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The Autisms, Fourth Edition aids the clinician to diagnose autism and autism/epilepsy, and to learn what is known about the epidemiology, neuroanatomy, biochemistry, neuropsychology and genetics. There is now overwhelming evidence that autism is not a single disease and three chapters are devoted to genomic errors, shown to affect a number of final common pathways in the fetal brain.

Methyl CpG binding protein 2 (MeCP2) is a key component of constitutive heterochromatin, which is crucial for chromosome maintenance and transcriptional silencing 1 – 3 . Mutations in the MECP2 gene cause the progressive neurodevelopmental disorder Rett syndrome 3 – 5 , which is associated with severe mental disability and autism-like symptoms that affect girls during early childhood. Although previously thought to be a dense and relatively static structure 1 , 2 , heterochromatin is now understood to exhibit properties consistent with a liquid-like condensate 6 , 7 . Here we show that MeCP2 is a dynamic component of heterochromatin condensates in cells, and is stimulated by DNA to form liquid-like condensates. MeCP2 contains several domains that contribute to the formation of condensates, and mutations in MECP2 that lead to Rett syndrome disrupt the ability of MeCP2 to form condensates. Condensates formed by MeCP2 selectively incorporate and concentrate heterochromatin cofactors rather than components of euchromatic transcriptionally active condensates. We propose that MeCP2 enhances the separation of heterochromatin and euchromatin through its condensate partitioning properties, and that disruption of condensates may be a common consequence of mutations in MeCP2 that cause Rett syndrome. The chromatin protein MeCP2 is a component of dynamic, liquid-like heterochromatin condensates, and the ability of MeCP2 to form condensates is disrupted by mutations in the MECP2 gene that occur in the neurodevelopmental disorder Rett syndrome.

The immune and nervous systems have unique developmental trajectories that individually build intricate networks of cells with highly specialized functions. These two systems have extensive mechanistic overlap and frequently coordinate to accomplish the proper growth and maturation of an organism. Brain resident innate immune cells — microglia — have the capacity to sculpt neural circuitry and coordinate copious and diverse neurodevelopmental processes. Moreover, many immune cells and immune-related signalling molecules are found in the developing nervous system and contribute to healthy neurodevelopment. In particular, many components of the innate immune system, including Toll-like receptors, cytokines, inflammasomes and phagocytic signals, are critical contributors to healthy brain development. Accordingly, dysfunction in innate immune signalling pathways has been functionally linked to many neurodevelopmental disorders, including autism and schizophrenia. This review discusses the essential roles of microglia and innate immune signalling in the assembly and maintenance of a properly functioning nervous system.In this Review, Zengeler and Lukens consider how innate immune signalling pathways contribute to healthy brain development and the implications for neurodevelopmental disorders.

Methamphetamine (METH) is a potent stimulant that induces a euphoric state but also causes cognitive impairment, neurotoxicity and neurodevelopmental deficits. Yet, the molecular mechanisms by which METH causes neurodevelopmental defects have remained elusive. Here we utilized human cerebral organoids and single-cell RNA sequencing (scRNA-seq) to study the effects of prenatal METH exposure on fetal brain development. We analyzed 20,758 cells from eight untreated and six METH-treated cerebral organoids and found that the organoids developed from embryonic stem cells contained a diverse array of glial and neuronal cell types. We further identified transcriptionally distinct populations of astrocytes and oligodendrocytes within cerebral organoids. Treatment of organoids with METH-induced marked changes in transcription in multiple cell types, including astrocytes and neural progenitor cells. METH also elicited novel astrocyte-specific gene expression networks regulating responses to cytokines, and inflammasome. Moreover, upregulation of immediate early genes, complement factors, apoptosis, and immune response genes suggests a neuroinflammatory program induced by METH regulating neural stem cell proliferation, differentiation, and cell death. Finally, we observed marked METH-induced changes in neuroinflammatory and cytokine gene expression at the RNA and protein levels. Our data suggest that human cerebral organoids represent a model system to study drug-induced neuroinflammation at single-cell resolution.

Background Undernutrition is a significant public health challenge and one of the leading causes of child mortality in a wide range of developing countries, including Ethiopia. Poor access to water, sanitation, and hygiene (WASH) facilities commonly contributes to child growth failure. There is a paucity of information on the interrelationship between WASH and child undernutrition (stunting and wasting). This study aimed to assess the association between WASH and undernutrition among under-five-year-old children in Ethiopia. Methods A secondary data analysis was undertaken based on the Ethiopian Demographic and Health Surveys (EDHS) conducted from 2000 to 2016. A total of 33,763 recent live births extracted from the EDHS reports were included in the current analysis. Multilevel logistic regression models were used to investigate the association between WASH and child undernutrition. Relevant factors from EDHS data were identified after extensive literature review. Results The overall prevalences of stunting and wasting were 47.29% [95% CI: (46.75, 47.82%)] and 10.98% [95% CI: (10.65, 11.32%)], respectively. Children from households having unimproved toilet facilities [AOR: 1.20, 95% CI: (1.05,1.39)], practicing open defecation [AOR: 1.29, 95% CI: (1.11,1.51)], and living in households with dirt floors [AOR: 1.32, 95% CI: (1.12,1.57)] were associated with higher odds of being stunted. Children from households having unimproved drinking water sources were significantly less likely to be wasted [AOR: 0.85, 95% CI: (0.76,0.95)] and stunted [AOR: 0.91, 95% CI: (0.83, 0.99)]. We found no statistical differences between improved sanitation, safe disposal of a child’s stool, or improved household flooring and child wasting. Conclusion The present study confirms that the quality of access to sanitation and housing conditions affects child linear growth indicators. Besides, household sources of drinking water did not predict the occurrence of either wasting or stunting. Further longitudinal and interventional studies are needed to determine whether individual and joint access to WASH facilities was strongly associated with child stunting and wasting.

Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient-derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as loss-of-function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.

Background The existing epidemiological data cannot represent the situation of undernutrition among Chinese children, particularly those in rural China. Hence, in this community-based cross-sectional study, the prevalence and associated factors of stunting, underweight and wasting among children (age < 6 years) from rural Hunan Province were analyzed. Methods Totally 5529 children aged 0 to 71 months and their caregivers were randomly chosen by multistage stratified cluster sampling from 72 villages from rural Hunan, which were distributed in 24 towns of 12 counties. Data about the children and their mothers, caregivers and family conditions was acquired using unified questionnaire, and the length/height and weight of each child were measured using unified instruments. The prevalence of undernutrition among children was evaluated using the length/height for age, weight for age, weight for length/height, and body mass index for age z scores, which were computed according to the 2006 and 2007 WHO Child Growth Standards. Results The prevalence of stunting, underweight, and wasting among the 5529 children were 4.4% (241), 3.9% (217), and 4.0% (221), respectively. The significant associated factors on higher risks of undernutrition in the children were low birth weight, maternal gestational weight gain <10 kg (stunting); low birth weight, maternal gestational weight gain <10 kg, ethnicity of caregivers being minority, large family size (underweight); low birth weight, ethnicity of caregivers being minority, large family size (wasting). High education level of caregivers and high family food expenditure were common protective factors for all three types of undernutrition, except that high family food expenditure was not protective against wasting. Conclusions The prevalence of stunting, underweight and wasting is low among rural children under age of 6 years in Hunan. As for the measures, the gestational care and reasonable diet of mothers should be strengthened, and nutritional deficiency during pregnancy be avoided, which will prevent low birth weight. The local economic development and the education level of caregivers need to be further improved, especially for minorities.

Cerebral palsy (CP) is a disability caused by brain malformations or injuries occurring from conception to infancy. Hydrotherapy is a popular treatment for children with cerebral palsy and other neuromotor disorders. Despite evidence supporting the efficacy of hydrotherapy for treating children with cerebral palsy, there remains controversy regarding its effectiveness over different follow-up periods and in comparison with other physical therapy methods. To compare the effects of hydrotherapy on gross motor abilities, fine motor functions, balance, and muscle tone in children and adolescents with cerebral palsy, and to assess evaluate efficacy across different age stages and treatment durations. This meta-analysis was registered with PROSPERO (registration number CRD42024535838). Literature searches were conducted in databases including CNKI, VIP, WanFang, Web of Science, PubMed, Embase, and the Cochrane Library starting from June 2024. Randomized controlled trials (RCTs) that assessed the effects of hydrotherapy on gross motor functions, fine motor functions, balance, and muscle tone in children and adolescents with cerebral palsy were included. RCTs were evaluated for quality using the Cochrane risk of bias tool. Outcomes were analyzed by calculating mean difference (MD) or standardized mean difference (SMD) along with their 95% confidence intervals (CIs). Sixteen studies were included, assessing the impact of hydrotherapy compared to conventional care on gross motor functions in children and adolescents with cerebral palsy. The findings indicated that hydrotherapy significantly improved gross motor functions [SMD = 0.41, 95% CI = 0.15-0.68, I2 = 59.5%, p < 0.05], with consistent effects observed in children aged ≤6 years [SMD = 0.42, 95% CI = 0.16-0.68, I2 = 38.2%, p < 0.05] and those aged >6 years [SMD = 0.43, 95% CI = 0.22-0.63, I2 = 59.5%, p < 0.05]. Subgroup analysis based on intervention duration revealed that programs lasting more than 10 weeks were associated with significant improvements [SMD = 0.48, 95% CI = 0.31-0.66, I2 = 65.1%, p < 0.05], whereas no significant effects were found in interventions lasting 10 weeks or less [SMD = 0.14, 95% CI = -0.26-0.53, I2 = 35.6%, p > 0.05]. Hydrotherapy demonstrated a certain positive effect on fine motor functions [SMD = 0.78, 95% CI = 0.46-1.10, I2 = 46.4%, p > 0.05].In contrast, no statistically significant improvements were observed in balance [SMD = 0.64, 95% CI = -0.05-1.34, I2 = 80.7%, p > 0.05] or muscle tone [SMD = -0.45, 95% CI = -0.98-0.07, I2 = 58.2%, p > 0.05]. The results indicate that hydrotherapy is more effective than conventional treatment in improving gross motor functions in children and adolescents with cerebral palsy, with consistent benefits observed across different age groups and in interventions of longer duration. Hydrotherapy also showed a positive trend in enhancing fine motor functions, although no significant improvements were observed in balance or muscle tone.

Maternal immune activation (MIA) disrupts the central innate immune system during a critical neurodevelopmental period. Microglia are primary innate immune cells in the brain although their direct influence on the MIA phenotype is largely unknown. Here we show that MIA alters microglial gene expression with upregulation of cellular protrusion/neuritogenic pathways, concurrently causing repetitive behavior, social deficits, and synaptic dysfunction to layer V intrinsically bursting pyramidal neurons in the prefrontal cortex of mice. MIA increases plastic dendritic spines of the intrinsically bursting neurons and their interaction with hyper-ramified microglia. Treating MIA offspring by colony stimulating factor 1 receptor inhibitors induces depletion and repopulation of microglia, and corrects protein expression of the newly identified MIA-associated neuritogenic molecules in microglia, which coalesces with correction of MIA-associated synaptic, neurophysiological, and behavioral abnormalities. Our study demonstrates that maternal immune insults perturb microglial phenotypes and influence neuronal functions throughout adulthood, and reveals a potent effect of colony stimulating factor 1 receptor inhibitors on the correction of MIA-associated microglial, synaptic, and neurobehavioral dysfunctions.