the patients had tumors. All patients received first-line immunotherapy and 8 patients both received first and second-line immunotherapy. 30 of the 33 patients achieved good outcomes (score on the modified Rankin Scale [mRS] of 0-2), whilst the other 3 patients had poor outcomes (mRS score of 3-6). CONCLUSIONS:Patients with higher CSF anti-NMDAR body titer were more likely to develop sleep disorders, consciousness disturbances and more severe disease states.

Purpose: To assess the efficacy and safety of rituximab treatment as second-line immunotherapy in pediatric cases of anti-NMDA receptor (NMDAR) encephalitis.Methods: We retrospectively recruited 8 patients with anti-NMDAR encephalitis who were treated with rituximab as second-line immunotherapy. We evaluated the clinical features, laboratory examination results and treatment protocols of the Chinese children and defined good outcomes based on the modified Rankin scale (mRS) score (0–2) at the last follow-up.Results: A total of eight pediatric patients (median age 6.7 years; four female) with refractory anti-NMDAR encephalitis were recruited to the study. Rituximab was given after a median duration of disease of 57 days (range 50.5–113.75 days). The use of rituximab led to a significant reduction in the mRS and CD19+ B-cells compared to before rituximab infusion (P < 0.05). Five patients (62.5%) had a good outcome (mRS ≤ 2) including four patients (50%) who showed complete recovery (mRS = 0) at the last follow-up. Transient infusion adverse events were recorded in 2 patients (25%). Two patients (25%) had severe infectious adverse events (AEs) and two patients with grade 5 (death). None of the patients developed progressive multifocal leukoencephalopathy (PML).Conclusion: Our study provides evidence that rituximab can efficiently improve the clinical symptoms of anti-NMDAR encephalitis in children. However, due to the risk of adverse infections, rituximab should be restricted in pediatric patients with high rates of mortality and disability.

Object: Autism spectrum disorders (ASD) is characterized by stereotyped behavior, attention deficit and/or impaired sensory perception to external stimuli. Its neurobiological mechanisms remain unclear. In this study we examined the resting-state functional connectivity of the premotor area and investigated its correlation with behavioral variables to determine whether connectivity alterations can distinguish ASD from healthy controls. Methods: 39 children with ASD and 42 healthy children with matched age, sex and intelligence were recruited. All the 81 subjects had behavioral index evaluation and underwent resting-state functional magnetic resonance imaging (fMRI) scans. After MRI data preprocessing, the left and right premotor areas were selected as region of interest (ROI) seeds to perform functional connectivity. Groups were compared, and the correlation between functional connectivity and behavioral indicators was analyzed. Results: Compared with healthy controls, ASD children showed significantly increased functional connectivity between the left premotor area and the posterior cingulate gyrus or anterior lobe of wedge, but functional connectivity between the left premotor area and the left insular lobe was decreased (p < 0.05, FDR correction). In addition, the connectivity between the left premotor area and the left insular lobe was negatively correlated with the behavioral scores (p < 0.05). Conclusion: Imbalanced premotor functional connectivity may be one possible mechanism of stereotyped behavior in ASD.

Pearson syndrome (PS) is a rare, mitochondrial DNA (mtDNA) deletion disorder mainly affecting hematopoietic system and exocrine pancreas in early infancy, which is characterized by multi-organ involvement, variable manifestations and poor prognosis. Since the clinical complexity and uncertain outcome of PS, the ability to early diagnose and anticipate disease progression is of great clinical importance. We described a patient with severe anemia and hyperglycinemia at birth was diagnosed with neonatal diabetes mellitus, and later with PS. Genetic testing revealed that a novel mtDNA deletion existed in various non-invasive tissues from the patient. The disease course was monitored by mtDNA deletion heteroplasmy and mtDNA/nucleus DNA genome ratio in different tissues and at different time points, showing a potential genotype-phenotype correlation. Our findings suggest that for patient suspected for PS, it may be therapeutically important to first perform detailed mtDNA analysis on non-invasive tissues at the initial diagnosis and during disease progression.

We aimed to identify novel copy number variations (CNV) that might contribute to the pathogenesis of epilepsy. Epilepsy is a common brain disorder characterized by recurring seizures and various serious comorbidities, including respiratory, cardiovascular, and neurologic dysfunction. CNV have recently been considered as important risk factors for epilepsy. With public gene expression data from brain tissue of 23 epilepsy patients and 23 healthy controls, we detected CNV using the R language package CAFÉ. Real-time quantitative polymerase chain reaction validation was performed in a further nine patients and 10 controls. Functional analyses of the genes in the validated CNV were also carried out, using Ingenuity pathway analysis. Three copy number abnormalities (19q13.33, 19q13.11 and 4q35.1) were detected with the gene expression data. The duplication in 19q13.33 (approximately 1.22 million bases) was further validated in three additional epilepsy patients, and the deletion in 19q13.11 (approximately 855 kilobases) was further validated in another two epilepsy patients. The functional analyses of the genes in these two CNV suggested that they may be involved in the pathogenesis of epilepsy. The CNV that we detected may be common genetic etiological factors of epilepsy, and there is potential for the identification of a novel biomarker for treatment from these CNV regions.

Purpose. Epilepsy is a common chronic neurological disorder. We aim to investigate the underlying mechanism of epilepsy with partial least squares- (PLS-) based gene expression analysis, which is more sensitive than routine variance/regression analysis. Methods. Two microarray data sets were downloaded from the Gene Expression Omnibus (GEO) database. PLS analysis was used to identify differentially expressed genes. Gene ontology and network analysis were also implemented. Results. A total of 752 genes were identified to be differentially expressed, including 575 depressed and 177 overexpressed genes in patients. For GO enrichment analysis, except for processes related to the nervous system, we also identified overrepresentation of dysregulated genes in angiogenesis. Network analysis revealed two hub genes, CUL3 and EP300, which may serve as potential targets in further therapeutic studies. Conclusion. Our results here may provide new understanding for the underlying mechanisms of epilepsy pathogenesis and will offer potential targets for producing new treatments.