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Brain Communications 2023In this study, we have evaluated the underlying aetiologies, yield of genetic testing and long-term outcomes in patients with early-infantile developmental and epileptic...
In this study, we have evaluated the underlying aetiologies, yield of genetic testing and long-term outcomes in patients with early-infantile developmental and epileptic encephalopathies. We have prospectively studied patients with seizure onset before 3 months of age. Based on the clinical details, neuroimaging, metabolic testing and comprehensive genetic evaluation, patients were classified into different aetiological groups. The phenotypic differences between genetic/unknown groups and remaining aetiologies were compared. Factors that could affect seizure control were also assessed. A total of 80 children (M:F ratio-1.5:1) were recruited. The median seizure onset age was 28 days (range, 1-90 days). The aetiologies were confirmed in 66 patients (83%). The patients were further classified into four aetiological groups: genetic (50%), structural (19%), metabolic (14%; all were vitamin responsive) and unknown (17%). On comparing for the phenotypic differences between the groups, children in the 'genetic/unknown' groups were more frequently observed to have severe developmental delay (Odds Ratio = 57; < 0.0001), autistic behaviours (Odds Ratio = 37; < 0.0001), tone abnormalities (Odds Ratio = 9; = 0.0006) and movement disorder (Odds Ratio = 19; < 0.0001). Clonic seizures were more common in the vitamin responsive/structural groups (Risk Ratio = 1.36; = 0.05) as compared to patients with 'genetic/unknown' aetiologies. On the contrary, vitamin responsive/structural aetiology patients were less likely to have tonic seizures (Risk Ratio = 0.66; = 0.04). Metabolic testing was diagnostic in three out of 41 patients tested (all three had biotinidase deficiency). MRI was abnormal in 35/80 patients (malformation observed in 16/35; 19/35 had non-specific changes that did not contribute to underlying aetiology). A molecular diagnosis was achieved in 53 out of 77 patients tested (69%). Next-generation sequencing had a yield of 51%, while microarray had a yield of 14%. was the most common (five patients) single-gene defect identified. There were 24 novel variants. The mean follow-up period was 30 months (range, 4-72 months). On multivariate logistic regression for the important factors that could affect seizure control (seizure onset age, time lag of first visit to paediatric neurologist and aetiologies), only vitamin responsive aetiology had a statistically significant positive effect on seizure control ( = 0.02). Genetic aetiologies are the most common cause of early-infantile developmental and epileptic encephalopathies. Patients in the genetic/unknown groups had a more severe phenotype. Patients with vitamin responsive epilepsies had the best probability of seizure control.
PubMed: 38074073
DOI: 10.1093/braincomms/fcad243 -
The Journal of Adolescent Health :... Sep 2023Overweight in youth is influenced by genes and environment. Gene-environment interaction (G×E) has been demonstrated in twin studies and recent developments in genetics...
PURPOSE
Overweight in youth is influenced by genes and environment. Gene-environment interaction (G×E) has been demonstrated in twin studies and recent developments in genetics allow for studying G×E using individual genetic predispositions for overweight. We examine genetic influence on trajectories of overweight during adolescence and early adulthood and determine whether genetic predisposition is attenuated by higher socioeconomic status and having physically active parents.
METHODS
Latent class growth models of overweight were fitted using data from the TRacking Adolescents' Individual Lives Survey (n = 2720). A polygenic score for body mass index (BMI) was derived using summary statistics from a genome-wide association study of adult BMI (N = ∼700,000) and tested as predictor of developmental pathways of overweight. Multinomial logistic regression models were used to examine effects of interactions of genetic predisposition with socioeconomic status and parental physical activity (n = 1675).
RESULTS
A three-class model of developmental pathways of overweight fitted the data best ("non-overweight", "adolescent-onset overweight", and "persistent overweight"). The polygenic score for BMI and socioeconomic status distinguished the persistent overweight and adolescent-onset overweight trajectories from the non-overweight trajectory. Only genetic predisposition differentiated the adolescent-onset from the persistent overweight trajectory. There was no evidence for G×E.
DISCUSSION
Higher genetic predisposition increased the risk of developing overweight during adolescence and young adulthood and was associated with an earlier age at onset. We did not find that genetic predisposition was offset by higher socioeconomic status or having physically active parents. Instead, lower socioeconomic status and higher genetic predisposition acted as additive risk factors for developing overweight.
Topics: Adult; Adolescent; Humans; Young Adult; Longitudinal Studies; Genetic Predisposition to Disease; Genome-Wide Association Study; Overweight; Body Mass Index; Pediatric Obesity; Risk Factors; Seizures
PubMed: 37318409
DOI: 10.1016/j.jadohealth.2023.04.028 -
Frontiers in Pediatrics 2023Developmental and epileptic encephalopathies (DEEs) signify a group of heterogeneous neurodevelopmental disorder associated with early-onset seizures accompanied by...
BACKGROUND
Developmental and epileptic encephalopathies (DEEs) signify a group of heterogeneous neurodevelopmental disorder associated with early-onset seizures accompanied by developmental delay, hypotonia, mild to severe intellectual disability, and developmental regression. Variants in the gene have been associated with autosomal dominant DEE type 31A and autosomal recessive DEE type 31B.
METHODS
In the current study, a consanguineous Pakistani family consisting of a proband (IV-2) was clinically evaluated and genetically analyzed manifesting in severe neurodevelopmental phenotypes. WES followed by Sanger sequencing was performed to identify the disease-causing variant. Furthermore, 3D protein modeling and dynamic simulation of wild-type and mutant proteins along with reverse transcriptase (RT)-based mRNA expression were checked using standard methods.
RESULTS
Data analysis of WES revealed a novel homozygous non-sense variant (c.1402G>T; p. Glu468*) in exon 11 of the gene that was predicted as pathogenic class I. Variants in the gene have been associated with DEE types 31A and B. Different bioinformatics prediction tools and American College of Medical Genetics guidelines were used to verify the identified variant. Sanger sequencing was used to validate the disease-causing variant. Our approach validated the pathogenesis of the variant as a cause of heterogeneous neurodevelopmental disorders. In addition, 3D protein modeling showed that the mutant protein would lose most of the amino acids and might not perform the proper function if the surveillance non-sense-mediated decay mechanism was skipped. Molecular dynamics analysis showed varied trajectories of wild-type and mutant DNM1 proteins in terms of root mean square deviation, root mean square fluctuation and radius of gyration. Similarly, RT-qPCR revealed a substantial reduction of the gene in the index patient.
CONCLUSION
Our finding further confirms the association of homozygous, loss-of-function variants in associated with DEE type 31B. The study expands the genotypic and phenotypic spectrum of pathogenic variants related to -associated pathogenesis.
PubMed: 37900685
DOI: 10.3389/fped.2023.1266376 -
Annals of Clinical and Translational... Aug 2023The efficacy of perampanel (PER) in pediatric epilepsy with specific etiologies has not been well established. Here, we investigated outcome and predictors of PER...
OBJECTIVE
The efficacy of perampanel (PER) in pediatric epilepsy with specific etiologies has not been well established. Here, we investigated outcome and predictors of PER treatment in a pediatric cohort with known and presumed genetic etiology.
METHODS
We included pediatric patients with potential genetic epilepsy who received PER treatment and underwent whole-exome sequencing (WES) from January 2020 to September 2021. All patients were followed up for >12 months.
RESULTS
A total of 124 patients were included. Overall response rates were 51.6% and 49.6% at 6 months and 12 months, respectively. Pathogenic or likely pathogenic variants in 27 multiple genes were detected among 58 patients (46.8%) by WES. On performing multivariate logistic regression analysis, only developmental delay (OR = 0.406, P = 0.042) was a negative predictor of treatment response. However, the seizure onset age, positive WES results, and number of ASMs before PER administration were not significantly. Thirteen carriers with variants in the SCN1A gene showed a better response compared to eight patients with other sodium channels (P = 0.007), and to the other 45 patients with positive WES results (OR = 7.124, 95% CI = 1.306-38.860, P = 0.023). Adverse events were only reported in 23 patients, the most common being emotional problems.
INTERPRETATION
PER is safe and efficacious in pediatric patients with known and presumed genetic etiology. The response rate is comparable to that reported in other pediatric populations, and lower among those with developmental delay. A gene-specific response to PER is found along with better efficacy links to pathogenic variants in the SCN1A gene.
Topics: Humans; Child; Epilepsy; Seizures; Pyridones; Causality
PubMed: 37329172
DOI: 10.1002/acn3.51828 -
JAMA Pediatrics Dec 2023Social determinants of health (SDOH) influence child health. However, most previous studies have used individual, small-set, or cherry-picked SDOH variables without...
IMPORTANCE
Social determinants of health (SDOH) influence child health. However, most previous studies have used individual, small-set, or cherry-picked SDOH variables without examining unbiased computed SDOH patterns from high-dimensional SDOH factors to investigate associations with child mental health, cognition, and physical health.
OBJECTIVE
To identify SDOH patterns and estimate their associations with children's mental, cognitive, and physical developmental outcomes.
DESIGN, SETTING, AND PARTICIPANTS
This population-based cohort study included children aged 9 to 10 years at baseline and their caregivers enrolled in the Adolescent Brain Cognitive Development (ABCD) Study between 2016 and 2021. The ABCD Study includes 21 sites across 17 states.
EXPOSURES
Eighty-four neighborhood-level, geocoded variables spanning 7 domains of SDOH, including bias, education, physical and health infrastructure, natural environment, socioeconomic status, social context, and crime and drugs, were studied. Hierarchical agglomerative clustering was used to identify SDOH patterns.
MAIN OUTCOMES AND MEASURES
Associations of SDOH and child mental health (internalizing and externalizing behaviors) and suicidal behaviors, cognitive function (performance, reading skills), and physical health (body mass index, exercise, sleep disorder) were estimated using mixed-effects linear and logistic regression models.
RESULTS
Among 10 504 children (baseline median [SD] age, 9.9 [0.6] years; 5510 boys [52.5%] and 4994 girls [47.5%]; 229 Asian [2.2%], 1468 Black [14.0%], 2128 Hispanic [20.3%], 5565 White [53.0%], and 1108 multiracial [10.5%]), 4 SDOH patterns were identified: pattern 1, affluence (4078 children [38.8%]); pattern 2, high-stigma environment (2661 children [25.3%]); pattern 3, high socioeconomic deprivation (2653 children [25.3%]); and pattern 4, high crime and drug sales, low education, and high population density (1112 children [10.6%]). The SDOH patterns were distinctly associated with child health outcomes. Children exposed to socioeconomic deprivation (SDOH pattern 3) showed the worst health profiles, manifesting more internalizing (β = 0.75; 95% CI, 0.14-1.37) and externalizing (β = 1.43; 95% CI, 0.83-2.02) mental health problems, lower cognitive performance, and adverse physical health.
CONCLUSIONS
This study shows that an unbiased quantitative analysis of multidimensional SDOH can permit the determination of how SDOH patterns are associated with child developmental outcomes. Children exposed to socioeconomic deprivation showed the worst outcomes relative to other SDOH categories. These findings suggest the need to determine whether improvement in socioeconomic conditions can enhance child developmental outcomes.
Topics: Male; Female; Adolescent; Humans; Child; Cohort Studies; Social Determinants of Health; Mental Health; Child Development; Cognition
PubMed: 37843837
DOI: 10.1001/jamapediatrics.2023.4218 -
Translational Psychiatry Aug 2023Down syndrome regression disorder (DSRD) is a clinical symptom cluster consisting of neuropsychiatric regression without an identifiable cause. This study evaluated the... (Observational Study)
Observational Study
Down syndrome regression disorder (DSRD) is a clinical symptom cluster consisting of neuropsychiatric regression without an identifiable cause. This study evaluated the clinical effectiveness of IVIg and evaluated clinical characteristics associated with relapse after therapy discontinuation. A prospective, multi-center, non-randomized, observational study was performed. Patients met criteria for DSRD and were treated with IVIg. All patients underwent a standardized wean-off therapy after 9-12 months of treatment. Baseline, on-therapy, and relapse scores of the Neuropsychiatric Inventory Total Score (NPITS), Clinical Global Impression-Severity (CGI-S), and the Bush-Francis Catatonia Rating Scale (BFCRS) were used to track clinical symptoms. Eighty-two individuals were enrolled in this study. Patients had lower BFCRS (MD: -6.68; 95% CI: -8.23, -5.14), CGI-S (MD: -1.27; 95% CI: -1.73, -0.81), and NPITS scores (MD: -6.50; 95% CI: -7.53, -5.47) while they were on therapy compared to baseline. Approximately 46% of the patients (n = 38) experienced neurologic relapse with wean of IVIg. Patients with neurologic relapse were more likely to have any abnormal neurodiagnostic study (χ = 11.82, P = 0.001), abnormal MRI (χ = 7.78, P = 0.005), and abnormal LP (χ = 5.45, P = 0.02), and a personal history of autoimmunity (OR: 6.11, P < 0.001) compared to patients without relapse. IVIg was highly effective in the treatment of DSRD. Individuals with a history of personal autoimmunity or neurodiagnostic abnormalities were more likely to relapse following weaning of immunotherapy, indicating the potential for, a chronic autoimmune etiology in some cases of DSRD.
Topics: Humans; Down Syndrome; Immunoglobulins, Intravenous; Prospective Studies; Immunotherapy; Recurrence
PubMed: 37553347
DOI: 10.1038/s41398-023-02579-z -
Child and Adolescent Psychiatry and... Jul 2023This is one of the few studies that examines adolescent Internet addiction (IA) among Middle Eastern population. The purpose of this study is to determine whether...
BACKGROUND
This is one of the few studies that examines adolescent Internet addiction (IA) among Middle Eastern population. The purpose of this study is to determine whether adolescents' family and school environments play a role in their Internet Addiction.
METHODS
We conduced a survey that included 479 adolescents in Qatar. The survey collected demographic data, the Internet Addiction Diagnostic Questionnaire (IADQ), the Brief Family Relationship Scale (BFRS) and questions from the WHO Health Behavior in School-aged Children (HBSC) survey that assess school environment, academic performance, teacher support, and peer support of the adolescents. Factorial analysis, multiple regression, and logistic regression were used for statistical analysis.
RESULTS
Family environment and school environment were negative and significant predictors of adolescent Internet addiction. The prevalence rate was 29.64%.
CONCLUSION
Results imply that interventions and digital parenting programs should not only target adolescents, but also include entities in the developmental environment of adolescents, i.e. their family and school.
PubMed: 37403108
DOI: 10.1186/s13034-023-00626-7 -
Computational and Structural... Dec 2024Cancer immunotherapy has shown to be a promising method in treating hepatocellular carcinoma (HCC), but suboptimal responses in patients are attributed to cellular and...
Cancer immunotherapy has shown to be a promising method in treating hepatocellular carcinoma (HCC), but suboptimal responses in patients are attributed to cellular and molecular heterogeneity. Iron metabolism-related genes (IRGs) are important in maintaining immune system homeostasis and have the potential to help develop new strategies for HCC treatment. Herein, we constructed and validated the iron-metabolism gene prognostic index (IPX) using univariate Cox proportional hazards regression and LASSO Cox regression analysis, successfully categorizing HCC patients into two groups with distinct survival risks. Then, we performed single-sample gene set enrichment analysis, weighted correlation network analysis, gene ontology enrichment analysis, cellular lineage analysis, and SCENIC analysis to reveal the key determinants underlying the ability of this model based on bulk and single-cell transcriptomic data. We identified several driver transcription factors specifically activated in specific malignant cell sub-populations to contribute to the adverse survival outcomes in the IPX-high subgroup. Within the tumor microenvironment (TME), T cells displayed significant diversity in their cellular characteristics and experienced changes in their developmental paths within distinct clusters identified by IPX. Interestingly, the proportion of Treg cells was increased in the high-risk group compared with the low-risk group. These results suggest that iron-metabolism could be involved in reshaping the TME, thereby disrupting the cell cycle of immune cells. This study utilized IRGs to construct a novel and reliable model, which can be used to assess the prognosis of patients with HCC and further clarify the molecular mechanisms of IRGs in HCC at single-cell resolution.
PubMed: 38375529
DOI: 10.1016/j.csbj.2024.01.022 -
The Lancet. Psychiatry Oct 2023Childhood maltreatment is a risk factor for the development of post-traumatic stress disorders and psychosis. However, the association between post-traumatic stress...
Associations between post-traumatic stress disorders and psychotic symptom severity in adult survivors of developmental trauma: a multisite cross-sectional study in the UK and South Korea.
BACKGROUND
Childhood maltreatment is a risk factor for the development of post-traumatic stress disorders and psychosis. However, the association between post-traumatic stress disorder (PTSD), including complex PTSD, and psychotic symptoms is unknown. We investigated whether the presence of PTSD and complex PTSD was associated with psychotic symptom severity within survivors of developmental trauma.
METHODS
As part of the Investigating Mechanisms underlying Psychosis Associated with Childhood Trauma (IMPACT) study, from Aug 20, 2020, to Jan 24, 2021, and from Sept 9, 2022, to Feb 21, 2023, using study advertisement on online platforms we recruited adult (≥18 years) participants who had experienced developmental trauma without a psychiatric diagnosis in the UK and South Korea. We measured whether participants met diagnostic thresholds for PTSD and complex PTSD using the self-reported International Trauma Questionnaire, and psychotic symptoms using the self-reported Community Assessment of Psychic Experiences. We used linear regression, adjusting for sociodemographic variables such as age, sex, ethnicity, educational attainment, and socioeconomic status, to examine whether there was an association between PTSD and complex PTSD and psychotic symptoms. The study is registered in the UK (University College London Research Ethics Committee [14317/001] and the National Health Service Research Ethics Committee [22/YH/0096]) and South Korea (Institutional Review Board of Seoul National University Bundang Hospital [B-2011-648-306]), and is ongoing.
FINDINGS
Of the 2675 participants who took part in the study, 1273 had experienced developmental trauma and were included in the study in the UK (n=475) and South Korea (n=798), comprising 422 (33%) men and 851 (67%) women with a mean age of 26·9 years (SD 6, range 18-40), mostly of White British (n=328) or South Korean (n=798) ethnicity. We found no significant association between PTSD and psychotic symptom severity (total severity β=-2·40 [SE 3·28], p=0·47), compared with participants who did not meet PTSD or complex PTSD caseness. We found a significant relationship between complex PTSD and psychotic symptom severity (total severity β=22·62 [SE 1·65], p<0·0001), including for positive (β=12·07 [SE 0·99], p<0·0001) and negative symptoms (β=10·5 [SE 0·95], p<0·0001), compared with participants who did not meet PTSD or complex PTSD caseness.
INTERPRETATION
Health systems must assess individuals with previous developmental trauma for complex PTSD and treat those affected. These individuals should also be assessed for psychotic symptoms, and if necessary, preventative measures should be taken to reduce risk of conversion. Further work should assess whether treating complex PTSD modifies the risk of conversion to psychosis.
FUNDING
UKRI Future Leaders Fellowship, British Medical Association Margaret Temple Award for Schizophrenia Research, and the National Research Foundation of Korea-Korea Government.
Topics: Male; Adult; Female; Humans; Adolescent; Young Adult; Stress Disorders, Post-Traumatic; Cross-Sectional Studies; State Medicine; Psychotic Disorders; Republic of Korea; United Kingdom
PubMed: 37739583
DOI: 10.1016/S2215-0366(23)00228-6 -
Molecular Autism Oct 2023There has been increasing evidence for atypical white matter (WM) microstructure in autistic people, but findings have been divergent. The development of autistic people...
OBJECTIVE
There has been increasing evidence for atypical white matter (WM) microstructure in autistic people, but findings have been divergent. The development of autistic people in early childhood is clouded by the concurrently rapid brain growth, which might lead to the inconsistent findings of atypical WM microstructure in autism. Here, we aimed to reveal the developmental nature of autistic children and delineate atypical WM microstructure throughout early childhood while taking developmental considerations into account.
METHOD
In this study, diffusion tensor imaging was acquired from two independent cohorts, containing 91 autistic children and 100 typically developing children (TDC), aged 4-7 years. Developmental prediction modeling using support vector regression based on TDC participants was conducted to estimate the WM atypical development index of autistic children. Then, subgroups of autistic children were identified by using the k-means clustering method and were compared to each other on the basis of demographic information, WM atypical development index, and autistic trait by using two-sample t-test. Relationship of the WM atypical development index with age was estimated by using partial correlation. Furthermore, we performed threshold-free cluster enhancement-based two-sample t-test for the group comparison in WM microstructures of each subgroup of autistic children with the rematched subsets of TDC.
RESULTS
We clustered autistic children into two subgroups according to WM atypical development index. The two subgroups exhibited distinct developmental stages and age-dependent diversity. WM atypical development index was found negatively associated with age. Moreover, an inverse pattern of atypical WM microstructures and different clinical manifestations in the two stages, with subgroup 1 showing overgrowth with low level of autistic traits and subgroup 2 exhibiting delayed maturation with high level of autistic traits, were revealed.
CONCLUSION
This study illustrated age-dependent heterogeneity in early childhood autistic children and delineated developmental stage-specific difference that ranged from an overgrowth pattern to a delayed pattern. Trial registration This study has been registered at ClinicalTrials.gov (Identifier: NCT02807766) on June 21, 2016 ( https://clinicaltrials.gov/ct2/show/NCT02807766 ).
Topics: Child; Humans; Child, Preschool; Diffusion Tensor Imaging; Autistic Disorder; Brain; White Matter; Cluster Analysis
PubMed: 37899464
DOI: 10.1186/s13229-023-00573-2