Search Results (99)

Background/Objectives: We aimed to report three novel MAGED2 variants associated with transient antenatal Bartter syndrome (TABS) and to summarize the prenatal and postnatal features of MAGED2-related TABS through case analysis and literature review. Methods: Three unrelated Chinese families with polyhydramnios-affected pregnancies underwent genetic testing. Clinical data, including prenatal imaging, delivery details, and postnatal outcomes were reviewed. A literature review of reported MAGED2 variants and associated phenotypes was conducted. Results: Three previously unreported MAGED2 variants were identified: two frameshift variants (c.1511del [p.Gly504Alafs*72] and c.338del [p.Pro113ArgfsTer4]) and one deletion (chrX:54,820,664–54,839,053 [GRCh37]). All fetuses presented with polyhydramnios; two were large for gestational age (LGA). Additional findings included ventriculomegaly and scrotal enlargement. Two male infants were delivered at 33 weeks following repeated amnioreduction, with transient postnatal electrolyte abnormalities and normal neurodevelopment at 3 and 4 years. One fetus with a frameshift variant died in utero at 26 + 1 weeks. A literature review of 53 cases revealed 38 distinct MAGED2 variants, predominantly null variants (65.8%). Polyhydramnios was the most consistent antenatal sign. No intellectual disability was reported in surviving individuals. Conclusions: These findings expand the MAGED2 mutational spectrum. Polyhydramnios and LGA represents the most frequent features in TABS. In fetuses presenting with early-onset severe polyhydramnios (around 19–20 weeks of gestation), particular attention should be paid to possible exon-level or partial deletions involving MAGED2 during genetic evaluation. Full article

Background: Postnatal corticosteroids (CS) improve respiratory outcomes in preterm infants, but effects on growth and neurodevelopment remain incompletely understood. Methods: This third instalment of a narrative review series builds on physiologic principles to examine systemic CS consequences. Main Findings: We explore the interplay between growth restriction, hypoxia, and neurodevelopmental vulnerability, discussing brain imaging, metabolic disruptions, and HPA axis suppression. Conclusion: This review advocates for a holistic, physiology-informed approach to optimize outcomes by integrating nutritional vulnerability with cardiorespiratory status. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by genetic heterogeneity. Post-transcriptional regulation—particularly alternative polyadenylation (APA)—plays a critical role in the pathogenesis of ASD. APA controls mRNA stability, translational efficiency, and subcellular localization through modulating the length of the 3′ untranslated region of mRNA. APA profiling can uncover functionally relevant post-transcriptional alterations often missed by conventional gene expression analyses. However, current ASD analyses still largely rely on differential gene expression or individual APA event detection, which ignores the collective explanatory power of ASD risk genes or co-dysregulated functional gene modules within specific cell types. In this study, we present an integrative computational framework that combines matrix factorization and machine learning to identify ASD-associated gene modules driven by APA and to predict cell-type-specific ASD-related cells. Applied to human brain single-nucleus RNA sequencing (snRNA-seq) data, our approach systematically uncovers APA regulatory patterns that are specific to cell type, brain region, and sex in ASD. The identified APA modules are significantly enriched in pathways related to synaptic function, neurodevelopment, and immune response, with the strongest signals observed in excitatory neurons of the prefrontal cortex. Using APA genes from these modules as features, we built a classification model that effectively distinguishes ASD cells from normal cells. Moreover, we found that integrating APA with gene expression—two complementary modalities—substantially improves prediction accuracy, underscoring APA as an independent and biologically informative regulatory layer. Our work delineates a high-resolution APA regulatory landscape in ASD, offering novel insights and potential therapeutic avenues beyond transcriptional abundance. Full article

Hippocalcin (HPCA), a neuron-enriched calcium-binding protein, plays a critical role in brain function, but its role in neural precursor cells remains unclear. N-methyl-D-aspartate (NMDA) receptors are calcium-permeable glutamate receptors essential for neurodevelopment and synaptic plasticity, and their function has been implicated in neurological conditions. In this study, we investigated the role of HPCA in regulating NMDA receptor expression and function in mouse hippocampal neural precursor cells (mHNPCs). HPCA knockdown significantly reduced the expression of NMDA receptor-related genes, including Grin2C, Shank1, Serpine2, and selectively attenuated NMDA-induced calcium signaling. Transcriptomic analysis identified ELAV-like RNA-binding protein 3 (Elavl3), a neuron-enriched factor associated with neuronal activity, as a downstream candidate affected by HPCA knockdown. Consistently, Elavl3 suppression phenocopied HPCA deficiency, resulting in impaired NMDA receptor activity and reduced neuronal differentiation. Furthermore, hippocampal HPCA knockdown in vivo led to alterations in locomotor activity, contextual memory, and affective behaviors. Taken together, these findings demonstrate that HPCA supports NMDA receptor function and neuronal development, in part through Elavl3-associated pathways, and highlight HPCA as an important regulator of hippocampal function. Full article

(1) Background: Few studies have examined gestational paraben exposure and early childhood neurodevelopment. We evaluated associations between gestational exposure to methyl, ethyl and propyl paraben and neurodevelopment via the Child Behavior Checklist (CBCL) administered at ages 2, 3, and 4 years. (2) Methods: Gestational exposures were assessed using pooled prenatal urine samples from five time points across pregnancy. CBCL outcomes included internalizing, externalizing, and sub-scale scores. Covariate-adjusted generalized linear regression was employed to assess individual paraben exposures. Mixture analysis was performed using Bayesian Kernel Machine Regression and Quantile g-computation. (3) Results: In individual paraben analyses, each paraben was associated with increased externalizing behaviors, particularly ethylparaben (age 2: β = 0.40, 95% CI = −0.02, 0.83; age 3: β = 0.42, 95% CI = −0.19, 0.01; age 4: β = 0.18, 95% CI = −0.34, 0.70), ADHD problems at age 2 (β = 0.21, 95% CI = 0.05, 0.37), and both aggressive behavior (β = 0.38, 95% CI = 0.01, 0.74) and oppositional defiant problems (β = 0.25, 95% CI = 0.09, 0.41) at age 3. All three parabens were also associated with a reduction in withdrawn symptoms for males, especially at age 2 (ethylparaben: β = −0.09, 95% CI = −0.01, 0.85; methylparaben: β = −0.20, 95% CI = −0.34, −0.05; propylparaben: β = −0.13, 95% CI = −0.24, −0.03). The parabens mixture was associated with elevated scores in multiple CBCL subscales, though only association with oppositional defiant scores at age 3 reached significance in both BKMR (change in score when all components are at 50th percentile values compared with their 75th percentile values = 0.15; 95% CI = 0.01, 0.29) and quantile g-computation (β = 0.33, 95% CI = 0.02, 0.65), driven primarily by ethylparaben. (4) Conclusions: Individual parabens and the paraben mixture showed significant association with domains of childhood neurodevelopment, with possible detriments especially evident (a) at earlier time points, (b) in male children, and (c) in terms of externalizing behaviors. Full article

Excessive right heart load imposes an acute or chronic injury on the right ventricle (RV), predisposing critically ill neonates and cardiac surgical patients to RV failure, low cardiac output syndrome, and death. Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator that improves ventilation–perfusion matching and unloads the RV without systemic hypotension; nonetheless, its application beyond established neonatal indications remains contentious. Our review synthesizes current mechanistic, translational, and clinical evidence regarding iNO use in three major settings characterized by excessive RV load: (1) neonatal pulmonary hypertension, particularly PPHN; (2) acute and chronic RV overload in older children and adults, including secondary pulmonary hypertension, acute respiratory distress syndrome (ARDS), and acute pulmonary embolism; and (3) perioperative and post-cardiopulmonary bypass (CPB) management in congenital and adult cardiac surgery. In term and near-term infants with hypoxic respiratory failure, pivotal randomized trials show that iNO consistently improves oxygenation and reduces extracorporeal membrane oxygenation (ECMO) use, but this has little effect on survival and long-term neurodevelopment. In ARDS and other adult critical-care indications, iNO provides transient improvements in gas exchange and RV performance without reducing mortality or ventilator duration, and meta-analyses signal an increased risk of acute kidney injury, particularly with prolonged use. In contrast, perioperative studies around CPB demonstrate that prophylactic postoperative iNO and intra-CPB nitric oxide administration can attenuate pulmonary hypertensive crises, facilitate separation from CPB, shorten ventilation and intensive care stay, and, in selected high-risk cohorts, may reduce cardiac surgery-associated acute kidney injury, although survival benefits remain unproven. Across these scenarios, iNO should be used judiciously and in a pathophysiology-driven manner as a time-limited, targeted adjunct to stabilize patients with documented or anticipated RV strain rather than a disease-modifying therapy. Future work should refine patient selection, timing, dosing, and weaning strategies, and define the long-term safety and cost-effectiveness of iNO within contemporary multimodal RV support pathways. Full article

Background: Preterm infants are at risk of growth faltering at term age. Our primary objective is to assess post-discharge growth patterns in these infants and investigate the association between growth faltering and neurodevelopment. Methods: We divided the sample into two groups according to growth during the initial hospital stay: infants who suffered from growth faltering (GF, loss of >1 weight z-score from birth to 36 weeks postmenstrual age, n = 115) and infants who did not suffer from GF (non-growth faltering, NGF, n = 85). Results: The NFG group weight z-score was significantly lower at 36 postmenstrual ages (PMA) compared to birth (p < 0.001), at 1-year corrected age (CA), it was significantly higher than at birth (p = 0.0026), and by 2 years CA, there were no differences compared to the birth z-scores. In the GF infants’ group, statistical differences were found at all time points. At 3 and 6 months, CA GF infants were still in weight z-score values lower than −1 point compared to the birth median value. At 12 and 24 months CA, they still had not achieved birth z-score values (p < 0.001). In the Parent Report of Children’s Abilities-Revised (PARCA), NGF infants had a higher score in the language development scale at 2 years than GF infants (88.5 [78.5; 96.5] vs. 84.5 [69.5; 91.5], p = 0.03). The Bayley-III test was available for 35 infants. We found a significant difference in motor development, with a higher score in the NGF group (94 [88; 100] vs. 85 [79; 91], p = 0.03). Conclusions: In this cohort study, GF is associated with growth differences till 2 years CA, and with lower scores in neurodevelopment assessment. Full article

Maternal exposure to infectious agents has been associated with an increased risk of mental disorders in offspring, such as autism spectrum disorder. Evidence suggests that maternal immune responses during infection can significantly impact the neurodevelopment of the offspring, potentially affecting central nervous system functions in the future. Inulin is an indigestible soluble fiber that acts as a prebiotic. It promotes the production of short-chain fatty acids, such as butyrate, which can help inhibit the production of pro-inflammatory cytokines. Thus, this study aims to investigate whether inulin treatment during pregnancy can mitigate or reduce the impact of maternal immune activation (MIA) on the neurodevelopment of the offspring. Swiss mice were used in a dose–response study to evaluate the protective effects of inulin against maternal exposure to soluble Toxoplasma gondii antigen. Adult offspring of both sexes underwent behavioral assessments, and their gut microbiota was characterized. Both males and females in the soluble T. gondii antigen (STAg) group exhibited reduced sociability, as evidenced by the three-chamber social interaction test. Moreover, co-treatment with inulin mitigated this effect. Additionally, anhedonia was observed only in female offspring from the MIA group, but treatment with 1% and 3% inulin also mitigated this effect. The analysis of fecal microbiota showed significant differences between the STAg and inulin treatments at both the family and genus levels. Therefore, inulin appears to have a potential protective effect on the neurodevelopment of the offspring exposed to maternal antigenic challenges during pregnancy mediated by offspring microbiome modulations. Full article

Tourette syndrome (TS), or Tourette’s, is a tic disorder (TD) belonging to a group of neuropsychiatric conditions marked by recurrent motor movements or vocalizations known as tics. TD, including TS, typically begins in childhood between 4 and 18 years of age and affects approximately 3% of children and adolescents. The etiology and pathogenesis of TD are multifactorial, involving genetic, immunologic, psychological, and environmental factors. Evidence suggests that neurotransmitter dysregulation, particularly within the cortical dopaminergic networks of the basal ganglia and limbic system, which support motor control and cognition, may be involved in the development of TD. Nutritional factors may modulate TD through various mechanisms, including effects on neurotransmitter synthesis and metabolism, neurodevelopment, neural architecture, and neuroimmune activity. This review integrates current evidence on the roles of vitamins D, B6, and A, as well as iron, magnesium, zinc, and copper, in TD. For each micronutrient, its physiological and neurobiological functions are discussed, along with possible mechanistic links to TD pathophysiology. Additionally, we summarize the impact of nutrient deficiencies and assess available evidence regarding their potential therapeutic potential role in TD management. Overall, this synthesis highlights how nutritional status may influence TD onset and symptom severity, suggesting that nutrient-based interventions could potentially serve as valuable adjunctive strategies in treatment. Full article

KMT2C (histone lysine N-methyltransferase 2C, also known as MML3, myeloid/lymphoid or mixed-lineage leukemia 3) is a causal gene for Kleefstra syndrome 2, a rare neurodevelopmental disorder. Recent human genetic studies have identified it as a high-risk gene for autism spectrum disorder (ASD), with 79% of patients harboring KMT2C variants having ASD. However, the causal link between KMT2C haploinsufficiency and ASD remains unclear. KMT2C/MLL3 encodes a histone methyltransferase, a core protein of the KMT2C/D COMPASS (complex proteins associated with Set1) complex, which plays fundamental roles in chromatin modification, occupancy, and gene expression. The expression of KMT2C/Kmt2c peaks during the developmental period in the human/mouse brain, which indicates the critical roles of KMT2C/Kmt2c in neurodevelopment. Here, we investigated the impact of germline Kmt2c haploinsufficiency on autism-like behavioral deficits in mice, which modeled humans carrying diverse KMT2C variants. Compared with Kmt2c^+/+ controls, Kmt2c haploinsufficiency mice had normal motor function without anxiety-like behaviors. Notably, Kmt2c haploinsufficiency mice exhibited autism-like social deficits and increased self-grooming in both males and females, which recapitulated the core phenotypes of ASD patients. Novel object recognition and spatial memory deficits were observed in male and female Kmt2c haploinsufficiency mice. This study reveals a causal link between Kmt2c haploinsufficiency and ASD-like behavioral deficits. These germline Kmt2c haploinsufficiency mice can be used for further studying the molecular mechanisms and developing therapeutic interventions for KMT2C haploinsufficiency-associated behavioral deficits. Full article

Neurodevelopmental disorders (NDDs) represent significant public health challenges due to their multifactorial etiology and clinical heterogeneity. Current treatments remain limited, highlighting the need for novel therapeutic strategies. This study aimed to identify neuroprotective natural compounds targeting NDD-associated pathways and describe an integrative computational pipeline combining in silico screening, network pharmacology, and molecular docking approaches to accelerate NDD drug discovery. An integrative computational pipeline was developed through sequential phases: (1) systematic screening of the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) for natural compounds meeting drug-likeness criteria and toxicity thresholds; (2) biological activity prediction; (3) network pharmacology analysis integrating compound targets and NDD-associated genes; (4) protein–protein interaction network construction and functional enrichment; and (5) molecular docking validation of top compounds against prioritized targets. From 2634 initial compounds, 10 met all selection criteria. Network analysis revealed significant interactions between compound targets and NDD-associated genes, with enrichment in neurodevelopment, cognition, and synaptic regulation pathways. Three key targets emerged as hubs: CSNK2B, GRIN1, and MAPK1. Molecular docking demonstrated high-affinity binding of caryophyllene oxide, linoleic acid, and tangeretin, supported by stable interactions with catalytic residues. This study identifies caryophyllene oxide, linoleic acid, and tangeretin as promising multi-target compounds for NDD intervention, with verified interactions against key neurodevelopmental targets. The integrative computational pipeline effectively bridges traditional medicine knowledge with modern drug discovery, offering a strategy to accelerate neurotherapeutic development while reducing experimental costs. These findings warrant further experimental validation of the prioritized compounds. Full article

Background/Objectives: Breastmilk offers numerous benefits for the health and development of preterm infants, while prolonged hospitalization may impair neurodevelopment. At our institution, the implementation of enhanced family-centered care (FCC) has enabled earlier discharge of preterm infants. This study aimed to assess the impact of early discharge on breastfeeding and breastmilk provision. Methods: This analysis is based on data from a prospective single-center longitudinal cohort study conducted from October 2020 to November 2023, involving six consecutive cohorts (one baseline and five intervention cohorts; n = 184). FCC was progressively enhanced across cohorts. The primary outcome of the main study was postmenstrual age (PMA) at discharge. In this secondary analysis, breastfeeding and breastmilk provision were assessed at four time points: 4 weeks postnatal age, at discharge, 4 weeks post-discharge, and at 3 months PMA. Results: From baseline to intervention cohort 5, the PMA at discharge declined significantly from 37.8 ± 2.1 to 35.7 ± 0.91 weeks (p = 0.03), while the percentage of infants necessitating home nasogastric tube feeding increased from 6.3% to 66.7% (p < 0.01). The proportion of breastmilk of daily feeding volume remained unchanged at 4 weeks postnatal age (0.66 ± 0.42 vs. 0.9 ± 0.28) and at discharge (0.6 ± 0.45 vs. 0.79 ± 0.36). At 4 weeks post-discharge, 65.8% vs. 62.5% of the infants were on partial or exclusive breastmilk (p = 0.91) feeding. Similarly, the percentage of exclusively breastfed infants at 4 weeks post-discharge (23.7% vs. 19.8%) and at 3 months PMA (20% vs. 28.6%) did not differ significantly between baseline and intervention cohort 5. Conclusions: Early discharge did not reduce breastmilk supply or exclusive breastfeeding. However, the persistently low rate of exclusive breastfeeding post-discharge highlights the need for additional support strategies during and after hospitalization. Full article

Background/Objectives: Atypical sensory processing is increasingly recognized as a transdiagnostic dimension of neurodevelopmental disorders (NDDs), with critical implications for emotional and behavioral regulation. This study aimed to identify distinct sensory profiles in preschool children with NDDs and to examine their associations with emotional–behavioral and cognitive/developmental functioning. Methods: A total of 263 children (aged 21–71 months) diagnosed with autism spectrum disorder (ASD), language disorder (LD), or other NDDs (ONDD) were recruited. Sensory processing was assessed using the SPM-P, emotional–behavioral functioning was assessed via the CBCL 1½–5, and cognitive/developmental levels were assessed through standardized instruments. Latent profile analysis (LPA) was conducted to identify sensory subtypes. Group comparisons and multinomial logistic regression were used to examine profile characteristics and predictors of profile membership. Results: Three sensory profiles emerged: (1) Multisystemic Sensory Dysfunction (20.1%), characterized by pervasive sensory and emotional difficulties, primarily observed in ASD; (2) Typical Sensory Processing (44.9%), showing normative sensory and emotional functioning, predominantly LD; and (3) Mixed Subclinical Sensory Processing (35%), with subclinical-range scores across multiple sensory and emotional domains, spanning all diagnoses. Higher cognitive functioning and fewer internalizing symptoms significantly predicted membership in the typical profile. A gradient of symptom severity was observed across profiles, with the Multisystemic group showing the most pronounced emotional–behavioral impairments. Conclusions: Distinct sensory–emotional phenotypes were identified across diagnostic categories, supporting a dimensional model of neurodevelopment. Sensory profiles were strongly associated with emotional functioning, independently of diagnostic status. Early sensory assessment may therefore offer clinically meaningful insights into emotional vulnerability and inform targeted interventions in preschool populations with NDDs. Full article

Haploinsufficiency disorders are genetic diseases caused by reduced gene expression, leading to developmental, metabolic, and tumorigenic abnormalities. The dosage-sensitive Retinoic Acid Induced 1 (RAI1) gene, located within the 17p11.2 region, is central to the core features of Smith––Magenis syndrome (SMS) and Potocki––Lupski syndrome (PTLS), caused by the reciprocal microdeletions and microduplications of this region, respectively. SMS and PTLS present contrasting phenotypes. SMS is characterized by severe neurobehavioral manifestations, sleep disturbances, and metabolic abnormalities, and PTLS shows milder features. Here, we detail the molecular functions of RAI1 in its wild-type and haploinsufficiency conditions (RAI1+/−), as studied in animal and cellular models. RAI1 acts as a transcription factor critical for neurodevelopment and synaptic plasticity, a chromatin remodeler within the Histone 3 Lysine 4 (H3K4) writer complex, and a regulator of faulty 5′-capped pre-mRNA degradation. Alterations of RAI1 functions lead to synaptic scaling and transcriptional dysregulation in neural networks. This review highlights key molecular mechanisms of RAI1, elucidating its role in the interplay between genetics and phenotypic features and summarizes innovative therapeutic approaches for SMS. These data provide a foundation for potential therapeutic strategies targeting RAI1, its mRNA products, or downstream pathways. Full article

Background/Objectives: Body composition plays a crucial role in neurodevelopment and the long-term health of preterm and term infants. Air displacement plethysmography (ADP), especially with the PEAPOD^® system, is well established in research and increasingly explored in clinical practice. Building on our team’s earlier experiences, this study aimed to (1) evaluate the safety and feasibility of ADP in preterm infants, (2) identify published clinical protocols, and (3) implement and assess a standardized routine—the Bavarian Clinical Protocol (BCP). Methods: We conducted two systematic literature reviews: one on the eligibility-to-assessment rate and safety of ADP in research contexts, and a second focusing on existing clinical protocols. In addition, we retrospectively analyzed routine ADP assessments at the NICU of Nuremberg Children’s University Hospital from January 2022 to December 2024, where the BCP had been introduced. Results: The literature review included 76 studies reporting a total of 8,317 assessments without adverse events. In experimental settings, the eligibility-to-assessment rate was 41%. We identified three published clinical protocols. Following BCP implementation, 626 of 702 eligible infants (89.1%) underwent a total of 851 ADP measurements. No adverse events were observed, and repeated assessments were integrated smoothly into clinical workflows. Conclusions: ADP can be safely and effectively incorporated into neonatal routine care. The Bavarian Clinical Protocol provides a practical framework for standardized application, improves comparability across centers, and supports the clinical use of body composition data to inform individualized nutritional strategies. Full article