ABSTRACT
La falta de información sobre el uso de la tecnología en niños con trastorno del espectro autista (TEA) de diferentes perfiles puede dificultar que docentes y alumnos se estén beneficiando del apoyo tecnológico más eficaz y ajustado a sus necesidades. El objetivo de esta revisión fue analizar y sintetizar la evidencia científica sobre la eficacia de los recursos tecnológicos en la mejora de la comprensión emocional de estudiantes con TEA con perfiles de alto y bajo funcionamiento. Para ello se realizó una revisión sistemática de las publicaciones científicas indexadas en algunas de las bases de datos de mayor relevancia siguiendo los criterios establecidos en la declaración PRISMA. En total se analizaron 38 artículos que cumplieron con los criterios de inclusión preestablecidos. Los resultados muestran la importancia de diseñar sistemas versátiles que puedan personalizarse y adaptarse en tiempo real y en contextos naturales con un enfoque claramente inclusivo. Pero también sugieren que la tecnología puede no ser una herramienta de intervención complementaria adecuada para todos los niños con TEA. Lo que subraya la necesidad de ensayos adicionales bien controlados sobre las características que permitan identificar qué estudiantes podrían o no beneficiarse de diferentes modalidades de tecnología. (AU)
The lack of information on the use of technology in children with autism spectrum disorder (ASD) of different profiles can make it difficult for teachers and students to benefit from the most effective technology support tailored to their needs. The aim of this review was to analyze and synthesize scientific evidence on the effectiveness of technological resources in improving the emotional understanding of students with high and low functioning ASD profiles. A systematic review of the scientific publications indexed in some of the most relevant databases was carried out following the criteria established in the PRISMA declaration. A total of 38 articles that met the pre-established inclusion criteria were analyzed. The results show the importance of designing versatile systems that can be customized and adapted in real time and in natural contexts with a clearly inclusive approach. But they also suggest that technology may not be an appropriate complementary intervention tool for all children with ASD. This underlines the need for additional well-controlled tests on the characteristics that would allow identifying which students might or might not benefit from different technology modalities. (AU)
Subject(s)
Humans , Child, Preschool , Child , Adolescent , Educational Technology , Autism Spectrum Disorder , Autistic DisorderABSTRACT
La falta de información sobre el uso de la tecnología en niños con trastorno del espectro autista (TEA) de diferentes perfiles puede dificultar que docentes y alumnos se estén beneficiando del apoyo tecnológico más eficaz y ajustado a sus necesidades. El objetivo de esta revisión fue analizar y sintetizar la evidencia científica sobre la eficacia de los recursos tecnológicos en la mejora de la comprensión emocional de estudiantes con TEA con perfiles de alto y bajo funcionamiento. Para ello se realizó una revisión sistemática de las publicaciones científicas indexadas en algunas de las bases de datos de mayor relevancia siguiendo los criterios establecidos en la declaración PRISMA. En total se analizaron 38 artículos que cumplieron con los criterios de inclusión preestablecidos. Los resultados muestran la importancia de diseñar sistemas versátiles que puedan personalizarse y adaptarse en tiempo real y en contextos naturales con un enfoque claramente inclusivo. Pero también sugieren que la tecnología puede no ser una herramienta de intervención complementaria adecuada para todos los niños con TEA. Lo que subraya la necesidad de ensayos adicionales bien controlados sobre las características que permitan identificar qué estudiantes podrían o no beneficiarse de diferentes modalidades de tecnología. (AU)
The lack of information on the use of technology in children with autism spectrum disorder (ASD) of different profiles can make it difficult for teachers and students to benefit from the most effective technology support tailored to their needs. The aim of this review was to analyze and synthesize scientific evidence on the effectiveness of technological resources in improving the emotional understanding of students with high and low functioning ASD profiles. A systematic review of the scientific publications indexed in some of the most relevant databases was carried out following the criteria established in the PRISMA declaration. A total of 38 articles that met the pre-established inclusion criteria were analyzed. The results show the importance of designing versatile systems that can be customized and adapted in real time and in natural contexts with a clearly inclusive approach. But they also suggest that technology may not be an appropriate complementary intervention tool for all children with ASD. This underlines the need for additional well-controlled tests on the characteristics that would allow identifying which students might or might not benefit from different technology modalities. (AU)
Subject(s)
Humans , Child, Preschool , Child , Adolescent , Educational Technology , Autism Spectrum Disorder , Autistic DisorderABSTRACT
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social and communication deficits and repetitive behaviors. The genetic heterogeneity of ASD presents a challenge to the development of an effective treatment targeting the underlying molecular defects. ASD gating charge mutations in the KCNQ/KV7 potassium channel cause gating pore currents (Igp) and impair action potential (AP) firing of dopaminergic neurons in brain slices. Here, we investigated ASD gating charge mutations of the voltage-gated SCN2A/NaV1.2 brain sodium channel, which ranked high among the ion channel genes with mutations in individuals with ASD. Our results show that ASD mutations in the gating charges R2 in Domain-II (R853Q), and R1 (R1626Q) and R2 (R1629H) in Domain-IV of NaV1.2 caused Igp in the resting state of ~0.1% of the amplitude of central pore current. The R1626Q mutant also caused significant changes in the voltage dependence of fast inactivation, and the R1629H mutant conducted proton-selective Igp. These potentially pathogenic Igp were exacerbated by the absence of the extracellular Mg2+ and Ca2+. In silico simulation of the effects of these mutations in a conductance-based single-compartment cortical neuron model suggests that the inward Igp reduces the time to peak for the first AP in a train, increases AP rates during a train of stimuli, and reduces the interstimulus interval between consecutive APs, consistent with increased neural excitability and altered input/output relationships. Understanding this common pathophysiological mechanism among different voltage-gated ion channels at the circuit level will give insights into the underlying mechanisms of ASD.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Voltage-Gated Sodium Channels , Humans , Autism Spectrum Disorder/genetics , Autistic Disorder/genetics , Brain , MutationABSTRACT
BACKGROUND: Artificial intelligence-powered interventions have emerged as promising tools to support autistic individuals. However, more research must examine how teachers and educators perceive and experience these AI systems when implemented. OBJECTIVES: The first objective was to investigate informants' perceptions and experiences of AI-empowered interventions for children with autism. Mainly, it explores the informants' perceived benefits and challenges of using AI-empowered interventions and their recommendations for avoiding the perceived challenges. METHODOLOGY: A qualitative phenomenological approach was used. Twenty educators and parents with experience implementing AI interventions for autism were recruited through purposive sampling. Semi-structured and focus group interviews conducted, transcribed verbatim, and analyzed using thematic analysis. FINDINGS: The analysis identified four major themes: perceived benefits of AI interventions, implementation challenges, needed support, and recommendations for improvement. Benefits included increased engagement and personalized learning. Challenges included technology issues, training needs, and data privacy concerns. CONCLUSIONS: AI-powered interventions show potential to improve autism support, but significant challenges must be addressed to ensure effective implementation from an educator's perspective. The benefits of personalized learning and student engagement demonstrate the potential value of these technologies. However, with adequate training, technical support, and measures to ensure data privacy, many educators will likely find integrating AI systems into their daily practices easier. IMPLICATIONS: To realize the full benefits of AI for autism, developers must work closely with educators to understand their needs, optimize implementation, and build trust through transparent privacy policies and procedures. With proper support, AI interventions can transform how autistic individuals are educated by tailoring instruction to each student's unique profile and needs.
Subject(s)
Autistic Disorder , Educational Personnel , Child , Humans , Autistic Disorder/therapy , Artificial Intelligence , Learning , StudentsABSTRACT
Genes implicated in translation control have been associated with autism spectrum disorders (ASDs). However, some important genetic causes of autism, including the 16p11.2 microdeletion, bear no obvious connection to translation. Here, we use proteomics, genetics, and translation assays in cultured cells and mouse brain to reveal altered translation mediated by loss of the kinase TAOK2 in 16p11.2 deletion models. We show that TAOK2 associates with the translational machinery and functions as a translational brake by phosphorylating eukaryotic elongation factor 2 (eEF2). Previously, all signal-mediated regulation of translation elongation via eEF2 phosphorylation was believed to be mediated by a single kinase, eEF2K. However, we show that TAOK2 can directly phosphorylate eEF2 on the same regulatory site, but functions independently of eEF2K signaling. Collectively, our results reveal an eEF2K-independent signaling pathway for control of translation elongation and suggest altered translation as a molecular component in the etiology of some forms of ASD.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Ursidae , Animals , Mice , Autistic Disorder/genetics , Peptide Elongation Factor 2 , Phosphorylation , Autism Spectrum Disorder/genetics , Biological AssayABSTRACT
Glutamate (Glu) is important for memory and learning. Hence, Glu imbalance is speculated to affect autism spectrum disorder (ASD) pathophysiology. The action of Glu is mediated through receptors and we analyzed four metabotropic Glu receptors (mGluR/GRM) in Indo-Caucasoid families with ASD probands and controls. The trait scores of the ASD probands were assessed using the Childhood Autism Rating Scale2-ST. Peripheral blood was collected, genomic DNA isolated, and GRM5 rs905646, GRM6 rs762724 & rs2067011, and GRM7 rs3792452 were analyzed by PCR/RFLP or Taqman assay. Expression of mGluRs was measured in the peripheral blood by qPCR. Significantly higher frequencies of rs2067011 'A' allele/ AA' genotype were detected in the probands. rs905646 'A 'exhibited significantly higher parental transmission. Genetic variants showed independent as well as interactive effects in the probands. Receptor expression was down-regulated in the probands, especially in the presence of rs905646 'AA', rs762724 'TT', rs2067011 'GG', and rs3792452 'CC'. Trait scores were higher in the presence of rs762724 'T' and rs2067011 'G'. Therefore, in the presence of risk genetic variants, down-regulated mGluR expression may increase autistic trait scores. Since our investigation was confined to the peripheral system, in-depth exploration involving peripheral as well as central nervous systems may validate our observation.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Receptors, Metabotropic Glutamate , Humans , Child , Autistic Disorder/genetics , Autism Spectrum Disorder/genetics , Gene Expression , Glutamic Acid , Receptors, Metabotropic Glutamate/geneticsABSTRACT
BACKGROUND: Autism spectrum disorder (hereafter referred to as autism) is characterised by difficulties with (i) social communication, social interaction, and (ii) restricted and repetitive interests and behaviours. Estimates of autism prevalence within the criminal justice system (CJS) vary considerably, but there is evidence to suggest that the condition can be missed or misidentified within this population. Autism has implications for an individual's journey through the CJS, from police questioning and engagement in court proceedings through to risk assessment, formulation, therapeutic approaches, engagement with support services, and long-term social and legal outcomes. METHODS: This consensus based on professional opinion with input from lived experience aims to provide general principles for consideration by United Kingdom (UK) CJS personnel when working with autistic individuals, focusing on autistic offenders and those suspected of offences. Principles may be transferable to countries beyond the UK. Multidisciplinary professionals and two service users were approached for their input to address the effective identification and support strategies for autistic individuals within the CJS. RESULTS: The authors provide a consensus statement including recommendations on the general principles of effective identification, and support strategies for autistic individuals across different levels of the CJS. CONCLUSION: Greater attention needs to be given to this population as they navigate the CJS.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Humans , Autistic Disorder/diagnosis , Autistic Disorder/epidemiology , Autistic Disorder/therapy , Autism Spectrum Disorder/diagnosis , Autism Spectrum Disorder/epidemiology , Autism Spectrum Disorder/therapy , Criminal Law , Communication , United Kingdom/epidemiologyABSTRACT
Eye contact is a central component in face-to-face interactions. It is important in structuring communicative exchanges and offers critical insights into others' interests and intentions. To better understand eye contact in face-to-face interactions, we applied a novel, non-intrusive deep-learning-based dual-camera system and investigated associations between eye contact and autistic traits as well as self-reported eye contact discomfort during a referential communication task, where participants and the experimenter had to guess, in turn, a word known by the other individual. Corroborating previous research, we found that participants' eye gaze and mutual eye contact were inversely related to autistic traits. In addition, our findings revealed different behaviors depending on the role in the dyad: listening and guessing were associated with increased eye contact compared with describing words. In the listening and guessing condition, only a subgroup who reported eye contact discomfort had a lower amount of eye gaze and eye contact. When describing words, higher autistic traits were associated with reduced eye gaze and eye contact. Our data indicate that eye contact is inversely associated with autistic traits when describing words, and that eye gaze is modulated by the communicative role in a conversation.
Subject(s)
Autistic Disorder , Humans , Communication , Nonverbal Communication , Fixation, Ocular , IntentionABSTRACT
BACKGROUND: Clinicians diagnosing autism rely on diagnostic criteria and instruments in combination with an implicit knowledge based on clinical expertise of the specific signs and presentations associated with the condition. This implicit knowledge influences how diagnostic criteria are interpreted, but it cannot be directly observed. Instead, insight into clinicians' understanding of autism can be gained by investigating their diagnostic certainty. Modest correlations between the certainty of an autism diagnosis and symptom load have been previously reported. Here, we investigated the associations of diagnostic certainty with specific items of the ADOS as well as other clinical features including head circumference. METHODS: Phenotypic data from the Simons Simplex Collection was used to investigate clinical correlates of diagnostic certainty in individuals diagnosed with Autistic Disorder (n = 1511, age 4 to 18 years). Participants were stratified by the ADOS module used to evaluate them. We investigated how diagnostic certainty was associated with total ADOS scores, age, and ADOS module. We calculated the odds-ratios of being diagnosed with the highest possible certainty given the presence or absence of different signs during the ADOS evaluation. Associations between diagnostic certainty and other cognitive and clinical variables were also assessed. RESULTS: In each ADOS module, some items showed a larger association with diagnostic certainty than others. Head circumference was significantly higher for individuals with the highest certainty rating across all three ADOS modules. In turn, head circumference was positively correlated with some of the ADOS items that were associated with diagnostic certainty, and was negatively correlated with verbal/nonverbal IQ ratio among those assessed with ADOS module 2. LIMITATIONS: The investigated cohort was heterogeneous, e.g. in terms of age, IQ, language level, and total ADOS score, which could impede the identification of associations that only exist in a subgroup of the population. The variability of the certainty ratings in the sample was low, limiting the power to identify potential associations with other variables. Additionally, the scoring of diagnostic certainty may vary between clinicians. CONCLUSION: Some ADOS items may better capture the signs that are most associated with clinicians' implicit knowledge of Autistic Disorder. If replicated in future studies, new diagnostic instruments with differentiated weighting of signs may be needed to better reflect this, possibly resulting in better specificity in standardized assessments.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Child , Humans , Adolescent , Child, Preschool , Autistic Disorder/diagnosis , Language , Autism Spectrum Disorder/diagnosisABSTRACT
Importance: Several studies suggest that acetaminophen (paracetamol) use during pregnancy may increase risk of neurodevelopmental disorders in children. If true, this would have substantial implications for management of pain and fever during pregnancy. Objective: To examine the associations of acetaminophen use during pregnancy with children's risk of autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability. Design, Setting, and Participants: This nationwide cohort study with sibling control analysis included a population-based sample of 2â¯480â¯797 children born in 1995 to 2019 in Sweden, with follow-up through December 31, 2021. Exposure: Use of acetaminophen during pregnancy prospectively recorded from antenatal and prescription records. Main Outcomes and Measures: Autism, ADHD, and intellectual disability based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes in health registers. Results: In total, 185â¯909 children (7.49%) were exposed to acetaminophen during pregnancy. Crude absolute risks at 10 years of age for those not exposed vs those exposed to acetaminophen were 1.33% vs 1.53% for autism, 2.46% vs 2.87% for ADHD, and 0.70% vs 0.82% for intellectual disability. In models without sibling control, ever-use vs no use of acetaminophen during pregnancy was associated with marginally increased risk of autism (hazard ratio [HR], 1.05 [95% CI, 1.02-1.08]; risk difference [RD] at 10 years of age, 0.09% [95% CI, -0.01% to 0.20%]), ADHD (HR, 1.07 [95% CI, 1.05-1.10]; RD, 0.21% [95% CI, 0.08%-0.34%]), and intellectual disability (HR, 1.05 [95% CI, 1.00-1.10]; RD, 0.04% [95% CI, -0.04% to 0.12%]). To address unobserved confounding, matched full sibling pairs were also analyzed. Sibling control analyses found no evidence that acetaminophen use during pregnancy was associated with autism (HR, 0.98 [95% CI, 0.93-1.04]; RD, 0.02% [95% CI, -0.14% to 0.18%]), ADHD (HR, 0.98 [95% CI, 0.94-1.02]; RD, -0.02% [95% CI, -0.21% to 0.15%]), or intellectual disability (HR, 1.01 [95% CI, 0.92-1.10]; RD, 0% [95% CI, -0.10% to 0.13%]). Similarly, there was no evidence of a dose-response pattern in sibling control analyses. For example, for autism, compared with no use of acetaminophen, persons with low (<25th percentile), medium (25th-75th percentile), and high (>75th percentile) mean daily acetaminophen use had HRs of 0.85, 0.96, and 0.88, respectively. Conclusions and Relevance: Acetaminophen use during pregnancy was not associated with children's risk of autism, ADHD, or intellectual disability in sibling control analysis. This suggests that associations observed in other models may have been attributable to familial confounding.
Subject(s)
Acetaminophen , Attention Deficit Disorder with Hyperactivity , Autistic Disorder , Intellectual Disability , Prenatal Exposure Delayed Effects , Child , Female , Humans , Pregnancy , Acetaminophen/adverse effects , Attention Deficit Disorder with Hyperactivity/chemically induced , Attention Deficit Disorder with Hyperactivity/epidemiology , Autistic Disorder/chemically induced , Autistic Disorder/epidemiology , Cohort Studies , Confounding Factors, Epidemiologic , Follow-Up Studies , Intellectual Disability/chemically induced , Intellectual Disability/epidemiology , Neurodevelopmental Disorders/chemically induced , Neurodevelopmental Disorders/epidemiology , Prenatal Exposure Delayed Effects/chemically induced , Prenatal Exposure Delayed Effects/epidemiology , Sweden/epidemiologyABSTRACT
Though visuospatial skills are often considered a relative strength in autism spectrum disorder (ASD), unexplained difficulties relative to neurotypical (NT) peers have also been observed. Dissociations between spatial cognition and language skills in ASD may explain these difficulties given that these systems are linked in NT individuals. The current study examined performance on a mental rotation task that systematically varied stimulus features and the degree to which performance was associated with language in ASD relative to NT peers. Participants were children and young adults with ASD and 25 pairwise age- and IQ-matched NT peers (p's>0.53). The mental rotation task involved four conditions: two-dimensional (2D) abstract figures, three-dimensional (3D) abstract figures, 2D common objects, and 3D common objects. Structural language was measured using the grammar subscale from the Test of Language Development: Intermediate adapted for Norwegian. Mixed-effects model results indicated that autistic individuals were less accurate and had slower reaction time across mental rotation task conditions than NT peers. Language was associated with mental rotation accuracy for both groups across conditions, but with reaction time only for the NT group. The current study demonstrated selective associations between language and performance on a classic spatial cognition task in autistic individuals. Namely, there was a dissociation between language and in-the-moment efficiency in the ASD group, and this dissociation may reflect a broader dissociation between visuospatial and language systems.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Child , Young Adult , Humans , Autism Spectrum Disorder/complications , Language , Cognition , Autistic Disorder/complications , LinguisticsABSTRACT
A core feature of autism is deficits in executive functioning (EF), including difficulty with planning, cognitive flexibility, and working memory. Despite a growing need for evidence-based assessments of EF for autism populations, statistical models of many commonly used measures of EF, including the Delis-Kaplan Executive Function System (D-KEFS), have not been investigated for a sample of autistic participants. The purpose of this study was to address a gap in the literature regarding the latent structure of the D-KEFS in a sample of autistic individuals. The D-KEFS is one of the most widely used clinical assessments of executive function, but its factor structure has not been examined in a sample of autistic participants. Reliability analyses were performed for sample subgroups based on participants' clinical and demographic characteristics, including IQ, autism severity, age, and race/ethnicity. Verbal Fluency (VF) was found to consistently decrease or not affect the overall reliability score. Additionally, one- and two-factor structure models were tested for the D-KEFS with a sample of autistic participants. The one-factor model was not found to be a good fit for the data. However, the two-factor model, with Cognitive Flexibility and Abstraction latent factors, was found to fit the data relatively well. This two-factor model was reexamined excluding the VF observed variable, resulting in a better overall model fit. Communication deficits are a common feature of autism, which explains why the VF task, that requires participants to produce novel words, may not be an adequate measure of executive function for autism populations.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Humans , Neuropsychological Tests , Reproducibility of Results , Executive FunctionABSTRACT
OBJETIVO: O presente trabalho teve por objetivo avaliar e comparar a habilidade do comportamento verbal em crianças com distintos níveis de suporte do TEA. MÉTODO: Foram avaliadas onze crianças diagnosticadas com autismo e com faixa etária entre 2 e 7 anos e que apresentassem diversidade entre si quanto ao nível de suporte TEA. Para a averiguação do repertório de comunicação, eles foram avaliados a partir de um instrumento elaborado por uma equipe de profissionais especializados, investigando o comportamento não verbal, ecoico, mando, tato e intraverbal em três tentativas. RESULTADOS: Apesar do número reduzido de participantes, os resultados indicaram que pacientes no nível 3 de suporte apresentam maior comprometimento na comunicação comparado aos demais. O estudo destacou a importância do rastreio de habilidades comportamentais para um planejamento com maior eficácia para a intervenção e concomitantemente evolução clínica, respeitando assim as particularidades e singularidades de cada pessoa no espectro. CONCLUSÃO: Concluiu-se assim, a importância da análise de comportamentos e a investigação detalhada para cada paciente, a fim de que as intervenções sejam focadas em suas reais necessidades.
OBJECTIVE: The present work aimed to evaluate and compare the verbal behavior ability in children with different levels of ASD support. METHOD: Eleven children diagnosed with autism and aged between 2 and 7 years old and who presented diversity among themselves in terms of the level of ASD support were evaluated. To investigate their communication repertoire, they were evaluated using an instrument developed by a team of specialized professionals, investigating non-verbal, echoic, command, tact and intraverbal behavior in three attempts. RESULTS: Despite the small number of participants, the results indicated that patients at level 3 of support have greater impairment in communication compared to the others. The study highlighted the importance of screening behavioral skills for more effective planning for intervention and concomitant clinical evolution, thus respecting the particularities and singularities of each person on the spectrum. CONCLUSION: This concludes the importance of behavioral analysis and detailed investigation for each patient, so that interventions are focused on their real needs.
OBJETIVO: El presente trabajo tuvo como objetivo evaluar y comparar la capacidad de conducta verbal en niños con diferentes niveles de apoyo al TEA. MÉTODO: Se evaluaron once niños diagnosticados con autismo, con edades entre 2 y 7 años y que presentaban diversidad entre sí en cuanto al nivel de apoyo al TEA. Para investigar su repertorio comunicativo, fueron evaluados mediante un instrumento desarrollado por un equipo de profesionales especializados, investigando el comportamiento no verbal, ecoico, de mando, tacto e intraverbal en tres intentos. RESULTADOS: A pesar del pequeño número de participantes, los resultados indicaron que los pacientes en el nivel 3 de apoyo tienen un mayor deterioro en la comunicación en comparación con los demás. El estudio destacó la importancia del cribado de habilidades conductuales para una planificación más eficaz de la intervención y la evolución clínica concomitante, respetando así las particularidades y singularidades de cada persona del espectro. CONCLUSIÓN: Se concluye la importancia del análisis conductual y la investigación detallada de cada paciente, para que las intervenciones estén enfocadas a sus necesidades reales.
Subject(s)
Autistic Disorder , Verbal Behavior , Behavioral MedicineABSTRACT
Autism Spectrum Disorders (ASD) are principally diagnosed by three core behavioural symptoms, such as stereotyped repertoire, communication impairments and social dysfunctions. This complex pathology has been linked to abnormalities of corticostriatal and limbic circuits. Despite experimental efforts in elucidating the molecular mechanisms behind these abnormalities, a clear etiopathogenic hypothesis is still lacking. To this aim, preclinical studies can be really helpful to longitudinally study behavioural alterations resembling human symptoms and to investigate the underlying neurobiological correlates. In this regard, the BTBR T+ Itpr3tf/J (BTBR) mice are an inbred mouse strain that exhibits a pattern of behaviours well resembling human ASD-like behavioural features. In this study, the BTBR mice model was used to investigate neurochemical and biomolecular alterations, regarding Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), together with GABAergic, glutamatergic, cholinergic, dopaminergic and noradrenergic neurotransmissions and their metabolites in four different brain areas, i.e. prefrontal cortex, hippocampus, amygdala and hypothalamus. In our results, BTBR strain reported decreased noradrenaline, acetylcholine and GABA levels in prefrontal cortex, while hippocampal measurements showed reduced NGF and BDNF expression levels, together with GABA levels. Concerning hypothalamus, no differences were retrieved. As regarding amygdala, we found reduced dopamine levels, accompanied by increased dopamine metabolites in BTBR mice, together with decreased acetylcholine, NGF and GABA levels and enhanced glutamate content. Taken together, our data showed that the BTBR ASD model, beyond its face validity, is a useful tool to untangle neurotransmission alterations that could be underpinned to the heterogeneous ASD-like behaviours, highlighting the crucial role played by amygdala.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Mice , Animals , Humans , Autistic Disorder/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Acetylcholine , Dopamine , Nerve Growth Factor/metabolism , Mice, Inbred C57BL , Mice, Inbred Strains , Synaptic Transmission/physiology , Autism Spectrum Disorder/metabolism , Amygdala/metabolism , gamma-Aminobutyric Acid , Disease Models, AnimalABSTRACT
Monogenic disorders account for a large proportion of population-attributable risk for neurodevelopmental disabilities. However, the data necessary to infer a causal relationship between a given genetic variant and a particular neurodevelopmental disorder is often lacking. Recognizing this scientific roadblock, 13 Intellectual and Developmental Disabilities Research Centers (IDDRCs) formed a consortium to create the Brain Gene Registry (BGR), a repository pairing clinical genetic data with phenotypic data from participants with variants in putative brain genes. Phenotypic profiles are assembled from the electronic health record (EHR) and a battery of remotely administered standardized assessments collectively referred to as the Rapid Neurobehavioral Assessment Protocol (RNAP), which include cognitive, neurologic, and neuropsychiatric assessments, as well as assessments for attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Co-enrollment of BGR participants in the Clinical Genome Resource's (ClinGen's) GenomeConnect enables display of variant information in ClinVar. The BGR currently contains data on 479 participants who are 55% male, 6% Asian, 6% Black or African American, 76% white, and 12% Hispanic/Latine. Over 200 genes are represented in the BGR, with 12 or more participants harboring variants in each of these genes: CACNA1A, DNMT3A, SLC6A1, SETD5, and MYT1L. More than 30% of variants are de novo and 43% are classified as variants of uncertain significance (VUSs). Mean standard scores on cognitive or developmental screens are below average for the BGR cohort. EHR data reveal developmental delay as the earliest and most common diagnosis in this sample, followed by speech and language disorders, ASD, and ADHD. BGR data has already been used to accelerate gene-disease validity curation of 36 genes evaluated by ClinGen's BGR Intellectual Disability (ID)-Autism (ASD) Gene Curation Expert Panel. In summary, the BGR is a resource for use by stakeholders interested in advancing translational research for brain genes and continues to recruit participants with clinically reported variants to establish a rich and well-characterized national resource to promote research on neurodevelopmental disorders.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Intellectual Disability , Neurodevelopmental Disorders , Humans , Male , Female , Autism Spectrum Disorder/genetics , Brain , Registries , MethyltransferasesABSTRACT
BACKGROUND: Helsmoortel-Van der Aa syndrome is a neurodevelopmental disorder in which patients present with autism, intellectual disability, and frequent extra-neurological features such as feeding and gastrointestinal problems, visual impairments, and cardiac abnormalities. All patients exhibit heterozygous de novo nonsense or frameshift stop mutations in the Activity-Dependent Neuroprotective Protein (ADNP) gene, accounting for a prevalence of 0.2% of all autism cases worldwide. ADNP fulfills an essential chromatin remodeling function during brain development. In this study, we investigated the cerebellum of a died 6-year-old male patient with the c.1676dupA/p.His559Glnfs*3 ADNP mutation. RESULTS: The clinical presentation of the patient was representative of the Helsmoortel-Van der Aa syndrome. During his lifespan, he underwent two liver transplantations after which the child died because of multiple organ failure. An autopsy was performed, and various tissue samples were taken for further analysis. We performed a molecular characterization of the cerebellum, a brain region involved in motor coordination, known for its highest ADNP expression and compared it to an age-matched control subject. Importantly, epigenome-wide analysis of the ADNP cerebellum identified CpG methylation differences and expression of multiple pathways causing neurodevelopmental delay. Interestingly, transcription factor motif enrichment analysis of differentially methylated genes showed that the ADNP binding motif was the most significantly enriched. RNA sequencing of the autopsy brain further identified downregulation of the WNT signaling pathway and autophagy defects as possible causes of neurodevelopmental delay. Ultimately, label-free quantification mass spectrometry identified differentially expressed proteins involved in mitochondrial stress and sirtuin signaling pathways amongst others. Protein-protein interaction analysis further revealed a network including chromatin remodelers (ADNP, SMARCC2, HDAC2 and YY1), autophagy-related proteins (LAMP1, BECN1 and LC3) as well as a key histone deacetylating enzyme SIRT1, involved in mitochondrial energy metabolism. The protein interaction of ADNP with SIRT1 was further biochemically validated through the microtubule-end binding proteins EB1/EB3 by direct co-immunoprecipitation in mouse cerebellum, suggesting important mito-epigenetic crosstalk between chromatin remodeling and mitochondrial energy metabolism linked to autophagy stress responses. This is further supported by mitochondrial activity assays and stainings in patient-derived fibroblasts which suggest mitochondrial dysfunctions in the ADNP deficient human brain. CONCLUSION: This study forms the baseline clinical and molecular characterization of an ADNP autopsy cerebellum, providing novel insights in the disease mechanisms of the Helsmoortel-Van der Aa syndrome. By combining multi-omic and biochemical approaches, we identified a novel SIRT1-EB1/EB3-ADNP protein complex which may contribute to autophagic flux alterations and impaired mitochondrial metabolism in the Helsmoortel-Van der Aa syndrome and holds promise as a new therapeutic target.
Subject(s)
Autistic Disorder , Intellectual Disability , Male , Child , Animals , Mice , Humans , Intellectual Disability/genetics , Autistic Disorder/genetics , Sirtuin 1/genetics , Sirtuin 1/metabolism , Genes, Mitochondrial , Homeodomain Proteins/genetics , Cerebellum/metabolism , Autopsy , Methylation , Nerve Tissue Proteins/metabolism , DNA-Binding Proteins/metabolism , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
IMPORTANCE: Caregivers are essential partners in caregiver-mediated interventions that build on family routines and practices. Research identifying how participation as an intervention partner influences caregivers' outcomes, including stress and self-efficacy, is scarce. OBJECTIVE: To evaluate caregiver outcomes (stress, self-efficacy, and positive feeding responses and confidence) after participation in the Engaged Eaters Program. DESIGN: Quasi-experimental pretest-posttest design. SETTING: In-home via telehealth. PARTICIPANTS: Fourteen primary caregivers of an autistic child (ages 2-7 yr) with feeding challenges. INTERVENTION: The Engaged Eaters Program-Telehealth, a caregiver-mediated 6-mo in-home telehealth feeding intervention for autistic children ages 2 to 7 yr that included 24 intervention visits, eight caregiver training modules, and consultation with a dietician. OUTCOMES AND MEASURES: Relationships between child feeding challenge severity and caregiver outcomes and individual differences in caregivers' intervention responses were evaluated. We assessed caregivers' stress (Parenting Stress Index, Fourth Edition Short Form), self-efficacy (Parent Sense of Competence Scale), Positive Feeding Responses and Confidence (PFRC; composite score of items from other assessments), and individual intervention response using pre- to postintervention change in scores. RESULTS: Exploration of individual differences revealed that only caregivers with intake PFRC scores below the mean made significant improvements by the end of the intervention. No significant group-level changes were identified for stress, self-efficacy, or PFRC. Feeding challenge severity was not significantly related to caregiver outcomes. CONCLUSIONS AND RELEVANCE: The results emphasize the importance of considering baseline practices, efficacy, and caregiver confidence when engaging caregivers in intervention. Future research should explore the nuanced relationship between caregiver outcomes and child characteristics. Plain-Language Summary: Caregivers are essential partners with feeding interventions that build on family routines and practices. When working with caregivers, occupational therapists should consider caregivers' readiness for and responses to an intervention because intervention practices may differentially affect caregivers' parenting practices, confidence, and self-efficacy. Caregivers' responses may also affect the overall effectiveness of a caregiver-mediated intervention. Positionality Statement: The term caregiver-mediated in used throughout this article in place of parent-mediated to be inclusive of all types of caregivers.
Subject(s)
Autistic Disorder , Caregivers , Child , Humans , Caregivers/education , Parents , Self Efficacy , Caregiver BurdenABSTRACT
IMPORTANCE: Community participation of autistic adults is important for health and well-being. Many clinical efforts and interventions aim to enhance community participation in this population. OBJECTIVE: To empirically examine the relationship between community participation and community mobility. DESIGN: A randomized controlled trial using data from baseline and 4- to 6-wk follow-up. SETTING: Community organizations serving autistic adults in Philadelphia. PARTICIPANTS: Sixty-three autistic young adults with data on community mobility and participation from a prior study on public transportation use. OUTCOMES AND MEASURES: Participants were tracked with GPS-enabled cell phones over a 2-wk period. A spatiotemporal data mining algorithm was used to compute the total number of destinations, nonhome destinations, unique destinations, percentage of time spent outside the home, and median daily activity space area from the GPS data. The Temple University Community Participation measure was used to collect self-report data in 21 different areas, and total amount, breadth, and sufficiency of participation were calculated. RESULTS: Moderate and statistically significant associations were found between community mobility and participation variables at baseline and follow-up. However, changes in community mobility were not related to changes in community participation. CONCLUSION: Health policymakers and providers should consider community mobility as a factor that can affect community participation in autistic individuals. Plain-Language Summary: Lower levels of community participation among autistic young adults affect health outcomes and overall quality of life. Community mobility is often a barrier to community participation. An understanding of the relationship between community mobility and community participation can lead to occupational therapists tailoring specific interventions and policies that support autistic young adults to engage in important life activities within the community.
