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Medicina Sep 2023Autism is a neurodevelopmental disorder characterized by deficits in social cognition and communication, restricted interests, and stereotyped behaviors. Frequently... (Review)
Review
Autism is a neurodevelopmental disorder characterized by deficits in social cognition and communication, restricted interests, and stereotyped behaviors. Frequently associated with sensory dysfunction, other neurodevelopmental disorders, neuropsychiatric disorders, epilepsy and/or sleep disorders. This condition will accompany people throughout their lives, which will generate various support and treatment needs. Although there are no drugs that modify the core symptoms of autism, various drugs have shown their usefulness in associated conditions. Atypical antipsychotics for hyperactivity, impulsivity, agitation, auto or heteroaggression crises. Serotonin reuptake inhibitors, to decrease anxiety, obsessive-compulsive symptoms, and irritability/agitation. Stimulants and atomoxetine used for hyperactivity, inattention, and impulsivity. Clonidine and guanfacine show some efficacy on hyperactivity and stereotyped behaviors. Buspirone has been used for restrictive behaviors and anxiety. There are drugs in the research phase such as oxytocin, vasopressin and even some developed for specific entities related to autism such as arbaclofen in Fragile X and Trofinetide that has just been approved for use in Rett syndrome. As specific entities and their pathophysiology are identified, it is likely that tailored treatments will be developed for each entity associated with autism..
Topics: Humans; Autistic Disorder; Stereotyped Behavior; Anxiety; Anxiety Disorders; Autism Spectrum Disorder
PubMed: 37714122
DOI: No ID Found -
Nature Sep 2023The development of the human brain involves unique processes (not observed in many other species) that can contribute to neurodevelopmental disorders. Cerebral organoids...
The development of the human brain involves unique processes (not observed in many other species) that can contribute to neurodevelopmental disorders. Cerebral organoids enable the study of neurodevelopmental disorders in a human context. We have developed the CRISPR-human organoids-single-cell RNA sequencing (CHOOSE) system, which uses verified pairs of guide RNAs, inducible CRISPR-Cas9-based genetic disruption and single-cell transcriptomics for pooled loss-of-function screening in mosaic organoids. Here we show that perturbation of 36 high-risk autism spectrum disorder genes related to transcriptional regulation uncovers their effects on cell fate determination. We find that dorsal intermediate progenitors, ventral progenitors and upper-layer excitatory neurons are among the most vulnerable cell types. We construct a developmental gene regulatory network of cerebral organoids from single-cell transcriptomes and chromatin modalities and identify autism spectrum disorder-associated and perturbation-enriched regulatory modules. Perturbing members of the BRG1/BRM-associated factor (BAF) chromatin remodelling complex leads to enrichment of ventral telencephalon progenitors. Specifically, mutating the BAF subunit ARID1B affects the fate transition of progenitors to oligodendrocyte and interneuron precursor cells, a phenotype that we confirmed in patient-specific induced pluripotent stem cell-derived organoids. Our study paves the way for high-throughput phenotypic characterization of disease susceptibility genes in organoid models with cell state, molecular pathway and gene regulatory network readouts.
Topics: Humans; Autism Spectrum Disorder; Autistic Disorder; Brain; Cell Lineage; Chromatin; CRISPR-Associated Protein 9; CRISPR-Cas Systems; Developmental Disabilities; Gene Editing; Loss of Function Mutation; Mosaicism; Neurons; Organoids; RNA, Guide, CRISPR-Cas Systems; Single-Cell Gene Expression Analysis; Transcription, Genetic
PubMed: 37704762
DOI: 10.1038/s41586-023-06473-y -
Nutrients Aug 2023Since its introduction, aspartame-the leading sweetener in U.S. diet sodas (DS)-has been reported to cause neurological problems in some users. In prospective studies,...
Since its introduction, aspartame-the leading sweetener in U.S. diet sodas (DS)-has been reported to cause neurological problems in some users. In prospective studies, the offspring of mothers who consumed diet sodas/beverages (DSB) daily during pregnancy experienced increased health problems. We hypothesized that gestational/early-life exposure to ≥1 DS/day (DS) or equivalent aspartame (ASP: ≥177 mg/day) increases autism risk. The case-control Autism Tooth Fairy Study obtained retrospective dietary recalls for DSB and aspartame consumption during pregnancy/breastfeeding from the mothers of 235 offspring with autism spectrum disorder (ASD: cases) and 121 neurotypically developing offspring (controls). The exposure odds ratios (ORs) for DS and ASP were computed for autism, ASD, and the non-regressive conditions of each. Among males, the DS odds were tripled for autism (OR = 3.1; 95% CI: 1.02, 9.7) and non-regressive autism (OR = 3.5; 95% CI: 1.1, 11.1); the ASP odds were even higher: OR = 3.4 (95% CI: 1.1, 10.4) and 3.7 (95% CI: 1.2, 11.8), respectively ( < 0.05 for each). The ORs for non-regressive ASD in males were almost tripled but were not statistically significant: DS OR = 2.7 (95% CI: 0.9, 8.4); ASP OR = 2.9 (95% CI: 0.9, 8.8). No statistically significant associations were found in females. Our findings contribute to the growing literature raising concerns about potential offspring harm from maternal DSB/aspartame intake in pregnancy.
Topics: Female; Male; Pregnancy; Humans; Aspartame; Autistic Disorder; Case-Control Studies; Autism Spectrum Disorder; Retrospective Studies; Prospective Studies; Diet
PubMed: 37686804
DOI: 10.3390/nu15173772 -
Autism : the International Journal of... Nov 2023The way autism is represented in fictional media can impact people's views of autistic people. For example, representations may contribute to negative views of autistic... (Review)
Review
The way autism is represented in fictional media can impact people's views of autistic people. For example, representations may contribute to negative views of autistic people as being unusual or dangerous, or they may challenge stereotypes and instead highlight the strengths of autistic people. This work aimed to review previous research to understand how autistic people have been represented in fictional media (Part A). It also sought to understand whether viewing fictional portrayals of autism has an impact on people's knowledge of autism and attitudes towards autistic people (Part B). Of 14 studies that were included in Part A, several unhelpful and stereotypical portrayals of autism emerged. Positive portrayals were those that highlighted the strengths of autistic people and reflected nuance. There is a need for greater diversity in representation of autism in fictional media. For example, not all autistic people are white heterosexual males. Across the five studies included in Part B, there were no improvements in people's knowledge of autism after watching or reading a short segment from a fictional TV series or novel that depicts an autistic person. Although there was a significant improvement in people's attitudes towards autistic people, these findings do not provide a complete picture given the short length of the media exposure and small number of studies. Future studies should investigate how multiple exposures to the representation of autistic people in both fictional and non-fictional sources can affect people's understanding of autism. There is also a need to develop more accurate and respectful ways of measuring people's knowledge of, and attitudes towards, autism.
Topics: Male; Humans; Autistic Disorder; Autism Spectrum Disorder; Stereotyped Behavior; Respect; Stereotypic Movement Disorder
PubMed: 36802826
DOI: 10.1177/13623613231155770 -
Nature Medicine Jul 2023While over 100 genes have been associated with autism, little is known about the prevalence of variants affecting them in individuals without a diagnosis of autism. Nor...
While over 100 genes have been associated with autism, little is known about the prevalence of variants affecting them in individuals without a diagnosis of autism. Nor do we fully appreciate the phenotypic diversity beyond the formal autism diagnosis. Based on data from more than 13,000 individuals with autism and 210,000 undiagnosed individuals, we estimated the odds ratios for autism associated to rare loss-of-function (LoF) variants in 185 genes associated with autism, alongside 2,492 genes displaying intolerance to LoF variants. In contrast to autism-centric approaches, we investigated the correlates of these variants in individuals without a diagnosis of autism. We show that these variants are associated with a small but significant decrease in fluid intelligence, qualification level and income and an increase in metrics related to material deprivation. These effects were larger for autism-associated genes than in other LoF-intolerant genes. Using brain imaging data from 21,040 individuals from the UK Biobank, we could not detect significant differences in the overall brain anatomy between LoF carriers and non-carriers. Our results highlight the importance of studying the effect of the genetic variants beyond categorical diagnosis and the need for more research to understand the association between these variants and sociodemographic factors, to best support individuals carrying these variants.
Topics: Humans; Autistic Disorder; Phenotype; Heterozygote; Brain; Autism Spectrum Disorder
PubMed: 37365347
DOI: 10.1038/s41591-023-02408-2 -
JAMA Sep 2023In the US, children with signs of autism often experience more than 1 year of delay before diagnosis and often experience longer delays if they are from racially,... (Comparative Study)
Comparative Study
IMPORTANCE
In the US, children with signs of autism often experience more than 1 year of delay before diagnosis and often experience longer delays if they are from racially, ethnically, or economically disadvantaged backgrounds. Most diagnoses are also received without use of standardized diagnostic instruments. To aid in early autism diagnosis, eye-tracking measurement of social visual engagement has shown potential as a performance-based biomarker.
OBJECTIVE
To evaluate the performance of eye-tracking measurement of social visual engagement (index test) relative to expert clinical diagnosis in young children referred to specialty autism clinics.
DESIGN, SETTING, AND PARTICIPANTS
In this study of 16- to 30-month-old children enrolled at 6 US specialty centers from April 2018 through May 2019, staff blind to clinical diagnoses used automated devices to measure eye-tracking-based social visual engagement. Expert clinical diagnoses were made using best practice standardized protocols by specialists blind to index test results. This study was completed in a 1-day protocol for each participant.
MAIN OUTCOMES AND MEASURES
Primary outcome measures were test sensitivity and specificity relative to expert clinical diagnosis. Secondary outcome measures were test correlations with expert clinical assessments of social disability, verbal ability, and nonverbal cognitive ability.
RESULTS
Eye-tracking measurement of social visual engagement was successful in 475 (95.2%) of the 499 enrolled children (mean [SD] age, 24.1 [4.4] months; 38 [8.0%] were Asian; 37 [7.8%], Black; 352 [74.1%], White; 44 [9.3%], other; and 68 [14.3%], Hispanic). By expert clinical diagnosis, 221 children (46.5%) had autism and 254 (53.5%) did not. In all children, measurement of social visual engagement had sensitivity of 71.0% (95% CI, 64.7% to 76.6%) and specificity of 80.7% (95% CI, 75.4% to 85.1%). In the subgroup of 335 children whose autism diagnosis was certain, sensitivity was 78.0% (95% CI, 70.7% to 83.9%) and specificity was 85.4% (95% CI, 79.5% to 89.8%). Eye-tracking test results correlated with expert clinical assessments of individual levels of social disability (r = -0.75 [95% CI, -0.79 to -0.71]), verbal ability (r = 0.65 [95% CI, 0.59 to 0.70]), and nonverbal cognitive ability (r = 0.65 [95% CI, 0.59 to 0.70]).
CONCLUSIONS AND RELEVANCE
In 16- to 30-month-old children referred to specialty clinics, eye-tracking-based measurement of social visual engagement was predictive of autism diagnoses by clinical experts. Further evaluation of this test's role in early diagnosis and assessment of autism in routine specialty clinic practice is warranted.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03469986.
Topics: Child, Preschool; Humans; Infant; Ambulatory Care Facilities; Asian; Autistic Disorder; Eye Movements; Eye-Tracking Technology; Social Behavior; Visual Perception
PubMed: 37668621
DOI: 10.1001/jama.2023.13295 -
Development (Cambridge, England) Jul 2023Gene ontology analyses of high-confidence autism spectrum disorder (ASD) risk genes highlight chromatin regulation and synaptic function as major contributors to...
Gene ontology analyses of high-confidence autism spectrum disorder (ASD) risk genes highlight chromatin regulation and synaptic function as major contributors to pathobiology. Our recent functional work in vivo has additionally implicated tubulin biology and cellular proliferation. As many chromatin regulators, including the ASD risk genes ADNP and CHD3, are known to directly regulate both tubulins and histones, we studied the five chromatin regulators most strongly associated with ASD (ADNP, CHD8, CHD2, POGZ and KMT5B) specifically with respect to tubulin biology. We observe that all five localize to microtubules of the mitotic spindle in vitro in human cells and in vivo in Xenopus. Investigation of CHD2 provides evidence that mutations present in individuals with ASD cause a range of microtubule-related phenotypes, including disrupted localization of the protein at mitotic spindles, cell cycle stalling, DNA damage and cell death. Lastly, we observe that ASD genetic risk is significantly enriched among tubulin-associated proteins, suggesting broader relevance. Together, these results provide additional evidence that the role of tubulin biology and cellular proliferation in ASD warrants further investigation and highlight the pitfalls of relying solely on annotated gene functions in the search for pathological mechanisms.
Topics: Humans; Autistic Disorder; Chromatin; Autism Spectrum Disorder; Tubulin; Histones; Microtubules; Spindle Apparatus
PubMed: 37366052
DOI: 10.1242/dev.201515 -
Medicina Mar 2024The Autism Spectrum Disorder is a neurobiological based disorder with a high percentage of heritability and a wide list of possible etiologies that presents very...
The Autism Spectrum Disorder is a neurobiological based disorder with a high percentage of heritability and a wide list of possible etiologies that presents very heterogeneous changes in neuronal architecture, connectivity and synaptogenesis with characteristic clinical manifestations whose origin points to environmental, immunological, genetic and other causes, without having been confirmed specific biomarkers. Diagnosis continues to be based on typical features including repetitive behaviors and impaired communication and social interaction. Their genetic and non-genetic risk factors are reviewed to advance knowledge about the pathological processes that may be related to their origin.
Topics: Humans; Autistic Disorder; Autism Spectrum Disorder; Biomarkers
PubMed: 38350622
DOI: No ID Found -
Nature Neuroscience Sep 2023Idiopathic autism spectrum disorder (ASD) is highly heterogeneous, and it remains unclear how convergent biological processes in affected individuals may give rise to...
Idiopathic autism spectrum disorder (ASD) is highly heterogeneous, and it remains unclear how convergent biological processes in affected individuals may give rise to symptoms. Here, using cortical organoids and single-cell transcriptomics, we modeled alterations in the forebrain development between boys with idiopathic ASD and their unaffected fathers in 13 families. Transcriptomic changes suggest that ASD pathogenesis in macrocephalic and normocephalic probands involves an opposite disruption of the balance between excitatory neurons of the dorsal cortical plate and other lineages such as early-generated neurons from the putative preplate. The imbalance stemmed from divergent expression of transcription factors driving cell fate during early cortical development. While we did not find genomic variants in probands that explained the observed transcriptomic alterations, a significant overlap between altered transcripts and reported ASD risk genes affected by rare variants suggests a degree of gene convergence between rare forms of ASD and the developmental transcriptome in idiopathic ASD.
Topics: Male; Humans; Autistic Disorder; Autism Spectrum Disorder; Neurons; Neurogenesis; Prosencephalon; Organoids
PubMed: 37563294
DOI: 10.1038/s41593-023-01399-0 -
Molecular Autism Oct 2023Autism spectrum disorders (ASD) are neurodevelopmental conditions accompanied by differences in brain development. Neuroanatomical differences in autism are variable...
BACKGROUND
Autism spectrum disorders (ASD) are neurodevelopmental conditions accompanied by differences in brain development. Neuroanatomical differences in autism are variable across individuals and likely underpin distinct clinical phenotypes. To parse heterogeneity, it is essential to establish how the neurobiology of ASD is modulated by differences associated with co-occurring conditions, such as attention-deficit/hyperactivity disorder (ADHD). This study aimed to (1) investigate between-group differences in autistic individuals with and without co-occurring ADHD, and to (2) link these variances to putative genomic underpinnings.
METHODS
We examined differences in cortical thickness (CT) and surface area (SA) and their genomic associations in a sample of 533 individuals from the Longitudinal European Autism Project. Using a general linear model including main effects of autism and ADHD, and an ASD-by-ADHD interaction, we examined to which degree ADHD modulates the autism-related neuroanatomy. Further, leveraging the spatial gene expression data of the Allen Human Brain Atlas, we identified genes whose spatial expression patterns resemble our neuroimaging findings.
RESULTS
In addition to significant main effects for ASD and ADHD in fronto-temporal, limbic, and occipital regions, we observed a significant ASD-by-ADHD interaction in the left precentral gyrus and the right frontal gyrus for measures of CT and SA, respectively. Moreover, individuals with ASD + ADHD differed in CT to those without. Both main effects and the interaction were enriched for ASD-but not for ADHD-related genes.
LIMITATIONS
Although we employed a multicenter design to overcome single-site recruitment limitations, our sample size of N = 25 individuals in the ADHD only group is relatively small compared to the other subgroups, which limits the generalizability of the results. Also, we assigned subjects into ADHD positive groupings according to the DSM-5 rating scale. While this is sufficient for obtaining a research diagnosis of ADHD, our approach did not take into account for how long the symptoms have been present, which is typically considered when assessing ADHD in the clinical setting.
CONCLUSION
Thus, our findings suggest that the neuroanatomy of ASD is significantly modulated by ADHD, and that autistic individuals with co-occurring ADHD may have specific neuroanatomical underpinnings potentially mediated by atypical gene expression.
Topics: Humans; Autistic Disorder; Attention Deficit Disorder with Hyperactivity; Neuroanatomy; Brain; Autism Spectrum Disorder; Genomics
PubMed: 37794485
DOI: 10.1186/s13229-023-00568-z