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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.

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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.

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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.

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BACKGROUND: Structural variations (SVs) are key genetic contributors to neurodevelopmental disorders (NDDs). Exome sequencing (ES), the current first-line tool for genetic testing of NDDs, falls short in SVs detection. This diagnostic gap is being actively addressed by new methods such as optical genome mapping (OGM). METHODS: This study evaluated the utility of combining OGM and RNA-seq in the detection and interpretation of SVs in ES-negative NDDs. OGM was performed in 43 patients with NDDs with inconclusive ES results. Candidate SVs were selected based on disease association and pathogenicity evaluation, and further validated or reconstructed by alternative methods, including long-read sequencing for a complex rearrangement event. RNA-Seq was performed on blood samples from patients with candidate SVs to facilitate interpretation of pathogenicity. RESULTS: OGM detected four candidate SVs, and RNA-seq confirmed the pathogenicity of three SVs in the patient cohort. This combined approach solved three cases-two cases with de novo SVs in genes associated with autosomal dominant NDDs, including a deletion encompassing the promoter and 5'UTR of MBD5 and an intragenic duplication of PAFAH1B1, and a third case possessing an intragenic duplication in trans with a pathogenic single-nucleotide variant of PLA2G6, associated with autosomal recessive NDDs. The expression alteration of the affected genes and the tandem positioning of two intragenic duplications were confirmed by RNA-seq. In the fourth case, OGM detected a complex rearrangement involving chromosomes 2 and 6, much more complex than the de novo t(2:6)(q13;q15) indicated by conventional cytogenetic analysis. Reconstruction showed that 17 segments of 6q15 spanning 9.3 Mb were disarranged and joined 2q11.2, with four breakpoints detected in the 5' and 3' non-coding region of the NDD-associated gene SYNCRIP. RNA-seq revealed largely preserved SYNCRIP expression, leaving the pathogenicity of this complex rearrangement event uncertain. CONCLUSIONS: SVs in ES-negative NDDs can be identified by OGM, which is particularly useful for SVs in non-coding regions not covered by ES. OGM helps to construct complex SVs and provides information on the location and orientation of duplications, which is crucial for pathogenicity interpretation. The integration of RNA-seq facilitates the interpretation of the functional consequences of SVs at the transcriptional level. These findings demonstrate the utility and feasibility of combining OGM and RNA-seq in ES-negative cases with NDDs.

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With brain structure and function undergoing complex changes throughout childhood and adolescence, age is a critical consideration in neuroimaging studies, particularly for those of individuals with neurodevelopmental conditions. However, despite the increasing use of large, consortium-based datasets to examine brain structure and function in neurotypical and neurodivergent populations, it is unclear whether age-related changes are consistent between datasets and whether inconsistencies related to differences in sample characteristics, such as demographics and phenotypic features, exist. To address this, we built models of age-related changes of brain structure (regional cortical thickness and regional surface area; N = 1218) and function (resting-state functional connectivity strength; N = 1254) in two neurodiverse datasets: the Province of Ontario Neurodevelopmental Network and the Healthy Brain Network. We examined whether deviations from these models differed between the datasets, and explored whether these deviations were associated with demographic and clinical variables. We found significant differences between the two datasets for measures of cortical surface area and functional connectivity strength throughout the brain. For regional measures of cortical surface area, the patterns of differences were associated with race/ethnicity, while for functional connectivity strength, positive associations were observed with head motion. Our findings highlight that patterns of age-related changes in the brain may be influenced by demographic and phenotypic characteristics, and thus future studies should consider these when examining or controlling for age effects in analyses.

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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.

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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.

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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.

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Histamine (HA), a biogenic monoamine, exerts its pleiotropic effects through four H1R-H4R histamine receptors, which are also expressed in brain tissue. Together with the projections of HA-producing neurons located within the tuberomammillary nucleus (TMN), which innervate most areas of the brain, they constitute the histaminergic system. Thus, while remaining a mediator of the inflammatory reaction and immune system function, HA also acts as a neurotransmitter and a modulator of other neurotransmitter systems in the central nervous system (CNS). Although the detailed causes are still not fully understood, neuroinflammation seems to play a crucial role in the etiopathogenesis of both neurodevelopmental and neurodegenerative (neuropsychiatric) diseases, such as autism spectrum disorders (ASDs), attention-deficit/hyperactivity disorder (ADHD), Alzheimer's disease (AD) and Parkinson's disease (PD). Given the increasing prevalence/diagnosis of these disorders and their socioeconomic impact, the need to develop effective forms of therapy has focused researchers' attention on the brain's histaminergic activity and other related signaling pathways. This review presents the current state of knowledge concerning the involvement of HA and the histaminergic system within the CNS in the development of neurodevelopmental and neurodegenerative disorders. To this end, the roles of HA in neurotransmission, neuroinflammation, and neurodevelopment are also discussed.

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Maternal immune activation (MIA) during pregnancy has been increasingly recognized as a critical factor in the development of neurodevelopmental disorders, with potential sex-specific impacts that are not yet fully understood. In this study, we utilized a murine model to explore the behavioral and molecular consequences of MIA induced by lipopolysaccharide (LPS) administration on embryonic day 12.5. Our findings indicate that male offspring exposed to LPS exhibited significant increases in anxiety-like and depression-like behaviors, while female offspring did not show comparable changes. Molecular analyses revealed alterations in pro-inflammatory cytokine levels and synaptic gene expression in male offspring, suggesting that these molecular disruptions may underlie the observed behavioral differences. These results emphasize the importance of considering sex as a biological variable in studies of neurodevelopmental disorders and highlight the need for further molecular investigations to understand the mechanisms driving these sex-specific outcomes. Our study contributes to the growing evidence that prenatal immune challenges play a pivotal role in the etiology of neurodevelopmental disorders and underscores the potential for sex-specific preventative approaches of MIA.

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One in ten babies are born preterm, as defined as being less than 37 weeks of gestational age. Premature births are associated with a high risk of poor neurodevelopmental outcomes, including hearing, visual, motor, and cognitive impairments. Currently, there is no specific standardization for neurological follow-up infants born premature. Most formal neonatal intensive care units, follow-up programs monitor children until early childhood. However, some deficits, such as mild cognitive impairment, may only become apparent in school years. This review outlines a neurological follow-up timeline, as well as the different standardized measures that can be used to monitor development to ensure that children born preterm receive timely and appropriate therapies and services.

Uno de cada diez bebés nacidos es prematuro, el cual se define como el nacido antes de las 37 semanas de edad gestacional. La prematuridad está asociada con un alto riesgo de trastornos del neurodesarrollo con limitaciones en la audición, visión, área cognitiva y motora. Actualmente, no existen programas estandarizados específicos para el seguimiento neurológico de los prematuros. La mayoría son desarrollados por las unidades de cuidados intensivos neonatales y dan seguimiento hasta la edad pre-escolar. Sin embargo, algunas deficiencias, como el deterioro cognitivo leve, son reconocidos tardíamente. Esta revisión describe un cronograma para el seguimiento neurológico y las herramientas estandarizadas que pueden utilizarse para vigilar el desarrollo y asegurar que los niños nacidos prematuros reciban terapias y otros servicios adecuados y oportunos.

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It is estimated that about 1 in 100 live births has a congenital heart disease (CHD). Cognitive deficit, academic difficulties, and behavioral abnormalities, in combination, represent the most common morbidity affecting quality of life in survivors with CHD. Developmental dysfunction results from a complex interaction between patient-specific factors such as genetic susceptibility, cardiac diagnosis, fetal development, and environmental factors such as preoperative events, supportive techniques during surgical repair, postoperative events, socioeconomic status. A comprehensive neurodevelopmental assessment in all children with CHD is critical to identify any need for intervention early and provide the support needed to optimize their long-term development.

Se estima que aproximadamente 1 de cada 100 nacidos vivos presenta una cardiopatía congénita (CC). El déficit cognitivo, las dificultades académicas y anomalías conductuales, en combinación, representan la morbilidad más común que afecta la calidad de vida en sobrevivientes con CC. La disfunción del desarrollo resulta de una interacción compleja entre factores específicos del paciente como susceptibilidad genética, tipo de cardiopatía, desarrollo fetal y factores ambientales tales como eventos preoperatorios, técnicas de apoyo durante la reparación quirúrgica, eventos posoperatorios, estatus socioeconómico. Una evaluación integral del neurodesarrollo en todos los niños con CC es fundamental para identificar tempranamente cualquier necesidad de intervención y proporcionar el apoyo necesario para optimizar su desarrollo a largo plazo.

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The prevalence of sleep disorders (SD) is notoriously increased in children with chronic neurological disease, with a negative bidirectional link that aggravates their symptomatology and has a negative impact on the quality of life of the child and their families. Identifying and recognizing this association is key for the child neurologist since the treatment of SD significantly improves daytime symptomatology in neurodevelopmental disorders, epilepsy, primary headaches, cerebral palsy and neuromuscular diseases.

La prevalencia de los trastornos del sueño (TS) se incrementa notoriamente en niños con enfermedad neurológica crónica, con un vínculo bidireccional negativo que agrava su sintomatología y repercute negativamente en la calidad de vida del niño y su familia. Identificar y reconocer dicha asociación es clave para el neuropediatra, ya que el tratamiento del TS mejora significativamente la sintomatología diurna de los trastornos del neurodesarrollo, epilepsia, cefaleas primarias, parálisis cerebral y enfermedades neuromusculares.

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Iron deficiency (ID) and restlessness are associated with sleep/wake-disorders (e.g., restless legs syndrome (RLS)) and neurodevelopmental disorders (attention deficit/hyperactivity and autism spectrum disorders (ADHD; ASD)). However, a standardized approach to assessing ID and restlessness is missing. We reviewed iron status and family sleep/ID history data collected at a sleep/wake behavior clinic under a quality improvement/quality assurance project. Restlessness was explored through patient and parental narratives and a 'suggested clinical immobilization test'. Of 199 patients, 94% had ID, with 43% having a family history of ID. ADHD (46%) and ASD (45%) were common conditions, along with chronic insomnia (61%), sleep-disordered breathing (50%), and parasomnias (22%). In unadjusted analysis, a family history of ID increased the odds (95% CI) of familial RLS (OR: 5.98, p = 0.0002, [2.35-15.2]), insomnia/DIMS (OR: 3.44, p = 0.0084, [1.37-8.64]), and RLS (OR: 7.00, p = 0.01, [1.49-32.93]) in patients with ADHD, and of insomnia/DIMS (OR: 4.77, p = 0.0014, [1.82-12.5]), RLS/PLMS (OR: 5.83, p = 0.009, [1.54-22.1]), RLS (OR: 4.05, p = 0.01, [1.33-12.3]), and familial RLS (OR: 2.82, p = 0.02, [1.17-6.81]) in patients with ASD. ID and restlessness were characteristics of ADHD and ASD, and a family history of ID increased the risk of sleep/wake-disorders. These findings highlight the need to integrate comprehensive blood work and family history to capture ID in children and adolescents with restless behaviors.

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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.

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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.

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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.

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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.

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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.

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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.

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