Associations of inflammation related prenatal adversities with neurodevelopment of offspring in one year: a longitudinal prospective birth cohort study.

BACKGROUND: The recent Maternal Immune Activation (MIA) theory suggests maternal systemic inflammation may serve as a mediator in associations between prenatal maternal adversities and neurodevelopmental diseases in offspring. Given the co-exposure to multiple adversities may be experienced by pregnant person, it is unclear whether a quantitative index can be developed to characterize the inflammation related exposure level, and whether this index is associated with neurodevelopmental delays in offspring. METHODS: Based on Jiangsu Birth Cohort (JBC), a total of 3051 infants were included in the analysis. Inflammation related Prenatal Adversity Index (IPAI) was constructed using maternal data. Neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development, third edition, screening test in one year. Multivariate linear regression and Poisson regression model were performed to analyze the associations between IPAI and neurodevelopment in offspring. RESULTS: Compared with "low IPAI" group, offspring with "high IPAI" have lower scores of cognition, receptive communication, expressive communication, and fine motor. The adjusted ß were - 0.23 (95%CI: -0.42, -0.04), -0.47 (95%CI: -0.66, -0.28), -0.30 (95%CI: -0.49, -0.11), and - 0.20 (95%CI: -0.33, -0.06). Additionally, the elevated risk for noncompetent development of cognition and receptive communication among "high IPAI" group was observed. The relative risk [RR] and 95% confidence interval [CI] were 1.35 (1.01, 1.69) and 1.37 (1.09, 1.72). CONCLUSIONS: Our results revealed a significant association between higher IPAI and lower scores across cognition, receptive communication, expressive communication, and fine motor domains, and an increased risk of noncompetent development in the cognition and receptive communication domains.

Brain organoids: A new tool for modelling of neurodevelopmental disorders.

Neurodevelopmental disorders are mostly studied using mice as models. However, the mouse brain lacks similar cell types and structures as those of the human brain. In recent years, emergence of three-dimensional brain organoids derived from human embryonic stem cells or induced pluripotent stem cells allows for controlled monitoring and evaluation of early neurodevelopmental processes and has opened a window for studying various aspects of human brain development. However, such organoids lack original anatomical structure of the brain during maturation, and neurodevelopmental maturation processes that rely on unique cellular interactions and neural network connections are limited. Consequently, organoids are difficult to be used extensively and effectively while modelling later stages of human brain development and disease progression. To address this problem, several methods and technologies have emerged that aim to enhance the sophisticated regulation of brain organoids developmental processes through bioengineering approaches, which may alleviate some of the current limitations. This review discusses recent advances and application areas of human brain organoid culture methods, aiming to generalize optimization strategies for organoid systems, improve the ability to mimic human brain development, and enhance the application value of organoids.

Lipophilic compounds restore function to neurodevelopmental-associated KCNQ3 mutations.

A major driver of neuronal hyperexcitability is dysfunction of K+ channels, including voltage-gated KCNQ2/3 channels. Their hyperpolarized midpoint of activation and slow activation and deactivation kinetics produce a current that regulates membrane potential and impedes repetitive firing. Inherited mutations in KCNQ2 and KCNQ3 are linked to a wide spectrum of neurodevelopmental disorders (NDDs), ranging from benign familial neonatal seizures to severe epileptic encephalopathies and autism spectrum disorders. However, the impact of these variants on the molecular mechanisms underlying KCNQ3 channel function remains poorly understood and existing treatments have significant side effects. Here, we use voltage clamp fluorometry, molecular dynamic simulations, and electrophysiology to investigate NDD-associated variants in KCNQ3 channels. We identified two distinctive mechanisms by which loss- and gain-of function NDD-associated mutations in KCNQ3 affect channel gating: one directly affects S4 movement while the other changes S4-to-pore coupling. MD simulations and electrophysiology revealed that polyunsaturated fatty acids (PUFAs) primarily target the voltage-sensing domain in its activated conformation and form a weaker interaction with the channel's pore. Consistently, two such compounds yielded partial and complete functional restoration in R227Q- and R236C-containing channels, respectively. Our results reveal the potential of PUFAs to be developed into therapies for diverse KCNQ3-based channelopathies.

Trends in Body Mass Index Among Individuals With Neurodevelopmental Disorders.

Importance: Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are increasingly common. Individuals with NDDs have heightened obesity risks, but long-term data on body mass index (BMI) trends over time in this population are lacking. Objective: To assess secular BMI changes from 2004 to 2020 among children with NDDs compared with those without NDDs. Design, Setting, and Participants: This repeated cross-sectional study used data from the Child and Adolescent Twin Study in Sweden. Children born between January 1, 1992, and December 31, 2010, were screened for neurodevelopmental symptoms using the Autism-Tics, ADHD, and Other Comorbidities inventory between July 2004 and April 2020 when they were 9 or 12 years of age. Data analysis was conducted between September 27, 2023, and January 30, 2024. Main Outcomes and Measures: BMI percentiles (15th, 50th, and 85th) were modeled using quantile regression and compared between youths with and without NDDs. Secular changes in BMI percentiles over time spanning 2004 to 2020 were evaluated and stratified by NDD subtype. Results: The cohort included 24 969 Swedish twins (12 681 [51%] boys) born between 1992 and 2010, with mean (SD) age of 9 (0.6) years. Of these, 1103 (4%) screened positive for 1 or more NDDs, including ADHD, ASD, and/or learning disability. Results indicated that at the 85th BMI percentile, there was a greater increase in BMI from 2004 to 2020 among youths with NDDs compared with those without NDDs (ß for interaction [ßint] between NDD status and time, 1.67; 95% CI, 0.39-2.90). The greatest divergence was seen for ASD (ßint, 2.12; 95% CI, 1.26-3.70) and learning disability (ßint, 1.92; 95% CI, 0.65-3.82). Within the latest cohort (2016-2020), the 85th BMI percentile was 1.99 (95% CI, 1.08-2.89) points higher among children with NDDs compared with those without NDDs. Conclusions and Relevance: In this repeated cross-sectional study, at the higher end of the BMI distribution, children with NDDs had significantly greater increases in BMI compared with peers without NDDs over a 16-year period, highlighting an increasing risk of overweight over time in youths with NDDs compared with those without NDDs. Targeted obesity prevention efforts for this high-risk population are needed.

Neurological outcomes in neonates treated with therapeutic hypothermia: challenges in a developing country.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) affects 1.5 newborns per 1 thousand term live births. Therapeutic hypothermia (TH) does not prevent all adverse outcomes. The experience with TH is still limited in Latin America. In Rio de Janeiro, Hospital Universitário Pedro Ernesto treats neonates with HIE since 2017 using the servo-controlled system. OBJECTIVE: To describe the frequency of epilepsy, altered neurological exam, and neurodevelopmental delay at 12 months of age in patients treated with TH in a reference hospital in Rio de Janeiro and to evaluate the possible risk associations with clinical data and data from complementary exams. METHODS: We evaluated medical records from the Neonatal Intensive Care Unit hospitalization and from first evaluation recorded at 12 months of age in the High-Risk Neonate Follow-up Outpatient Sevice. RESULTS: A total of 30 subjects were included in the study. We found epilepsy in 18.2% of the patients, altered neurological exam in 40.9%, and neurodevelopmental delay in 36.4%. We also found a significant relationship between altered magnetic resonance imaging scan and subsequent altered neurological exam. Our findings are in line with those of the international literature, which shows that adverse outcomes are still observed, even when TH is applied. Brazilian data shows our limited access to complementary exams. The rate of loss to follow-up was of 26.6%, probably due to the coronavirus disease 2019 (COVID-19) pandemic and to unfavorable socioeconomic conditions. More time for prospective follow-up and protocol adjustments should contribute to improve our data. CONCLUSION: High incidences of epilepsy, altered neurological exams, and neurodevelopmental delay were found, despite the use of TH. A more efficient use of resources is needed, as well as measures such as early intervention.

ANTECEDENTES: A encefalopatia hipóxico-isquêmica (EHI) afeta 1,5 a cada mil nascidos vivos a termo. A hipotermia terapêutica (HT) não previne todos os desfechos negativos. A experiência com HT ainda é limitada na América Latina. No Rio de Janeiro, o Hospital Universitário Pedro Ernesto trata neonatos com EHI desde 2017 usando o sistema servo-controlado. OBJETIVO: Relatar a frequência de epilepsia, de alteração em exame neurológico e de atraso no desenvolvimento neuropsicomotor aos 12 meses de idade nos pacientes submetidos a HT em um hospital de referência no estado do Rio de Janeiro e avaliar as associações de risco com dados clínicos e de exames complementares. MéTODOS: Foi feita análise de dados do prontuário médico da internação na UTI Neonatal e da primeira avaliação registrada a partir de 12 meses completos de idade no Ambulatório de Seguimento de Recém-Nascido de Alto Risco. RESULTADOS: Ao todo, 30 pacientes foram incluídos. As frequências de epilepsia, de alteração em exame neurológico e de atraso no desenvolvimento neuropsicomotor aos 12 meses de idade foram, respectivamente, de 18,2%, 40,9% e 36,4%. Observamos relação significativa entre alteração na ressonância magnética e posterior alteração no exame neurológico. Nossos achados corroboram a literatura internacional, em que desfechos desfavoráveis ocorrem mesmo aplicando-se HT. Dados brasileiros mostram a limitação da disponibilidade dos exames complementares. Houve perda de seguimento de 26,6%, provavelmente pela pandemia da doença do coronavírus 2019 (coronavirus disease 2019, COVID-19, em inglês) e condições socioeconômicas desfavoráveis. Mais tempo de seguimento e ajustes no protocolo devem contribuir para melhorar nossos dados. CONCLUSãO: Foram encontradas elevadas incidências de epilepsia, de exame neurológico alterado e de atraso no neurodesenvolvimento, apesar da HT. Faz-se necessário uso mais eficiente dos recursos disponíveis, bem como de medidas como intervenção precoce.

Insight into the Association between Slitrk Protein and Neurodevelopmental and Neuropsychiatric Conditions.

Slitrk proteins belong the leucine-rich repeat transmembrane family and share structural similarities with the Slits and tropomyosin receptor kinase families, which regulate the development of the nervous system. Slitrks are highly expressed in the developing nervous system of vertebrates, modulating neurite outgrowth and enhancing synaptogenesis; however, the expression and function of Slitrk protein members differ. Slitrk protein variations have been associated with various sensory and neuropsychiatric conditions, including myopia, deafness, obsessive-compulsive disorder, autism spectrum disorders, schizophrenia, attention-deficit/hyperactivity disorder, glioma, and Tourette syndrome; however, the underlying mechanism remains unclear. Therefore, the Slitrk family members' protein expression, roles in the signaling cascade, functions, and gene mutations need to be comprehensively studied to develop therapeutics against neurodegenerative diseases. This study presents complete and pertinent information demonstrating the relationship between Slitrk family proteins and neuropsychiatric illnesses. This review briefly discusses neurodevelopmental disorders, the leucine-rich repeat family, the Slitrk family, and the association of Slitrk with the neuropathology of representative disorders.

Altered molecular and cellular mechanisms in KIF5A-associated neurodegenerative or neurodevelopmental disorders.

Mutations targeting distinct domains of the neuron-specific kinesin KIF5A associate with different neurodegenerative/neurodevelopmental disorders, but the molecular bases of this clinical heterogeneity are unknown. We characterised five key mutants covering the whole spectrum of KIF5A-related phenotypes: spastic paraplegia (SPG, R17Q and R280C), Charcot-Marie-Tooth disease (CMT, R864*), amyotrophic lateral sclerosis (ALS, N999Vfs*40), and neonatal intractable myoclonus (NEIMY, C975Vfs*73) KIF5A mutants. CMT-R864*-KIF5A and ALS-N999Vfs*40-KIF5A showed impaired autoinhibition and peripheral localisation accompanied by altered mitochondrial distribution, suggesting transport competence disruption. ALS-N999Vfs*40-KIF5A formed SQSTM1/p62-positive inclusions sequestering WT-KIF5A, indicating a gain of toxic function. SPG-R17Q-KIF5A and ALS-N999Vfs*40-KIF5A evidenced a shorter half-life compared to WT-KIF5A, and proteasomal blockage determined their accumulation into detergent-insoluble inclusions. Interestingly, SPG-R280C-KIF5A and ALS-N999Vfs*40-KIF5A both competed for degradation with proteasomal substrates. Finally, NEIMY-C975Vfs*73-KIF5A displayed a similar, but more severe aberrant behaviour compared to ALS-N999Vfs*40-KIF5A; these two mutants share an abnormal tail but cause disorders on the opposite end of KIF5A-linked phenotypic spectrum. Thus, our observations support the pathogenicity of novel KIF5A mutants, highlight abnormalities of recurrent variants, and demonstrate that both unique and shared mechanisms underpin KIF5A-related diseases.

Postnatal weight loss and neurodevelopmental outcomes at age 3 years in extremely preterm infants: a cohort study.

BACKGROUND: Previous research has suggested a correlation between postnatal maximum weight loss (MWL) and both neonatal mortality and morbidities in extremely preterm infants. However, the relationship between MWL and neurodevelopmental outcomes remains underexplored. METHODS: In a single-center, retrospective cohort study at Okayama Medical Center, we evaluated data from extremely preterm infants admitted to the neonatal intensive care unit from 2010 to 2020. Infants who died within the first 10 days of life were excluded. MWL in the first 10 days was the main exposure, categorized into three groups: >15%, 5-15%, and < 5%. The primary outcome evaluated was the occurrence of death or neurodevelopmental impairment (NDI) at age 3 years, defined as developmental impairments (developmental quotient [DQ] < 85), cerebral palsy, hearing impairments, or visual impairments. Data analysis involved robust Poisson regression, adjusted for perinatal confounders, with a restricted cubic spline function to examine the dose-response relationship. We also conducted a sensitivity analysis using a DQ of < 70 to define developmental impairment. RESULTS: Among 135 infants assessed for neurodevelopmental outcomes, 40 were in the > 15% MWL group, 71 in the 5-15% group, and 24 in the < 5% group. Median gestational ages and birth weights were 25.9 weeks and 821 g for > 15% MWL; 26.1 weeks and 818 g for 5-15% MWL; and 26.0 weeks and 734 g for < 5% MWL. Compared with the 5-15% MWL group, the < 5% group exhibited a higher risk of death or NDI at age 3 years (62.8% vs. 80.8%, risk ratio [RR] 1.36, 95% confidence interval [CI] 1.04-1.79) and NDI alone (59.2% vs. 79.2%, RR 1.43, 95% CI 1.06-1.94). Furthermore, higher risks of developmental impairment were also noted in the > 15% (RR 1.32, 95% CI 1.00-1.75) and < 5% (RR 1.46, 95% CI 1.08-1.98) groups. These associations were confirmed by spline analyses. In contrast, the associations between MWL and neurodevelopmental outcomes using a DQ of < 70 were not apparent. CONCLUSIONS: MWL within the first 10 days of life may be associated with increased risks of NDI and developmental impairments by age 3 years in extremely preterm infants.

Risk of alterations in neurodevelopment in infants and preschool children with cancer.

BACKGROUND: Some cancer survivors experience difficulties with concentration, attention, and memory; however, there are no studies on neurodevelopment in patients under 5 years of age who are undergoing cancer treatment. Our aim was to evaluate neurodevelopment in cancer patients under 5 years of age using the Early Development Instrument (EDI) test, considering factors such as nutritional status, type of cancer, and treatment effect. METHODS: A cross-sectional study was conducted from February 2018 to March 2019. Patients with cancer diagnoses outside the central nervous system in any phase of cancer treatment were included. RESULTS: A total of 45 patients were included. Regarding fine motor skills, 28% of patients with retinoblastoma and 23% of patients with leukemia or lymphoma had a risk of developmental delay compared to 0% of patients with solid tumors (p = 0.025). The final results showed that 19 (42.2%) patients had normal neurodevelopment (gray), 7 (15.5%) had a delay in neurodevelopment (light gray), and 19 (42.2%) had a risk of developmental delay (black). Regarding developmental delay, 52% of patients in the leukemia and lymphoma group, 71% in the retinoblastoma group, and 23% in the solid tumor group presented developmental delay (p = 0.06). CONCLUSIONS: The risk of delay and lag in neurodevelopment is common in cancer patients under 5 years of age undergoing treatment. However, more studies are required to evaluate the effect of treatment on this group of patients as it may be affected by various factors.

INTRODUCCIÓN: En algunos pacientes supervivientes de cáncer se presentan dificultades de concentración, atención y memoria, sin embargo no hay estudios en relación al neurodesarrollo en pacientes menores de 5 años que se encuentran en tratamiento oncológico. Por lo que el objetivo fue valorar el neurodesarrollo en pacientes con cáncer durante el tratamiento oncológico mediante la prueba EDI tomando en cuenta diversos factores como su estado nutricional, tipo de cancer, y el efecto del tratamiento. MÉTODOS: Se realizó un estudio transversal, de febrero de 2018 a marzo de 2019. Se incluyeron pacientes mayores de 1 año y menores de 5 años con diagnóstico de cáncer fuera del sistema nervioso central, en tratamiento oncológico. RESULTADOS: Se incluyeron 45 pacientes. En el área motor fina el 28% de los pacientes con retinoblastoma y 23% con leucemias y linfomas se encontraron en rojo (retraso) en comparación con 0% de los pacientes con tumores sólidos (p = 0.025). En el resultado global se encontró que 19 (42.2%) pacientes tuvieron neurodesarrollo normal (gris), 7 (15.5%) rezago en el neurodesarrollo (gris claro) y 19 (42.2%) con riesgo de retraso en el desarrollo (negro). De los pacientes que presentaron riesgo de retraso el 52% fueron del grupo de leucemias y linfomas, el 71% en el grupo de retinoblastoma y el 23% del grupo de tumores sólidos (p = 0.06). CONCLUSIONES: La presencia de riesgo de retraso y rezago en el neurodesarrollo es frecuente en menores de 5 años con diagnóstico de cáncer. Se requieren más estudios, para evaluar el efecto del tratamiento en este grupo de pacientes, ya que pueden influir diversos factores.

[The contribution of cerebral organoids to the understanding and treatment of rare genetic diseases with neurodevelopmental disorders]. / Des organoïdes cérébraux pour la compréhension et la thérapie des maladies génétiques rares avec troubles neurodéveloppementaux.

Rare genetic diseases with neurodevelopmental disorders (NDDs) encompass several heterogeneous conditions (autism spectrum disorder (ASD), intellectual disability (ID), attention deficit hyperactivity disorder (ADHD), specific learning disorder (SLD), among others). Currently, few treatments are available for these patients. The difficulty in accessing human brain samples and the discrepancies between human and animal models highlight the need for new research approaches. One promising approach is the use of the cerebral organoids. These 3D, self-organized structures, generated from induced pluripotent stem cells (iPSCs), enable the reproduction of the stages of human brain development, from the proliferation of neural stem cells to their differentiation into neurons, oligodentrocytes, and astrocytes. Cerebral organoids hold great promise in understanding brain development and in the search for treatments.

Title: Des organoïdes cérébraux pour la compréhension et la thérapie des maladies génétiques rares avec troubles neurodéveloppementaux. Abstract: Les maladies génétiques associées à des troubles neurodéveloppementaux (TND) regroupent plusieurs maladies pour lesquelles peu de traitements sont proposés. L'impossibilité d'accéder à des échantillons de cerveaux humains pour des études ex vivo, et les divergences entre l'homme et les modèles animaux rendent nécessaires de nouvelles approches de recherche. L'organoïde cérébral, une structure en trois dimensions, auto-organisée, et générée à partir de cellules souches pluripotentes induites, permet de reproduire les étapes de développement du cerveau humain, de la prolifération des cellules souches neurales à leur différenciation en neurones, en oligodendrocytes, ou en astrocytes. L'intérêt de ce modèle est désormais prouvé pour la compréhension du développement cérébral et pour la recherche de traitements. Après une présentation des cellules souches pluripotentes induites et des organoïdes, nous exposerons comment cette technique est actuellement déployée, en particulier pour étudier les mécanismes physiopathologiques résultant de variations génétiques pathogènes de gènes candidats de TND.

Effect of per- and polyfluoroalkyl substances on neurodevelopment: Evidence-based risk assessment in the TRAEC strategy context.

Although emerging evidence on the association between per- and polyfluoroalkyl substances (PFASs) and neurodevelopment have been investigated, there is no consensus on the effect of maternal PFASs on neurodevelopment in offspring. Here, we assessed the risk of maternal PFASs exposure on the neurodevelopment of offspring using a novel Targeted Risk Assessment of Environmental Chemicals (TRAEC) strategy based on multiple evidence. The evidence from five online databases were analyzed the effect of PFASs on neurodevelopment. The potential neurodevelopment risk of PFASs was evaluated by the TRAEC strategy, which was conducted on a comprehensive scoring system with reliability, correlation, outcome fitness and integrity. The studies from five databases and additional researchers' experiments were included the present study to proceed following risk assessment. Based on the framework with TRAEC strategy, the comprehensive evaluation of health risks was classified as low (absolute value 0-4), medium (absolute value 4-8), high (absolute value 8-10). In the present study, the effect of PFASs exposure on neurodevelopment was a medium-risk level with 5.61 overall risk-score. The population-attributable risk (PAR) was 8.26 % for maternal PFASs exposure. The study identified a low-risk effect of prenatal PFASs exposure on ASD and behavioral disabilities. The chain length, type of PFASs and neurodevelopmental trajectories contributed to the risk of maternal PFASs on the neurodevelopment of offspring. Consistent with results of four criteria-based tools (ToxRTool, SciRAP, OHAT and IRIS), health risk assessment based on the TRAEC strategy demonstrated robustness and reliability in the present study. These results illustrated a medium-risk effect of maternal PFASs exposure on neurodevelopmental disorders of offspring. In addition, the TRAEC strategy provided a scientific and structured method for effect evaluation between prenatal PFASs and neurodevelopmental disorders, promoting the consistency and validation in risk assessment.

Preterm birth as a determinant of neurodevelopment and cognition in children (PRENCOG): protocol for an exposure-based cohort study in the UK.

INTRODUCTION: Preterm birth (PTB) is strongly associated with encephalopathy of prematurity (EoP) and neurocognitive impairment. The biological axes linking PTB with atypical brain development are uncertain. We aim to elucidate the roles of neuroendocrine stress activation and immune dysregulation in linking PTB with EoP. METHODS AND ANALYSIS: PRENCOG (PREterm birth as a determinant of Neurodevelopment and COGnition in children: mechanisms and causal evidence) is an exposure-based cohort study at the University of Edinburgh. Three hundred mother-infant dyads comprising 200 preterm births (gestational age, GA <32 weeks, exposed) and 100 term births (GA >37 weeks, non-exposed), will be recruited between January 2023 and December 2027. We will collect parental and infant medical, demographic, socioeconomic characteristics and biological data which include placental tissue, umbilical cord blood, maternal and infant hair, infant saliva, infant dried blood spots, faecal material, and structural and diffusion MRI. Infant biosamples will be collected between birth and 44 weeks GA.EoP will be characterised by MRI using morphometric similarity networks (MSNs), hierarchical complexity (HC) and magnetisation transfer saturation imaging (MTsat). We will conduct: first, multivariable regressions and statistical association assessments to test how PTB-associated risk factors (PTB-RFs) relate to MSNs, HC and or MTsat; second, structural equation modelling to investigate neuroendocrine stress activation and immune dysregulation as mediators of PTB-RFs on features of EoP. PTB-RF selection will be informed by the variables that predict real-world educational outcomes, ascertained by linking the UK National Neonatal Research Database with the National Pupil Database. ETHICS AND DISSEMINATION: A favourable ethical opinion has been given by the South East Scotland Research Ethics Committee 02 (23/SS/0067) and NHS Lothian Research and Development (2023/0150). Results will be reported to the Medical Research Council, in scientific media, via stakeholder partners and on a website in accessible language (https://www.ed.ac.uk/centre-reproductive-health/prencog).

Association of Postnatal Opioid Exposure and 2-Year Neurodevelopmental Outcomes in Infants Undergoing Cardiac Surgery.

BACKGROUND: Opioids are commonly used to provide analgesia during and after congenital heart surgery. The effects of exposure to opioids on neurodevelopment in neonates and infants are not well understood. OBJECTIVES: This study sought to evaluate the associations between cumulative opioid exposure (measured in morphine mg equivalent) over the first year of life and 2-year neurodevelopmental outcomes (Bayley Scales of Infant and Toddler Development-Third/Fourth Edition [Bayley-III/IV] cognitive, language, and motor scores). METHODS: A single-center retrospective cohort study of infants undergoing congenital heart surgery was performed. Adjustment for measurable confounders was performed through multivariable linear regression. RESULTS: A total of 526 subjects were studied, of whom 32% underwent Society for Thoracic Surgeons-European Association for Cardio-Thoracic Surgery category 4 or 5 operations. In unadjusted analyses, higher total exposure to opioids was associated with worse scores across all 3 Bayley-III/IV domain scores (all P < 0.05). After adjustment for measured confounders, greater opioid exposure was associated with lower Bayley-III/IV scores (cognitive: ß = -1.0 per log-transformed morphine mg equivalents, P = 0.04; language: ß = -1.2, P = 0.04; and motor: ß = -1.1, P = 0.02). Total hospital length of stay, prematurity, genetic syndromes, and worse neighborhood socioeconomic status (represented either by Social Vulnerability Index or Childhood Opportunity Index) were all associated with worse Bayley-III/IV scores across all domains (all P < 0.05). CONCLUSIONS: Greater postnatal exposure to opioids was associated with worse neurodevelopmental outcomes across cognitive, language, and motor domains, independent of other less modifiable factors. This finding should motivate research and efforts to explore reduction in opioid exposure while preserving quality cardiac intensive care.

Helsmoortel-Van der Aa syndrome in a 13-year-old girl with autistic spectrum disorder, dysmorphism, a right solitary kidney, and polycystic ovaries: a case report.

BACKGROUND: Helsmoortel-Van der Aa syndrome was officially documented in 2014. Helsmoortel-Van der Aa syndrome is an extremely rare complex neurodegenerative disorder characterized by reduced intellectual capacity, motor dysfunction, facial dysmorphism, impaired development, and an increased predisposition to autism spectrum disorder. In addition, many patients also present with neuropsychiatric disorders, including attention deficit hyperactivity disorder, anxiety disorders, and various behavioral abnormalities. Helsmoortel-Van der Aa syndrome is challenging to identify solely on the basis of symptoms, and genetic investigations, including exome sequencing, may facilitate diagnosis. CASE PRESENTATION: We report a case of 13-year-old Saudi patient who presented with dysmorphic features as illustrated in Fig. 1, severe mental retardation, autism spectrum disorder, and attention deficit hyperactivity disorder. Initial genetic testing was unremarkable; thus, a clinical exome analysis was performed to identify the genetic basis of the condition. CONCLUSIONS: Clinical exome analysis indicated an autosomal dominant Helsmoortel-Van der Aa syndrome with a likely pathogenic de novo variant within the activity-dependent neuroprotector homeobox (ADNP) gene not previously reported in Helsmoortel-Van der Aa syndrome. The patient had a right-sided solitary kidney and polycystic ovaries, conditions that were not previously associated with HVDAS.

A Humanized Yeast Model for Studying TRAPP Complex Mutations; Proof-of-Concept Using Variants from an Individual with a TRAPPC1-Associated Neurodevelopmental Syndrome.

Variants in membrane trafficking proteins are known to cause rare disorders with severe symptoms. The highly conserved transport protein particle (TRAPP) complexes are key membrane trafficking regulators that are also involved in autophagy. Pathogenic genetic variants in specific TRAPP subunits are linked to neurological disorders, muscular dystrophies, and skeletal dysplasias. Characterizing these variants and their phenotypes is important for understanding the general and specialized roles of TRAPP subunits as well as for patient diagnosis. Patient-derived cells are not always available, which poses a limitation for the study of these diseases. Therefore, other systems, like the yeast Saccharomyces cerevisiae, can be used to dissect the mechanisms at the intracellular level underlying these disorders. The development of CRISPR/Cas9 technology in yeast has enabled a scar-less editing method that creates an efficient humanized yeast model. In this study, core yeast subunits were humanized by replacing them with their human orthologs, and TRAPPC1, TRAPPC2, TRAPPC2L, TRAPPC6A, and TRAPPC6B were found to successfully replace their yeast counterparts. This system was used for studying the first reported individual with an autosomal recessive disorder caused by biallelic TRAPPC1 variants, a girl with a severe neurodevelopmental disorder and myopathy. We show that the maternal variant (TRAPPC1 p.(Val121Alafs*3)) is non-functional while the paternal variant (TRAPPC1 p.(His22_Lys24del)) is conditional-lethal and affects secretion and non-selective autophagy in yeast. This parallels defects seen in fibroblasts derived from this individual which also showed membrane trafficking defects and altered Golgi morphology, all of which were rescued in the human system by wild-type TRAPPC1. This study suggests that humanized yeast can be an efficient means to study TRAPP subunit variants in the absence of human cells and can assign significance to variants of unknown significance (VUS). This study lays the foundation for characterizing further TRAPP variants through this system, rapidly contributing to disease diagnosis.

Genetic and Environmental Factors Co-Contributing to Behavioral Abnormalities in adnp/adnp2 Mutant Zebrafish.

Human mutations of ADNP and ADNP2 are known to be associated with neural developmental disorders (NDDs), including autism spectrum disorders (ASDs) and schizophrenia (SZ). However, the underlying mechanisms remain elusive. In this study, using CRISPR/Cas9 gene editing technology, we generated adnp and adnp2 mutant zebrafish models, which exhibited developmental delays, brain deficits, and core behavioral features of NDDs. RNA sequencing analysis of adnpa-/-; adnpb-/- and adnp2a-/-; adnp2b-/- larval brains revealed altered gene expression profiles affecting synaptic transmission, autophagy, apoptosis, microtubule dynamics, hormone signaling, and circadian rhythm regulation. Validation using whole-mount in situ hybridization (WISH) and real-time quantitative PCR (qRT-PCR) corroborated these findings, supporting the RNA-seq results. Additionally, loss of adnp and adnp2 resulted in significant downregulation of pan-neuronal HuC and neuronal fiber network α-Tubulin signals. Importantly, prolonged low-dose exposure to environmental endocrine disruptors (EEDs) aggravated behavioral abnormalities in adnp and adnp2 mutants. This comprehensive approach enhances our understanding of the complex interplay between genetic mutations and environmental factors in NDDs. Our findings provide novel insights and experimental foundations into the roles of adnp and adnp2 in neurodevelopment and behavioral regulation, offering a framework for future preclinical drug screening aimed at elucidating the pathogenesis of NDDs and related conditions.

High Diagnostic Yield and Clinical Utility of Next-Generation Sequencing in Children with Epilepsy and Neurodevelopmental Delays: A Retrospective Study.

Advances in genetics led to the identification of hundreds of epilepsy-related genes, some of which are treatable with etiology-specific interventions. However, the diagnostic yield of next-generation sequencing (NGS) in unexplained epilepsy is highly variable (10-50%). We sought to determine the diagnostic yield and clinical utility of NGS in children with unexplained epilepsy that is accompanied by neurodevelopmental delays and/or is medically intractable. A 5-year retrospective review was conducted at the American University of Beirut Medical Center to identify children who underwent whole exome sequencing (WES) or whole genome sequencing (WGS). Data on patient demographics, neurodevelopment, seizures, and treatments were collected. Forty-nine children underwent NGS with an overall diagnostic rate of 68.9% (27/38 for WES, and 4/7 for WGS). Most children (42) had neurodevelopmental delays with (18) or without (24) refractory epilepsy, and only three had refractory epilepsy without delays. The diagnostic yield was 77.8% in consanguineous families (18), and 61.5% in non-consanguineous families (26); consanguinity information was not available for one family. Genetic test results led to anti-seizure medication optimization or dietary therapies in six children, with subsequent improvements in seizure control and neurodevelopmental trajectories. Not only is the diagnostic rate of NGS high in children with unexplained epilepsy and neurodevelopmental delays, but also genetic testing in this population may often lead to potentially life-altering interventions.

Psychiatric phenotype in neurodevelopmental myoclonus-dystonia is underpinned by abnormality of cerebellar modulation on the cerebral cortex.

Psychiatric symptoms are common in neurodevelopmental movement disorders, including some types of dystonia. However, research has mainly focused on motor manifestations and underlying circuits. Myoclonus-dystonia is a rare and homogeneous neurodevelopmental condition serving as an illustrative paradigm of childhood-onset dystonias, associated with psychiatric symptoms. Here, we assessed the prevalence of psychiatric disorders and the severity of depressive symptoms in patients with myoclonus-dystonia and healthy volunteers (HV). Using resting-state functional neuroimaging, we compared the effective connectivity within and among non-motor and motor brain networks between patients and HV. We further explored the hierarchical organization of these networks and examined the relationship between their connectivity and the depressive symptoms. Comparing 19 patients to 25 HV, we found a higher prevalence of anxiety disorders and more depressive symptoms in the patient group. Patients exhibited abnormal modulation of the cerebellum on the cerebral cortex in the sensorimotor, dorsal attention, salience, and default mode networks. Moreover, the salience network activity was directed by the cerebellum in patients and was related to depressive symptoms. Altogether, our findings highlight the role of the cerebellar drive on both motor and non-motor cortical areas in this disorder, suggesting cerebellar involvement in the complex phenotype of such neurodevelopmental movement disorders.

A Novel De Novo STAG1 Variant in Monozygotic Twins with Neurodevelopmental Disorder: New Insights in Clinical Heterogeneity.

BACKGROUND: The STAG1 gene encodes a component of the cohesin complex, involved in chromosome segregation and DNA repair. Variants in genes of the cohesin complex determine clinical conditions characterized by facial dysmorphisms, upper limb anomalies, intellectual disability, and other neurological deficits. However, to date, the STAG1-related clinical phenotype has been poorly investigated (around 20 cases reported). METHODS AND RESULTS: We report, for the first time, two twins affected by a syndromic neurodevelopmental disorder associated with a de novo variant in the STAG1 gene. Although both the twins showed a neurodevelopmental delay, one of them showed a more severe phenotype with greater behavioral problems, speech defects and limb apraxia. CGH array showed a 15q13.3 microduplication, inherited from an unaffected mother. CONCLUSIONS: We found different degrees of behavioral, speech and cognitive impairment in two twins affected by a neurodevelopmental disorder associated with a STAG1 variant. These findings highlight the variability of the STAG1-associated phenotype or a probable role of associated variants (like the discovered 15q13.3 microduplication) in modulating the clinical features.