Unraveling the three-dimensional (3D) genome architecture in Neurodevelopmental Disorders (NDDs).

The human genome, comprising millions of pairs of bases, serves as the blueprint of life, encoding instructions for cellular processes. However, genomes are not merely linear sequences; rather, the complex of DNA and histones, known as chromatin, exhibits complex organization across various levels, which profoundly influence gene expression and cellular function. Central to understanding genome organization is the emerging field of three-dimensional (3D) genome studies. Utilizing advanced techniques such as Hi-C, researchers have unveiled non-random dispositions of genomic elements, highlighting their importance in transcriptional regulation and disease mechanisms. Topologically Associating Domains (TADs), that demarcate regions of chromatin with preferential internal interactions, play crucial roles in gene regulation and are increasingly implicated in various diseases such as cancer and schizophrenia. However, their role in Neurodevelopmental Disorders (NDDs) remains poorly understood. Here, we focus on TADs and 3D conservation across the evolution and between cell types in NDDs. The investigation into genome organization and its impact on disease has led to significant breakthroughs in understanding NDDs etiology such ASD (Autism Spectrum Disorder). By elucidating the wide spectrum of ASD manifestations, researchers aim to uncover the underlying genetic and epigenetic factors contributing to its heterogeneity. Moreover, studies linking TAD disruption to NDDs underscore the importance of spatial genome organization in maintaining proper brain development and function. In summary, this review highlights the intricate interplay between genome organization, transcriptional control, and disease pathology, shedding light on fundamental biological processes and offering insights into the mechanisms underlying NDDs like ASD.

[Tooth decay and autism spectrum disorders in children: is there a connection?] / Karies zubov i rasstroistva autisticheskogo spektra u detei: est' li svyaz'?

OBJECTIVE: The study of caries lesions of children 7 and 12 years old with different degrees of severity of autism and concomitant intellectual disabilities, in comparison with a control group of neurotypical patients of similar age. MATERIALS AND METHODS: The main study group included children with ASD ages 7 and 12 (n=214), and the comparison group included neurotypical children of the same age (n=140). To assess the incidence of dental caries, indicators of the prevalence and intensity of the process were used. RESULTS: The prevalence of dental caries in children with ASD is lower than in the comparison group or comparable. The average caries prevalence was found in the 7- and 12-year-old groups in children with mild autism without concomitant intellectual deficits (80.89±3.40 and 76.65±4.24, respectively). In children with severe and extremely severe autism, regardless of the presence of intellectual disability, the prevalence of dental caries was high in both age groups, which is comparable with the same indicator and age of neurotypical children. Moreover, both age groups of neurotypical children were also comparable in caries prevalence (89.67±1.65 and 90.32±1.20 respectively). Caries intensity did not seem to be related to years of autistic disorder (significantly lower in the group of 12-year-old children with ASD, compared to 7-year-olds). Caries intensity in children with ASD increased with increasing severity of autism and concomitant intellectual disability. CONCLUSION: Further comprehensive studies in terms of included variables are needed to identify contributing factors (impact of family socioeconomic opportunities, increased parental care, etc.).

Systematic review: Autism spectrum disorder and the gut microbiota.

OBJECTIVE: Autism spectrum disorders (ASD) are a varying group of disorders characterized by deficiency in social interaction and restrictive patterns of behavior and interests. While there are several studies focusing on the neuropsychiatric pathogenesis of ASD, its etiology remains unclear. The role of gut-brain-axis in ASD has been studied increasingly and a correlation between symptoms and the composition of gut microbiota has been documented in various works. Despite this, the significance of individual microbes and their function is still widely unknown. This work aims to elucidate the current knowledge of the interrelations between ASD and the gut microbiota in children based on scientific evidence. METHODS: This is a systematic review done by a literature search focusing on the main findings concerning the gut microbiota composition, interventions targeting the gut microbiota, and possible mechanisms explaining the results in children aged between 2 and 18 years of age. RESULTS: Most studies in this review found significant differences between microbial communities, while there was notable variation in results regarding diversity indices or taxonomic level abundance. The most consistent results regarding taxa differences in ASD children's gut microbiota were higher levels of Proteobacteria, Actinobacteria and Sutterella compared to controls. CONCLUSION: These results show that the gut microbiota of children with ASD is altered compared to one of neurotypically developed children. More research is needed to discover whether some of these features could be used as potential biomarkers for ASD and how the gut microbiota could be targeted in therapeutical interventions.

Two-sample Mendelian randomization study does not reveal a significant relationship between cytomegalovirus (CMV) infection and autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting ~ 2% of children worldwide and is characterized by repetitive, stereotypical behaviours and impaired expressive communication. Cytomegalovirus (CMV) is considered a risk factor for ASD; however, published studies are usually limited by covering too few events and have different conclusions, indicating that the relationship between CMV infection and ASD remains elusive. METHODS: To investigate the association between CMV infection and ASD, we conducted this 2-sample Mendelian randomization (MR) study using genome-wide association studies (GWAS) summary data from FinnGen and the IEU Open GWAS project. RESULTS: Our results showed no significant relationship between all 3 CMV infections (unspecified cytomegaloviral diseases, anti-CMV IgG levels, and maternal CMV) and ASD. CONCLUSIONS: Our results indicate that CMV infection does not significantly increase ASD risk. These results show that the relationship between CMV infection and ASD remains elusive and needs to be further clarified.

Successful lexical tone production of Mandarin Chinese autistic children with intellectual impairment.

BACKGROUND: Atypical speech prosody has been commonly found among autistic children. Yet it remains unknown whether prosody impairment originates from poor pitch ability in general or whether it is the result of the difficulty in understanding and using prosody for communicative purposes. AIMS: To investigate whether native Mandarin Chinese-speaking autistic children with intellectual impairment were able to accurately produce native lexical tones, which are pitch patterns that distinguish word meaning lexically and serve little social purpose. METHODS & PROCEDURES: Using a picture-naming task, thirteen 8-13-year-old Mandarin Chinese-speaking autistic children with intellectual impairment were tested on their production of Chinese lexical tones. Chronical age-matched typically developing (TD) children were included as the control group. Perceptual assessment and phonetic analyses were conducted with the produced lexical tones. OUTCOMES & RESULTS: The majority of the lexical tones produced by the autistic children were perceived as accurate by adult judges. Phonetic analysis of the pitch contours found no significant difference between the two groups, and the autistic children and TD children used the phonetic features in comparable ways when differentiating the lexical tones. However, the lexical tone accuracy rate was lower among the autistic children than among the TDs, and the larger individual difference was observed among the autistic children than the TD children. CONCLUSIONS & IMPLICATIONS: These results indicate that autistic children are able to produce the global contours of the lexical tones, and pitch deficits do not seem to qualify as a core feature of autism. WHAT THIS PAPER ADDS: What is already known on the subject Atypical prosody has been considered a maker of the speech of autistic children, and meta-analysis found a significant difference in mean pitch and pitch range between TD children and autistic children. Yet it remains unknown whether the pitch deficits are the result of impaired perceptual-motoric ability or if they reflect failure in learning sentential prosody, which requires an understanding of the interlocutors' mind. In addition, research on pitch ability of autistic children with intellectual disabilities has been scarce, and whether these children are able to produce pitch variation is largely unknown. What this paper adds to existing knowledge We tested native Mandarin Chinese autistic children with intellectual impairment on their production of native lexical tones. The lexical tones in Chinese are pitch variations realized on individual syllables that distinguish lexical meaning, but they do not serve social pragmatic purposes. We found that although these autistic children had only developed limited spoken language, the majority of their lexical tones were perceived as accurate. They were able to use the phonetic features in comparable ways with the TD children when distinguishing the lexical tones. What are the potential or actual clinical implications of this work? It seems unlikely that pitch processing at the lexical level is fundamentally impaired in autistic children, and pitch deficits do not seem to qualify for a core feature of their speech. Practitioners should be cautious when using pitch production as a clinical marker for autistic children.

The Role of SNAP-25 in Autism Spectrum Disorders Onset Patterns.

Autism spectrum disorders (ASD) can present with different onset and timing of symptom development; children may manifest symptoms early in their first year of life, i.e., early onset (EO-ASD), or may lose already achieved skills during their second year of life, thus showing a regressive-type onset (RO-ASD). It is still controversial whether regression represents a neurobiological subtype of ASD, resulting from distinct genetic and environmental causes. We focused this study on the 25 kD synaptosomal-associated protein (SNAP-25) gene involved in both post-synaptic formation and adhesion and considered a key player in the pathogenesis of ASD. To this end, four single nucleotide polymorphisms (SNPs) of the SNAP-25 gene, rs363050, rs363039, rs363043, and rs1051312, already known to be involved in neurodevelopmental and psychiatric disorders, were analyzed in a cohort of 69 children with EO-ASD and 58 children with RO-ASD. Both the rs363039 G allele and GG genotype were significantly more frequently carried by patients with EO-ASD than those with RO-ASD and healthy controls (HC). On the contrary, the rs1051312 T allele and TT genotype were more frequent in individuals with RO-ASD than those with EO-ASD and HC. Thus, two different SNAP-25 alleles/genotypes seem to discriminate between EO-ASD and RO-ASD. Notably, rs1051312 is located in the 3' untranslated region (UTR) of the gene and is the target of microRNA (miRNA) regulation, suggesting a possible epigenetic role in the onset of regressive autism. These SNPs, by discriminating two different onset patterns, may represent diagnostic biomarkers of ASD and may provide insight into the different biological mechanisms towards the development of better tailored therapeutic and rehabilitative approaches.

Screening for Autism Spectrum Disorders - Validation of the Portuguese Version of the Social Communication Questionnaire.

There are no assessment and screening tools for Autism Spectrum Disorders (ASD) validated for the Portuguese population. The Social Communication Questionnaire (SCQ) is an useful screening tool of ASD diagnosis. The main objectives of our study were to produce a Portuguese version of the SCQ (SCQ-PF), study its internal consistency, sensitivity and specificity in order to evaluate its validity as a screening instrument for ASD. We also wanted to study the impact of intellectual disability and verbal impairment and other mental disorders on SCQ-PF psychometric properties. The study included 211 children and adolescents, aged 4-17, divided in three groups: ASD Group (n = 96), Other Mental Disorders Group (OMD) (n = 63) and No Mental Disorders (NMD) Group (n = 52). Parents or other primary caregiver provided information on the SCQ items. The SCQ-PF score was significantly higher in the ASD group than in the other groups (p < 0.001). As to internal consistency, Cronbach's alpha was 87%. ASD subjects were distinguished from subjects without ASD (OMD and NMD Groups) and the area under the curve (AUC) was 0.897 (95% Confidence Interval: 0.852-0.943), for a cutoff of 14, which yielded the highest AUC, with values of sensitivity and specificity 0.76 and 0.93, respectively. These findings show that SCQ- PF with a cutoff of 14 is an acceptable and useful screening tool for ASD in the Portuguese population.

Metabolomics profiling of valproic acid-induced symptoms resembling autism spectrum disorders using 1H NMR spectral analysis in rat model.

Prenatal exposure to valproic acid (VPA) has been implicated in the manifestation of autism spectrum disorder (ASD)-like behavioral and functional changes both in human and rodents including mice and rats. The objective of this study was to determine metabolomics profiling and biomarkers related to VPA-induced symptoms resembling ASD using proton nuclear magnetic resonance (1H-NMR) spectral data. VPA was administered to pregnant rats at gestation day 12.5 and effects measured subsequently in male 4-week-old offspring pups. The sociability of VPA-treated animals was significantly diminished and exhibited ASD-like behavior as evidenced by reduction of social adaptation disorder and lack of social interactions. To find biomarkers related to ASD, the following were collected prefrontal brain cortices, urine bladder and blood samples directly from heart puncture. In all samples, principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) displayed significant clustering pattern differences between control and treated groups. Valine, taurine, myo-inositol, 3-hydroxybutyrate and 1,3-dihydroxyacetone were significantly decreased in brain cortices in treated rats. Serum metabolites of glucose, creatine phosphate, lactate, glutamine and threonine were significantly increased in VPA-administered animals. Urinary metabolites of pimelate, 3-hydroxyisovalerate and valerate were significantly reduced in VPA-treated rat, whereas galactose and galactonate levels were elevated. Various metabolites were associated with mitochondrial dysfunction metabolism and central nervous system disorders. Data demonstrated that VPA-induced alterations in endogenous metabolites of serum, urine, and brain cortex which might prove useful as biomarkers for symptoms resembling ASD as a model of this disorder.

Comprehensive in silico mutational-sensitivity analysis of PTEN establishes signature regions implicated in pathogenesis of Autism Spectrum Disorders.

An extensively studied cancer and Autism Spectrum Disorders (ASD) gene like PTEN provided an exclusive opportunity to map its mutational-landscape, compare and establish plausible genotypic predictors of ASD-associated phenotypic outcomes. Our exhaustive in silico analysis on 4252 SNPs using >30 tools identified increased mutational-density in exon7. Phosphatase domain, although evolutionarily conserved, had the most nsSNPs localised within signature regions. The evolutionarily variable C-terminal side contained the highest truncating-SNPs outside signature regions of C2 domain and most PTMs within C-tail site which displayed maximum intolerance to polymorphisms, and permitted benign but destabilising nsSNPs that enhanced its intrinsically-disordered nature. ASD-associated SNPs localised within ATP-binding motifs and Nuclear-Localising-Sequences were the most potent triggers of ASD manifestation. These, along with variations within P, WPD and TI loops, M1 within phosphatase domain, M2 and MoRFs of C2 domain, caused severe long-range conformational fluctuations altering PTEN's dynamic stability- not observed in variations outside signature regions. 3'UTR-SNPs affected 44 strong miRNA brain-specific targets; several 5' UTR-SNPs targeted transcription-factor POLR2A and 10 pathogenic Splice-Affecting-Variants were identified.

Detecting autism from picture book narratives using deep neural utterance embeddings.

BACKGROUND: Deficits in the ability to use language in social contexts, including storytelling skills, are observed across the autism spectrum. Development in machine-learning approaches may contribute to clinical psychology and psychiatry, given its potential to support decisions concerning the diagnosis and treatment of psychiatric conditions and disorders. AIMS: To evaluate the usefulness of deep neural networks for detecting autism spectrum disorder (ASD) from textual utterances, specifically from narrations produced by individuals with ASD. METHODS & PROCEDURES: We examined two text encoders: Embeddings from Language Models (ELMo) and Universal Sentence Encoder (USE), and three classification algorithms: XGBoost, support vector machines, and dense neural network layer. We aimed to classify 25 participants with ASD and 25 participants with typical development (TD) based on their narrations produced during the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) picture book task. The results of computational approaches were compared with the results of standardized testing and classifications made by two psychiatrists (raters). The raters were asked to read utterances produced by a participant (without an examiner's statements and additional information) and assign a participant to one of the two groups: ASD or with typical development (TD). OUTCOMES & RESULTS: The computer-based models had higher sensitivity, specificity, positive predictive values and negative predictive values than the raters, and lower than the two standardized instruments: ADOS-2 and Social Communication Questionnaire (SCQ). CONCLUSIONS & IMPLICATIONS: Our findings lay the groundwork for future studies involving deep neural network-based text representation models as tools for augmenting the ASD diagnosis or screening. Both ELMo and USE text encoders provided promising specificities, sensitivities, positive predictive values and negative predictive values. Our results indicate the usefulness of page-level embeddings for utterance representation in ADOS-2 picture book task. WHAT THIS PAPER ADDS: What is already known on this subject Deficits in the use of language in social contexts, and narrative ability in particular, are observed across the autism spectrum. Most research on narrative skills has applied hand-coding methods. Hitherto, machine-learning methods were used mostly for image recognition problems and data from screening questionnaires for ASD classification. Detection of mental and developmental disorders from textual input is an emerging field for machine and deep-learning methods. What this paper adds to existing knowledge This study explored the ability of several types of deep neural network-based text representation models to detect ASD. Both ELMo and USE provided the most promising values of specificity, sensitivity, positive predictive values and negative predictive values. What are the potential or actual clinical implications of this work? Competitive accuracy, repeatability, speed and ease of operation are all advantages of computerized methods. They allow for objective and quantitative assessment of narrative ability and complex language skills. Deep neural network-based text representation models could in the future support clinicians and augment the decision-making process related to ASD diagnosis, screening and intervention planning.

Beta-Carotene derivatives as novel therapy for the prevention and treatment of autistic symptoms.

Autistic Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by impaired social interaction & communication as well as restricted and repetitive behavior. The currently reported incidence of ASD is 1-2%, and it increases dramatically to 10-20% in families predisposed to ASD. To date, there is no effective way to treat or prevent ASD, and only symptomatic treatment with limited efficacy is available. Oxytocin (Oxt) enhances affiliative behavior and improves social cognition. Social deficits characteristic of autism may be related to dysfunctional Oxt neurotransmission. Thus, administration of Oxt may relieve ASD, however it has a short plasma half-life and poor Blood Brain Barrier (BBB) permeability. CD38, a multifunctional ecto-enzyme expressed in brain and immune cells, was found to be critical for social behavior via regulation of Oxt secretion. All-trans retinoic acid (ATRA) is a potent inducer of CD38 and improves social behavior, but it is toxic and teratogenic. We have shown that beta-carotene has a similar therapeutic effect. The present study aimed to investigate the activity of novel beta-carotene derivatives in rescuing low sociability found in BTBR mice, providing an in vivo "proof of principle" that beta-carotene derivatives are potential agents to prevent/ameliorate the reappearance of ASD in high-risk populations for ASD. Beta-carotene and its synthetic analogs were administered orally to newborn BTBR mice with ASD associated like behavior. After 2 months, they were tested (at dosages of 0.1 and 1.0 mg/kg) by cognitive (T-maze spontaneous alteration and neurological score) and behavioral tests (reciprocal social interaction, repetitive grooming / bedding behavior), previously shown as indicators for autistic behavior. The following biochemical and molecular biology parameters were also examined: serum Oxt; gene expression in hippocampus and hypothalamus of CD 38, Oxt, Oxt receptor, BDNF, and retinoic acid receptor. The new compounds were significantly more effective than control. The most effective compounds, both in the behavioral tests and in their biochemical effects, were (3R,3'R)-astaxanthin bis(N-Cbz-l-alanine ester) (3B(and (3S,3'S)-astaxanthin bis(N,N-dimethylglycine ester (5). They did not exert any neurological symptoms. Thus, beta-carotene derivatives may have the potential to prevent and/or ameliorate autistic symptoms when administered orally after birth to newborns of families predisposed to autism.

The comprehension of grammaticalized implicit meanings in SPCD and ASD children: A comparative study.

BACKGROUND: Autism spectrum disorder (ASD) and social pragmatic communication disorder (SPCD) are two neurodevelopmental disorders with many similarities in affected individuals' impairments in social-communicative and pragmatic development. A central question pertaining to their differentiation concerns whether the distinction is truly qualitative or, instead, quantitative in nature, and indeed, defining the boundary between SPCD and ASD with IQ in the normal range often presents differential-diagnostic difficulties. While deficits in the comprehension of certain linguistically systematic implicit verbal meanings have been targeted by experimental research in ASD, to date they have not been investigated in controlled experiments in SPCD. AIMS: The empirical objectives of our study are twofold. First, it is explored whether the comprehension of a set of highly systematic, grammaticalized implicit meanings is impaired in ASD and SPCD children compared to their typically developing (TD) peers, and whether ASD and SPCD children differ from each other in accessing these verbal meanings. Second, it is investigated whether receptive grammatical competence and first-order ToM abilities are associated with children's performance in any way and whether there is a difference in this regard between the ASD and the SPCD group. METHODS & PROCEDURES: Our main experiment, using a sentence-picture verification task, tested the comprehension of highly systematic implicit verbal meanings, including grammaticalized implicatures, presuppositions, and entailments. The experiment was complemented with a false-belief (ToM) task and a test of receptive grammar, among other measures. Seventy-one 4-to-9-year-old children participated in the study (ASD: n=19, SPCD: n=13, TD controls: n=39). OUTCOMES & RESULTS: While both children with SPCD and children with ASD performed significantly more poorly than the TD group, only the comprehension profile of the SPCD group differed significantly from that of the TD group. Importantly, while ASDs' performance exhibited an association with their ToM results, the performance of SPCDs showed a correlation with their receptive grammar skills. By contrast, the performance of TDs correlated with neither. CONCLUSIONS & IMPLICATIONS: These findings reveal potential divergences in the cognitive developmental mechanisms that underlie the semantic-pragmatic difficulties in the two clinical groups, suggesting that the communicative impairments in ASD and in SPCD differ qualitatively, rather than quantitatively. Specific implications for theories of pragmatic impairments in ASD and in SPCD are discussed. WHAT THIS PAPER ADDS: What is already known on the subject Linguistically systematic implicit meanings are understudied both in ASD and in SPCD. Within this domain of verbal meaning, the majority of relevant experimental work on ASD, concentrated on generalized (mostly: scalar) implicatures, has yielded somewhat divergent results, while the comprehension difficulties in SPCD have remained barely charted territory. Linguistically more highly conventionalized implicit verbal meanings have not been experimentally investigated in either neurodevelopmental disorder. What this study adds A primary finding of our study is that although both the SPCD and the ASD group show significant deficit in the comprehension of highly conventional, grammaticalized implicit meanings, SPCD children may diverge more in their comprehension profile from their TD peers than ASD children. Another key result is that the comprehension of grammaticalized implicit meanings is linked with different cognitive functions in ASD and in SPCD. While comprehension performance is associated with ToM in ASD but not in SPCD or in TD, it is correlated with receptive grammar skills in SPCD but not in ASD or in TD. Clinical implications of this study These findings provide potential support for the hypothesis that the difference between ASD and SPCD is qualitative rather than quantitative in nature, thereby casting doubt on the conception that pragmatic limitations in SPCD are to be approached as a less severe form of similar deficits in ASD. Uncovering differences in the underlying cognitive sources and in the comprehension deficits of children with ASD and SPCD are critical for the improvement of the accuracy of SPCD children's early diagnosis and timely therapeutic intervention.

Alterations in Tau Protein Level and Phosphorylation State in the Brain of the Autistic-Like Rats Induced by Prenatal Exposure to Valproic Acid.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficient social interaction and communication besides repetitive, stereotyped behaviours. A characteristic feature of ASD is altered dendritic spine density and morphology associated with synaptic plasticity disturbances. Since microtubules (MTs) regulate dendritic spine morphology and play an important role in spine development and plasticity the aim of the present study was to investigate the alterations in the content of neuronal α/ß-tubulin and Tau protein level as well as phosphorylation state in the valproic acid (VPA)-induced rat model of autism. Our results indicated that maternal exposure to VPA induces: (1) decrease the level of α/ß-tubulin along with Tau accumulation in the hippocampus and cerebral cortex; (2) excessive Tau phosphorylation and activation of Tau-kinases: CDK5, ERK1/2, and p70S6K in the cerebral cortex; (3) up-regulation of mTOR kinase-dependent signalling in the hippocampus and cerebral cortex of adolescent rat offspring. Moreover, immunohistochemical staining showed histopathological changes in neurons (chromatolysis) in both analysed brain structures of rats prenatally exposed to VPA. The observed changes in Tau protein together with an excessive decrease in α/ß-tubulin level may suggest destabilization and thus dysfunction of the MT cytoskeleton network, which in consequence may lead to the disturbance in synaptic plasticity and the development of autistic-like behaviours.

Prenatal Exposure to Valproic Acid Affects Microglia and Synaptic Ultrastructure in a Brain-Region-Specific Manner in Young-Adult Male Rats: Relevance to Autism Spectrum Disorders.

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental conditions categorized as synaptopathies. Environmental risk factors contribute to ASD aetiology. In particular, prenatal exposure to the anti-epileptic drug valproic acid (VPA) may increase the risk of autism. In the present study, we investigated the effect of prenatal exposure to VPA on the synaptic morphology and expression of key synaptic proteins in the hippocampus and cerebral cortex of young-adult male offspring. To characterize the VPA-induced autism model, behavioural outcomes, microglia-related neuroinflammation, and oxidative stress were analysed. Our data showed that prenatal exposure to VPA impaired communication in neonatal rats, reduced their exploratory activity, and led to anxiety-like and repetitive behaviours in the young-adult animals. VPA-induced pathological alterations in the ultrastructures of synapses accompanied by deregulation of key pre- and postsynaptic structural and functional proteins. Moreover, VPA exposure altered the redox status and expression of proinflammatory genes in a brain region-specific manner. The disruption of synaptic structure and plasticity may be the primary insult responsible for autism-related behaviour in the offspring. The vulnerability of specific synaptic proteins to the epigenetic effects of VPA may highlight the potential mechanisms by which prenatal VPA exposure generates behavioural changes.

Vitamin A and vitamin D deficiencies exacerbate symptoms in children with autism spectrum disorders.

Objectives: This study was designed to investigate the vitamin A (VA) and vitamin D (VD) levels in children with autism spectrum disorders (ASD) and to determine whether co-deficiency of VA and VD exacerbates clinical symptoms in autistic children. Methods: The Autism Behavior Checklist, Childhood Autism Rating Scale (CARS), and Social Responsiveness Scale (SRS) were used to assess the symptoms of 332 children diagnosed as ASD. And the Gesell Developmental Scale (GDS) was used to evaluate neurodevelopment in children with ASD. Anthropometric measurement and questionnaire results were compared for all autistic children and 197 age- and gender-matched control children. Serum retinol levels were detected with high-performance liquid chromatography, and serum levels of 25-OH vitamin D were measured with an immunoassay method in the two groups. Results: The ZHA, ZWA, and ZBMIA of the children with ASD were significantly lower than those of the control children. Furthermore, higher proportions of children with picky eating, resistance to new foods, and eating problems were observed in the ASD group when compared with the control group. Serum retinol and 25-OH vitamin D levels in autistic children were significantly lower than those in the control children. Additionally, VA and VD co-deficiency impacts more on the symptoms and development in autistic children. Conclusions: We found that children with autism have more VA and VD deficiencies than control children, and VA and VD co-deficiency may exacerbate the symptoms of children with ASD.

GeneAnalytics Pathways and Profiling of Shared Autism and Cancer Genes.

Recent research revealed that autism spectrum disorders (ASD) and cancer may share common genetic architecture, with evidence first reported with the PTEN gene. There are approximately 800 autism genes and 3500 genes associated with cancer. The VarElect phenotype program was chosen to identify genes jointly associated with both conditions based on genomic information stored in GeneCards. In total, 138 overlapping genes were then profiled with GeneAnalytics, an analysis pathway enrichment tool utilizing existing gene datasets to identify shared pathways, mechanisms, and phenotypes. Profiling the shared gene data identified seven significantly associated diseases of 2310 matched disease entities with factors implicated in shared pathology of ASD and cancer. These included 371 super-pathways of 455 matched entities reflecting major cell-signaling pathways and metabolic disturbances (e.g., CREB, AKT, GPCR); 153 gene ontology (GO) biological processes of 226 matched processes; 41 GO molecular functions of 78 matched functions; and 145 phenotypes of 232 matched phenotypes. The entries were scored and ranked using a matching algorithm that takes into consideration genomic expression, sequencing, and microarray datasets with cell or tissue specificity. Shared mechanisms may lead to the identification of a common pathology and a better understanding of causation with potential treatment options to lessen the severity of ASD-related symptoms in those affected.

Toxin profile of fecal Clostridium perfringens strains isolated from children with autism spectrum disorders.

Infectious factors are taken into consideration in pathophysiology of autism spectrum disorders (ASD). ASD patients often suffer from gastrointestinal disorders. The intestinal microbiota of autistic patients significantly differs from that in healthy individuals. The aim of the study was to compare the profile of toxins produced by C. perfringens strains isolated from feces of children with ASD, with healthy individuals and obese subjects. This study included 111 strains of C. perfringens: 49 isolates from 29 children with ASD, 30 - from 17 healthy individuals and 32 - from 24 young obese subjects. Alpha, beta, beta2, epsilon, iota and enterotoxin genes were detected using appropriate PCRs. The alpha toxin gene (cpa) was present in all 111 examined strains (100%). The beta2 gene (cpb2) was detected in 45/49 strains (91.8%) isolated from children with ASD, 17/30 (56.7%) isolates from healthy subjects, and 12 of 32 (37.5%) isolates from obese subjects. C. perfringens strains with cpb2 gene were detected in 27/29 ASD patients (93.1%), 10/17 healthy subjects (58.8%) and 11/24 (45.8%) obese subjects. Beta2 toxin encoding cpb2 gene was significantly more common in strains isolated from ASD patients, with no significant difference between control subjects regardless of diet. Further research to explain observed phenomena and pathomechanism of beta2 toxin is required.

Functional connection between the stereotyped behavior and the motor front area in children with autism.

OBJECT: Autism spectrum disorders (ASD) is characterized by stereotyped behavior, attention deficit and/or impaired sensory perception to external stimuli. Its neurobiological mechanisms remain unclear. In this study we examined the resting-state functional connectivity of the premotor area and investigated its correlation with behavioral variables to determine whether connectivity alterations can distinguish ASD from healthy controls. METHODS: 39 children with ASD and 42 healthy children with matched age, sex and intelligence were recruited. All the 81 subjects had behavioral index evaluation and underwent resting-state functional magnetic resonance imaging (fMRI) scans. After MRI data preprocessing, the left and right premotor areas were selected as region of interest (ROI) seeds to perform functional connectivity. Groups were compared, and the correlation between functional connectivity and behavioral indicators was analyzed. RESULTS: Compared with healthy controls, ASD children showed significantly increased functional connectivity between the left premotor area and the posterior cingulate gyrus or anterior lobe of wedge, but functional connectivity between the left premotor area and the left insular lobe was decreased (p < 0.05, FDR correction). In addition, the connectivity between the left premotor area and the left insular lobe was negatively correlated with the behavioral scores (p < 0.05). CONCLUSION: Imbalanced premotor functional connectivity may be one possible mechanism of stereotyped behavior in ASD.

Maternal exposure to carbamazepine at environmental concentrations can cross intestinal and placental barriers.

Psychoactive pharmaceuticals have been found as teratogens at clinical dosage during pregnancy. These pharmaceuticals have also been detected in minute (ppb) concentrations in drinking water in the US, and are environmental contaminants that may be complicit in triggering neurological disorders in genetically susceptible individuals. Previous studies have determined that psychoactive pharmaceuticals (fluoxetine, venlafaxine and carbamazepine) at environmentally relevant concentrations enriched sets of genes regulating development and function of the nervous system in fathead minnows. Altered gene sets were also associated with potential neurological disorders, including autism spectrum disorders (ASD). Subsequent in vitro studies indicated that psychoactive pharmaceuticals altered ASD-associated synaptic protein expression and gene expression in human neuronal cells. However, it is unknown if environmentally relevant concentrations of these pharmaceuticals are able to cross biological barriers from mother to fetus, thus potentially posing risks to nervous system development. The main objective of this study was to test whether psychoactive pharmaceuticals (fluoxetine, venlafaxine, and carbamazepine) administered through the drinking water at environmental concentrations to pregnant mice could reach the brain of the developing embryo by crossing intestinal and placental barriers. We addressed this question by adding (2)H-isotope labeled pharmaceuticals to the drinking water of female mice for 20 days (10 pre-and 10 post-conception days), and quantifying (2)H-isotope enrichment signals in the dam liver and brain of developing embryos using isotope ratio mass spectrometry. Significant levels of (2)H enrichment was detected in the brain of embryos and livers of carbamazepine-treated mice but not in those of control dams, or for fluoxetine or venlafaxine application. These results provide the first evidence that carbamazepine in drinking water and at typical environmental concentrations is transmitted from mother to embryo. Our results, combined with previous evidence that carbamazepine may be associated with ASD in infants, warrant the closer examination of psychoactive pharmaceuticals in drinking water and their potential association with neurodevelopmental disorders.