Search Results (25)

Approximately 18% of U.S. children experience cognitive and behavioral challenges, with both genetic and environmental contributors. We examined if household insecticides, particularly those used in and around the home and on pets, are associated with neurodevelopmental changes. Data were from children aged 24–60 months in the CHARGE study with the following classifications: autism spectrum disorder (ASD, n = 810), developmental delay (DD, n = 192), and typical development (TD, n = 531). Exposure to indoor, outdoor, and pet insecticides was reported for the period from three months pre-conception to the second birthday. Cognitive and adaptive functioning were assessed using the Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales. Linear regression was used to evaluate associations by diagnostic group, adjusting for confounders. Flea/tick soaps, shampoos, and powders used during year two were significantly associated with lower cognitive and adaptive scores in children with ASD after FDR correction. Flea/tick skin treatments in early pregnancy were associated with reduced scores in the DD group, though not significant after correction, especially when used with high frequency. No associations were observed in TD children. These findings underscore the need to examine early-life exposure to non-agricultural insecticides as modifiable risk factors for neurodevelopment. Full article

Background: Developmental delay and intellectual disability (DD/ID) are frequently accompanied by epilepsy, and growing evidence implicates variants in voltage-gated calcium channel genes in their pathogenesis. This study aimed to investigate the association of polymorphisms in CACNA1A, CACNA1C, and CACNA1H with DD/ID and epilepsy comorbidity in Korean children. Methods: We retrospectively analyzed 141 pediatric patients diagnosed with DD/ID who underwent whole-exome sequencing (WES) and were not found to have pathogenic monogenic variants. Nine single-nucleotide polymorphisms (SNPs) across CACNA1A, CACNA1C, and CACNA1H were selected based on functional annotation scores and prior literature. Genotype data were extracted from WES variant files, and allele and genotype frequencies were compared with control data from the gnomAD East Asian population and the Korean Reference Genome Database (KRGDB). Subgroup analyses were performed according to epilepsy comorbidity. Results: The CACNA1A rs16023 variant showed a significantly higher B allele frequency in DD/ID patients than in both control datasets and was also associated with epilepsy comorbidity. Genotype distribution analysis revealed that the BB genotype of rs16023 was more frequent in patients with epilepsy. Conclusions: The CACNA1A rs16023 variant may contribute to genetic susceptibility to DD/ID and epilepsy in Korean children, potentially through regulatory mechanisms. These findings support the relevance of calcium channel genes in neurodevelopmental disorders and highlight the importance of integrating functional annotation in variant prioritization. Full article

Aims: To develop and evaluate a novel AI-based video analysis tool for the quantitative assessment of “Places Pegs in” and “Blue Board” tasks in the Bayley Scales of Infant Development (BSID-II). Methods: A prospective cohort study was conducted from February 2022 to December 2022, including children aged 12–42 months referred for suspected developmental delay. Participants were evaluated using the BSID-II, and their performances on the two tasks were video recorded and analyzed with the novel tool. Sensitivity and specificity were determined by comparing the tool’s results to standard BSID-II assessments by therapists. Data collected included total time, number of trials, successful trials, and time and spatial intervals for each trial. Children were classified into typically developing (TD) (MDI ≥ 85) and developmental delay (DD) (MDI < 85) groups based on their mental developmental index (MDI). Results: A total of 75 children participated in the study, and the mean values of MDI and PDI for the enrolled children were 88.9 ± 18.7 and 80.0 ± 16.7. The “Places Pegs in” had 86.5% sensitivity and 100% specificity; the “Blue Board” had 96.9% sensitivity and 89.5% specificity. Differences in cumulative successes over time were observed between age groups and TD and DD groups. The tool automatically calculated maximum successes at specific time points. Interpretation: The AI-based tool showed high predictive accuracy for BSID-II tasks in children aged 12–42 months, indicating potential utility for developmental assessments. Full article

Background and Objectives: Neurodevelopmental disorders (NDDs), including developmental delay (DD), autism spectrum disorder (ASD), intellectual disability (ID), attention-deficit/hyperactivity disorder (ADHD), and specific learning disorders, affect 15% of children and adolescents worldwide. Advances in next-generation sequencing, particularly whole exome sequencing (WES), have improved the understanding of NDD genetics. Methodology: This study analyzed 3244 patients undergoing WES (single, duo, trio analyses), with 1028 meeting inclusion criteria (67% male; aged 0–50 years). Results: Pathogenic (P) or likely pathogenic (LP) variants were identified in 190 patients, achieving a diagnostic yield of 13.4% (singleton), 14% (duo), and 21.2% (trio). A total of 207 P/LP variants were identified in NDD-associated genes: 38% were missense (48 de novo), 29% frameshift (26 de novo), 21% nonsense (14 de novo), 11% splicing site (14 de novo), and 1% inframe (1 de novo). De novo variants accounted for 49.8% of cases, with 86 novels de novo variants and 27 novel non de novo variants unreported in databases like ClinVar or scientific literature. Conclusions: This is the largest study on WES in Colombian children with NDDs and one of the largest in Latino populations. It highlights WES as a cost-effective first-tier diagnostic tool in low-income settings, reducing diagnostic timelines and improving clinical care. These findings underscore the feasibility of implementing WES in underserved populations and contribute significantly to understanding NDD genetics, identifying novel variants with potential for further research and clinical applications. Full article

Background/Objectives: This study investigates the impact of maternal glycemic levels during early and late pregnancy on offspring neurodevelopment in China. Methods: Fasting plasma glucose (FPG) and triglyceride (TG) levels were measured in maternal blood during pregnancy, and the TyG index was calculated to assess insulin resistance. Hyperglycemia was defined as FPG > 5.1 mmol/L. Neurodevelopmental outcomes in offspring aged 6–36 months were evaluated using the China Developmental Scale for Children, focusing on developmental delay (DD) and developmental quotient (DQ). Mothers were categorized into four glycemic groups: healthy glycemia group (HGG), early pregnancy hyperglycemia group (EHG), late pregnancy hyperglycemia group (LHG), and full-term hyperglycemia group (FHG). Linear and logistic regression models were applied. Results: Among 1888 mother–child pairs, hyperglycemia and FPG were associated with an increased risk of overall DD (aOR = 1.68; 95% CI 1.07–2.64) and lower DQ (aBeta = −1.53; 95% CI −2.70 to −0.36). Elevated FPG was linked to DD in fine motor and social behaviors. Compared to HGG, LHG and FHG significantly increased the risk of overall DD (aOR = 2.18; 95% CI 1.26–3.77; aOR = 2.64; 95% CI 1.38–5.05), whereas EHG did not. Male offspring were particularly vulnerable to early pregnancy hyperglycemia (aBeta = −2.80; 95% CI −4.36 to −1.34; aOR = 2.05; 95% CI 1.10–3.80). Conclusions: Maternal glycemic levels during pregnancy influence offspring neurodevelopment, with persistent hyperglycemia significantly increasing DD risk. Early pregnancy hyperglycemia particularly affects male offspring, underscoring the need for glycemic management during pregnancy. Full article

Background/Objectives: The Parents’ Evaluation of Developmental Status (PEDS) and Developmental Milestones (PEDS:DM) are cost-effective, self-report tools that can be conveniently utilized in low- and middle-income countries to screen for developmental delays in children. This study assessed the diagnostic accuracy of PEDS and PEDS:DM in distinguishing children with typical development (TD) from those with developmental disabilities (DD). It also examined the relationship between parents’ general concerns and specific developmental concerns about their children. Method: The study included 407 children with TD and 59 children with DD, recruited from diverse socioeconomic backgrounds in Chandigarh, Himachal Pradesh, and the National Capital Region of India. Parents of children aged 4 to 8 years completed the PEDS and PEDS:DM online. Results: The PEDS demonstrated high sensitivity (91%) but low specificity (47%), whereas the PEDS:DM showed poor sensitivity (17%) and specificity (6%). Parents of TD children who expressed general developmental concerns were likely to report specific concerns related to behavior, self-help skills, health, and cognitive development. Parents of DD children with general concerns reported specific issues with fine motor skills, behavior, school performance, cognitive development, and health. Conclusions: These findings suggest that while PEDS and PEDS:DM can support early detection of developmental delays, their interpretation should be approached with caution. The study provides preliminary insights into the applicability of these screening tools for children aged 4–8 years in India. Full article

Developmental delays (DD) and congenital anomalies (CA) are prevalent yet often remain undiagnosed despite comprehensive genetic testing. This study aims to investigate the diagnostic yield of trio whole-genome sequencing (WGS) in children presenting with DD or CA who remained undiagnosed after previous genetic testing. A prospective cohort study was conducted on children with undiagnosed DD or CA at a single tertiary hospital. All participants suspected of genetic conditions had undergone chromosome analysis, chromosome microarray analysis (CMA), and clinical exome sequencing (CES); however, a subset remained undiagnosed. The WGS test was administered to both the affected children and their parents. A total of 52 children were included, and 10 (19.2%) had undergone a genetic diagnosis through WGS. Eight of these cases were associated with autosomal dominant and de novo variants. WGS led to successful diagnosis due to several factors, including small structural variants, genes not covered in the CES panel, the discovery of newly implicated genes, issues related to coverage depth, low variant allele frequency, challenges in variant interpretation, and differences in the interpretation of variants of unknown significance among clinicians. This study highlights the clinical value of trio WGS testing in undiagnosed children with DD or CA. Notably, an additional 19.2% of affected children were diagnosed through this method. Full article

Timely screening and surveillance of children for developmental delay and social–emotional learning difficulties are essential in Low- and Middle-Income Countries like India. Screening measures like the Parents’ Evaluation of Developmental Status (PEDS) and Strength and Difficulties Questionnaire (SDQ) are considered suitable for India due to their low cost, easy accessibility, and no training requirement for administration. However, India lacks validated screening measures, and the PEDS and SDQ have yet to be validated for children in India. The study aimed to translate the PEDS and SDQ from English to Hindi and psychometrically evaluate the same measures on children aged 4–8 years in India. The original PEDS and SDQ forms and their translations were pilot tested on 55 participants and evaluated using data from 407 children with typical development (TD) and 59 children with developmental disability (DD). Parents and teachers reported no meaningful discrepancy between the original and translated (Hindi) questionnaires. Internal consistency for the PEDS was acceptable, but unacceptable for most subscales on the SDQ, for both TD and DD samples. Test–retest reliability was poor for the PEDS but adequate for the SDQ. Results from known-group validity testing showed that the PEDS scores could be used to distinguish between the TD and DD samples. The results from this study provide further support for the use of the PEDS and SDQ in developing countries like India. Full article

(1) Background: In recent years, reviewing studies of aquatic activities for children with developmental delays has been a complex task due to the multitude of indices and professional languages. (2) Aim: To determine if the ICF-CY framework can be used as the unifying language in AA studies of children with DD. (3) Methods: Part One—A systematic review of selected studies focusing on goals that were found to be positive. These goals were linked to the ICF-CY categories. Part Two—Review of all studies using the ICF-CY’s functioning components. (4) Results: Most of the positive goals were properly linked to ICF-CY and made it possible to review the 71 articles in a uniform language. (5) Conclusions: It is feasible to use the ICF framework as a universal structure and language. Full article

Chromosomal imbalance is implicated in developmental delay (DD), congenital malformations (CM), and intellectual disability (ID), and, thus, precise identification of copy number variations (CNVs) is essential. We therefore aimed to investigate the genetic heterogeneity in Saudi children with DD/CM/ID. High-resolution array comparative genomic hybridization (array CGH) was used to detect disease-associated CNVs in 63 patients. Quantitative PCR was done to confirm the detected CNVs. Giemsa banding-based karyotyping was also performed. Array CGH identified chromosomal abnormalities in 24 patients; distinct pathogenic and/or variants of uncertain significance CNVs were found in 19 patients, and aneuploidy was found in 5 patients including 47,XXY (n = 2), 45,X (n = 2) and a patient with trisomy 18 who carried a balanced Robertsonian translocation. CNVs including 9p24p13, 16p13p11, 18p11 had gains/duplications and CNVs, including 3p23p14, 10q26, 11p15, 11q24q25, 13q21.1q32.1, 16p13.3p11.2, and 20q11.1q13.2, had losses/deletions only, while CNVs including 8q24, 11q12, 15q25q26, 16q21q23, and 22q11q13 were found with both gains or losses in different individuals. In contrast, standard karyotyping detected chromosomal abnormalities in ten patients. The diagnosis rate of array CGH (28%, 18/63 patients) was around two-fold higher than that of conventional karyotyping (15.87%, 10/63 patients). We herein report, for the first time, the extremely rare pathogenic CNVs in Saudi children with DD/CM/ID. The reported prevalence of CNVs in Saudi Arabia adds value to clinical cytogenetics. Full article

Genetic early-onset Parkinsonism is unique due to frequent co-occurrence of hyperkinetic movement disorder(s) (MD), or additional neurological of systemic findings, including epilepsy in up to 10–15% of cases. Based on both the classification of Parkinsonism in children proposed by Leuzzi and coworkers and the 2017 ILAE epilepsies classification, we performed a literature review in PubMed. A few discrete presentations can be identified: Parkinsonism as a late manifestation of complex neurodevelopmental disorders, characterized by developmental and epileptic encephalopathies (DE-EE), with multiple, refractory seizure types and severely abnormal EEG characteristics, with or without preceding hyperkinetic MD; Parkinsonism in the context of syndromic conditions with unspecific reduced seizure threshold in infancy and childhood; neurodegenerative conditions with brain iron accumulation, in which childhood DE-EE is followed by neurodegeneration; and finally, monogenic juvenile Parkinsonism, in which a subset of patients with intellectual disability or developmental delay (ID/DD) develop hypokinetic MD between 10 and 30 years of age, following unspecific, usually well-controlled, childhood epilepsy. This emerging group of genetic conditions leading to epilepsy or DE-EE in childhood followed by juvenile Parkinsonism highlights the need for careful long-term follow-up, especially in the context of ID/DD, in order to readily identify individuals at increased risk of later Parkinsonism. Full article

Neurodevelopmental disorders are associated with metabolic pathway imbalances; however, most metabolic measurements are made peripherally, leaving central metabolic disturbances under-investigated. Cerebrospinal fluid obtained intraoperatively from children with autism spectrum disorder (ASD, n = 34), developmental delays (DD, n = 20), and those without known DD/ASD (n = 34) was analyzed using large-scale targeted mass spectrometry. Eighteen also had epilepsy (EPI). Metabolites significantly related to ASD, DD and EPI were identified by linear models and entered into metabolite–metabolite network pathway analysis. Common disrupted pathways were analyzed for each group of interest. Central metabolites most involved in metabolic pathways were L-cysteine, adenine, and dodecanoic acid for ASD; nicotinamide adenine dinucleotide phosphate, L-aspartic acid, and glycine for EPI; and adenosine triphosphate, L-glutamine, ornithine, L-arginine, L-lysine, citrulline, and L-homoserine for DD. Amino acid and energy metabolism pathways were most disrupted in all disorders, but the source of the disruption was different for each disorder. Disruption in vitamin and one-carbon metabolism was associated with DD and EPI, lipid pathway disruption was associated with EPI and redox metabolism disruption was related to ASD. Two microbiome metabolites were also detected in the CSF: shikimic and cis-cis-muconic acid. Overall, this study provides increased insight into unique metabolic disruptions in distinct but overlapping neurodevelopmental disorders. Full article

The Child Behavior Checklist 1.5–5 (CBCL 1.5–5) is applied to identify emotional and behavioral problems on children with developmental disabilities (e.g., autism spectrum disorder [ASD] and developmental delays [DD]). To understand whether there are variations between these two groups on CBCL DSM-oriented scales, we took two invariance analyses on 443 children (228 children with ASD). The first analysis used measurement invariance and multiple-group factor analysis on the test structure. The second analysis used item-level analysis, i.e., differential item functioning (DIF), to discover whether group memberships responded differently on some items even though underlying trait levels were the same. It was discovered that, on the test structure, the Anxiety Problems scale did not achieve metric invariance. The other scales achieved metric invariance; DIF analyses further revealed that there were items that functioned differently across subscales. These DIF items were mostly about children’s reactions to the surrounding environment. Our findings provide implications for clinicians to use CBCL DSM-oriented scales on differentiating children with ASD and children with DD. In addition, researchers need to be mindful about how items were responded differently, even though there were no mean differences on the surface. Full article

Neurodiagnostic investigation requirements are expanding for diagnostic and therapeutic purposes in children, especially in those with developmental delay/intellectual disability (DD/ID). Thus, determination of optimal sedatives to achieve successful sedation and immobility without further neurological compromise is important in children with DD/ID. The purpose of this study is to assess the effectiveness and adverse reactions of chloral hydrate (CH) for brain magnetic resonance imaging (B-MRI) in children with DD/ID compared to those with normal intelligence (NI). We performed a retrospective chart review of children aged from 1 day to 12 years who required elective sedation using CH for B-MRI. About 730 cases (415 with DD/ID and 315 with NI) of CH sedation were conducted for B-MRI. Children with DD/ID showed a higher failure rate (22%) than did those with NI (6%); additional CH and prolonged sedation time were required. There was no difference in incidence of adverse reactions between DD/ID and NI groups (p = 0.338). Older or heavier children with DD/ID (p = 0.036 and p = 0.013, respectively), as well as those diagnosed with epilepsy or neuropsychiatric disorders showed higher risk of sedation failure (p < 0.001 for each). In conclusion, CH was a suboptimal sedative drug for children with DD/ID compared with those with NI. Other alternative or supplementary sedatives should be taken into consideration especially for those vulnerable groups. Full article