Pubmed du 07/11/19

jeudi 7 novembre 2019

1. Adams JB, Borody TJ, Kang DW, Khoruts A, Krajmalnik-Brown R, Sadowsky MJ. Microbiota transplant therapy and autism : lessons for the clinic. Expert Rev Gastroenterol Hepatol ;2019 (Nov 7):1-5.

Introduction : The purpose of this review is to discuss Microbiota Transplant Therapy (MTT), a type of intensive intestinal microbiota transplantation (IMT), for people with autism spectrum disorders (ASD) and chronic gastrointestinal disorders (constipation and/or diarrhea).Areas covered : This paper briefly reviews IMT, gastrointestinal symptoms and gastrointestinal bacteria in children with ASD, and results and lessons learned from intensive MTT for autism.Expert opinion : An open-label study and a two-year follow-up suggest that MTT is relatively safe and effective in significantly reducing gastrointestinal disorders and autism symptoms, changing the gut microbiome structure, and increasing gut microbial diversity. Further research with larger, randomized, double-blind, placebo-controlled studies is warranted.

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2. Asztely K, Kopp S, Gillberg C, Waern M, Bergman S. Chronic Pain And Health-Related Quality Of Life In Women With Autism And/Or ADHD : A Prospective Longitudinal Study. J Pain Res ;2019 ;12:2925-2932.

Purpose : To investigate the prevalence of chronic pain and its association with health-related quality of life (HRQoL) in a group of women, diagnosed with autism spectrum disorder (ASD) and/or attention deficit hyperactive disorder (ADHD) in childhood. Patients and methods : Prospective longitudinal 16-19 years follow-up study of 100 Swedish females diagnosed with ASD and/or ADHD in childhood/adolescence. Seventy-seven of the women were included in the current sub-study, using validated measures of pain perception and quality of life. Results : A large majority of the women (76.6%) reported chronic pain. HRQoL was low overall and lower still for those reporting chronic pain. Women with ADHD who had ongoing treatment with stimulants reported a significant lower prevalence of chronic widespread pain (CWP) than those not treated. Conclusion : Comorbidity with chronic pain is common in women with ASD and/or ADHD and important to address in the clinic since it is associated with an already low HRQoL. Treatment for ADHD might reduce the pain in some cases.

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3. Bankaitis VA, Xie Z. The neural stem cell/carnitine malnutrition hypothesis : New prospects for effective reduction of autism risk ?. J Biol Chem ;2019 (Nov 7)

Autism spectrum disorders (ASDs) are developmental neuropsychiatric disorders with heterogeneous etiologies. As the incidence of these disorders is rising, such disorders represent a major human health problem with escalating social cost. While recent years witnessed advances in our understanding of the genetic basis of some dysmorphic ASDs, little progress has been made in translating the improved understanding into effective strategies for ASD management or minimization of general ASD risk. Herein, we explore the idea, described in terms of the NSC/carnitine malnutrition hypothesis, that an unappreciated risk factor for ASD is diminished capacity for carnitine-dependent long-chain fatty acid beta-oxidation (FAO) in neural stem cells (NSCs) of the developing mammalian brain. The basic premise is that fetal carnitine status is a significant metabolic component in determining NSC vulnerability to derangements in their self-renewal program, and therefore to fetal ASD risk. As fetal carnitine status exhibits a genetic component that relates to de novo carnitine biosynthesis, and is sensitive to environmental and behavioral factors that affect maternal circulating carnitine levels to which the fetus is exposed, we propose reduced carnitine availability during gestation is a common risk factor that lurks beneath the genetically complex ASD horizon. One major prediction of the NSC/carnitine malnutrition hypothesis is that a significant component of ASD risk might be effectively managed from a public policy perspective by implementing a carnitine surveillance and dietary supplementation strategy for women planning pregnancies, and for women in their first trimester of pregnancy. We argue this prediction is deserving of serious clinical interrogation.

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4. Bottema-Beutel K, Oliveira G, Cohen SR, Miguel J. Question-response-evaluation sequences in the home interactions of a bilingual child with autism spectrum disorder. Int J Lang Commun Disord ;2019 (Nov 6)

BACKGROUND : Prior research has described the prevalence and utility of questions in children’s language learning environment. However, there has been little empirical investigation of the interaction sequences that ensue following caregiver questions. Understanding these interactions may be especially important for children with autism spectrum disorder (ASD), who may have difficulty engaging in reciprocal interactions. Question-response-evaluation sequences (QRE) are a particular type of interaction sequence launched by questions that have been examined primarily in classroom contexts. Less research has been devoted to understanding how caregivers and children with ASD leverage this interactional format in the context of home interactions. AIMS : We focus on QRE sequences within interactions between a 5-year-old bilingual child with ASD and his parents. In these sequences, the adult poses known-answer questions, the child responds and the adult evaluates the response. QRE sequences are primarily structured by the questioner (i.e., the parents in our context), and we examine the interactive work done by parents to initiate, maintain and close these sequences. We also examine the child’s contributions to these sequences. METHODS & PROCEDURES : We applied conversation analysis (CA) to video recordings of home routines, such as play, book-reading and schoolwork. Videos were fully transcribed using CA conventions, and 55 QRE segments were isolated from the data corpus for further analysis. OUTCOMES & RESULTS : Q-word questions (i.e., where, what, why, when, how questions) were the most prevalent question format, and repetition of the child’s response was the most prevalent form of evaluation. We found that QRE sequences were embedded within a variety of action trajectories that extend beyond pedagogical functions. These included repairing a prior utterance, extending collaborative play routines and engaging in topically connected labelling rituals. CONCLUSIONS & IMPLICATIONS : QRE sequences appeared to strike a balance in terms of the level of constraint they placed on the child’s contributions to interactions, and the affordances they provide for participating in and progressing through interactions. This study can help clinicians understand the types of interactions that can be pursued with QRE sequences in their work with children with ASD. The findings may also aid intervention researchers’ efforts to leverage caregivers’ existing strengths for adapting their interactional overtures to maximize children’s engagement. Finally, this study provides an illustration of caregiver-child interactions in a population that is currently under-represented in the literature.

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5. Cascio L, Chen CF, Pauly R, Srikanth S, Jones K, Skinner CD, Stevenson RE, Schwartz CE, Boccuto L. Abnormalities in the genes that encode Large Amino Acid Transporters increase the risk of Autism Spectrum Disorder. Mol Genet Genomic Med ;2019 (Nov 7):e1036.

BACKGROUND : Autism spectrum disorder (ASD) is a common neurodevelopmental disorder whose molecular mechanisms are largely unknown. Several studies have shown an association between ASD and abnormalities in the metabolism of amino acids, specifically tryptophan and branched-chain amino acids (BCAAs). METHODS : Ninety-seven patients with ASD were screened by Sanger sequencing the genes encoding the heavy (SLC3A2) and light subunits (SLC7A5 and SLC7A8) of the large amino acid transporters (LAT) 1 and 2. LAT1 and 2 are responsible for the transportation of tryptophan and BCAA across the blood-brain barrier and are expressed both in blood and brain. Functional studies were performed employing the Biolog Phenotype Microarray Mammalian (PM-M) technology to investigate the metabolic profiling in lymphoblastoid cell lines from 43 patients with ASD and 50 controls with particular focus on the amino acid substrates of LATs. RESULTS : We detected nine likely pathogenic variants in 11 of 97 patients (11.3%) : three in SLC3A2, three in SLC7A5, and three in SLC7A8. Six variants of unknown significance were detected in eight patients, two of which also carrying a likely pathogenic variant. The functional studies showed a consistently reduced utilization of tryptophan, accompanied by evidence of reduced utilization of other large aromatic amino acids (LAAs), either alone or as part of a dipeptide. CONCLUSION : Coding variants in the LAT genes were detected in 17 of 97 patients with ASD (17.5%). Metabolic assays indicate that such abnormalities affect the utilization of certain amino acids, particularly tryptophan and other LAAs, with potential consequences on their transport across the blood barrier and their availability during brain development. Therefore, abnormalities in the LAT1 and two transporters are likely associated with an increased risk of developing ASD.

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6. Chisholm K, Pelton M, Duncan N, Kidd K, Wardenaar KJ, Upthegrove R, Broome MR, Lin A, Wood SJ. A cross-sectional examination of the clinical significance of autistic traits in individuals experiencing a first episode of psychosis. Psychiatry Res ;2019 (Oct 18):112623.

Autism traits are found at elevated rates in individuals with schizophrenia spectrum disorders, however, there is a lack of evidence regarding potential clinical impact. The current research aimed to examine potential associations between autism traits and symptoms of psychosis, social and role functioning, and quality of life. 99 individuals experiencing a first episode of psychosis took part in a cross-sectional interview and self-report questionnaire which assessed current symptoms of psychosis, autism traits, functioning, and quality of life. Participants were found to have a high level of autism traits. Higher autism traits were associated with poorer quality of life, functioning, and current psychotic symptoms. Receiver operating characteristic curve (ROC) analyses indicated that optimal AQ cut-off scores to predict severity of psychosis symptoms, functioning, and quality of life were lower than those used to suggest likely autism-spectrum diagnosis. Results suggest that autism traits are associated with poorer clinical presentation in first-episode psychosis populations, even in those whose traits fall below potentially diagnostic thresholds for autism. Psychosis services should be prepared to adequately address the needs of individuals with higher autism traits.

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7. Crespi B, Read S, Ly A, Hurd P. AMBRA1, Autophagy, and the Extreme Male Brain Theory of Autism. Autism Res Treat ;2019 ;2019:1968580.

The extreme male brain theory of autism posits that its male bias is mediated by exaggeration of male-biased sex differences in the expression of autism-associated traits found in typical populations. The theory is supported by extensive phenotypic evidence, but no genes have yet been described with properties that fit its predictions. The autophagy-associated gene AMBRA1 represents one of the top genome-wide "hits" in recent GWAS studies of schizophrenia, shows sex-differential expression, and has been linked with autism risk and traits in humans and mice, especially or exclusively among females. We genotyped the AMBRA1 autism-risk SNP in a population of typical humans who were scored for the dimensional expression of autistic and schizotypal traits. Females, but not males, homozygous for the GG genotype showed a significant increase in score for the single trait, the Autism Quotient-Imagination subscale, that exhibits a strong, significant male bias in typical populations. As such, females with this genotype resembled males for this highly sexually dimorphic, autism-associated phenotype. These findings support the extreme male brain hypothesis and indicate that sex-specific genetic effects can mediate aspects of risk for autism.

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8. da Silva Montenegro EM, Costa CS, Campos G, Scliar M, de Almeida TF, Zachi EC, Silva IMW, Chan AJS, Zarrei M, Lourenco NCV, Yamamoto GL, Scherer S, Passos-Bueno MR. Meta-Analyses Support Previous and Novel Autism Candidate Genes : Outcomes of an Unexplored Brazilian Cohort. Autism Res ;2019 (Nov 6)

Large genomic databases of neurodevelopmental disorders (NDD) are helpful resources of genomic variations in complex and heterogeneous conditions, as Autism Spectrum Disorder (ASD). We evaluated the role of rare copy number variations (CNVs) and exonic de novo variants, in a molecularly unexplored Brazilian cohort of 30 ASD trios (n = 90), by performing a meta-analysis of our findings in more than 20,000 patients from NDD cohorts. We identified three pathogenic CNVs : two duplications on 1q21 and 17p13, and one deletion on 4q35. CNVs meta-analysis (n = 8,688 cases and n = 3,591 controls) confirmed 1q21 relevance by identifying duplications in other 16 ASD patients. Exome analysis led the identification of seven de novo variants in ASD genes (SFARI list) : three loss-of-function pathogenic variants in CUL3, CACNA1H, and SHANK3 ; one missense pathogenic variant in KCNB1 ; and three deleterious missense variants in ATP10A, ANKS1B, and DOCK1. From the remaining 12 de novo variants in non-previous ASD genes, we prioritized PRPF8 and RBM14. Meta-analysis (n = 13,754 probands ; n = 2,299 controls) identified six and two additional patients with validated de novo variants in PRPF8 and RBM14, respectively. By comparing the de novo variants with a previously established mutational rate model, PRPF8 showed nominal significance before multiple test correction (P = 0.039, P-value adjusted = 0.079, binomial test), suggesting its relevance to ASD. Approximately 60% of our patients presented comorbidities, and the diagnostic yield was estimated in 23% (7/30 : three pathogenic CNVs and four pathogenic de novo variants). Our uncharacterized Brazilian cohort with tetra-hybrid ethnic composition was a valuable resource to validate and identify possible novel candidate loci. Autism Res 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : We believed that to study an unexplored autistic population, such as the Brazilian, could help to find novel genes for autism. In order to test this idea, with our limited budget, we compared candidate genes obtained from genomic analyses of 30 children and their parents, with those of more than 20,000 individuals from international studies. Happily, we identified a genetic cause in 23% of our patients and suggest a possible novel candidate gene for autism (PRPF8).

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9. Dwivedi D, Chattarji S, Bhalla US. Impaired reliability and precision of spiking in adults but not juveniles in a mouse model of Fragile X Syndrome. eNeuro ;2019 (Nov 4)

Fragile X Syndrome (FXS) is the most common source of intellectual disability and autism. Extensive studies have been performed on the network and behavioral correlates of the syndrome but our knowledge about intrinsic conductance changes is still limited. In this study we show a differential effect of FMRP Knock Out (KO) in different sub-sections of hippocampus using whole cell patch clamp in mouse hippocampal slices. We observed no significant change in spike numbers in the CA1 region of hippocampus but a significant increase in CA3, in juvenile mice. However, in adult mice we see a reduction in spike number in the CA1 with no significant difference in CA3. In addition, we see increased variability in spike number in CA1 cells following a variety of steady and modulated current step protocols. This effect emerges in adult (8 weeks) but not juvenile (4 weeks) mice. This increased spiking variability was correlated with reduced spike number and with elevated AHP. The increased AHP arose from elevated SK currents (small conductance calcium activated potassium channels) but other currents involved in mAHP, such as Ih and M, were not significantly different. We obtained a partial rescue of the cellular variability phenotype when we blocked SK current using the specific blocker apamin. Our observations provide a single cell correlate of the network observations of response variability and loss of synchronization, and suggest that elevation of SK currents in FXS may provide a partial mechanistic explanation for this difference.Significance Statement Fragile-X syndrome leads to a range of intellectual disability effects and autism. We have found differential effect of FMRP KO in different sub sections of hippocampus where it caused an increased spiking in CA3 in juveniles and reduced spiking in CA1, in adults. We have also found that even individual neurons with this mutation exhibit increased variability in their activity patterns. Importantly, this effect emerges after six weeks of age in mice. We showed that a specific ion channel protein, SK channel, was partially responsible, and blockage of these channels led to a partial restoration of cellular activity. This is interesting as it provides a possible molecular link between activity variability in single cells, and reported irregularity in network activity.

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10. El-Ansary A, Chirumbolo S, Bhat RS, Dadar M, Ibrahim EM, Bjorklund G. The Role of Lipidomics in Autism Spectrum Disorder. Mol Diagn Ther ;2019 (Nov 5)

Autism spectrum disorder (ASD) is a complex neurodevelopmental syndrome commonly diagnosed in early childhood ; it is usually characterized by impairment in reciprocal communication and speech, repetitive behaviors, and social withdrawal with loss in communication skills. Its development may be affected by a variety of environmental and genetic factors. Trained physicians diagnose and evaluate the severity of ASD based on clinical evaluations of observed behaviors. As such, this approach is inevitably dependent on the expertise and subjective assessment of those administering the clinical evaluations. There is a need to identify objective biological markers associated with diagnosis or clinical severity of the disorder. Several important issues and concerns exist regarding the diagnostic competence of the many abnormal plasma metabolites produced in the different biochemical pathways evaluated in individuals with ASD. The search for high-performing bio-analytes to diagnose and follow-up ASD development is still a major target in medicine. Dysregulation in the oxidative stress response and proinflammatory processes are major etiological causes of ASD pathogenesis. Furthermore, dicarboxylic acid metabolites, cholesterol-related metabolites, phospholipid-related metabolites, and lipid transporters and mediators are impaired in different pathological conditions that have a role in the ASD etiology. A mechanism may exist by which pro-oxidant environmental stressors and abnormal metabolites regulate clinical manifestations and development of ASD.

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11. Font-Alaminos M, Cornella M, Costa-Faidella J, Hervas A, Leung S, Rueda I, Escera C. Increased subcortical neural responses to repeating auditory stimulation in children with autism spectrum disorder. Biol Psychol ;2019 (Nov 3):107807.

Recent research has highlighted atypical reactivity to sensory stimulation as a core symptom in children with autism spectrum disorder (ASD). However, little is known about the dysfunctional neurological mechanisms underlying these aberrant sensitivities. Here we tested the hypothesis that the ability to filter out auditory repeated information is deficient in children with ASD already from subcortical levels, yielding to auditory sensitivities. We recorded the frequency-following response (FFR), a non-invasive measure of the neural tracking of the periodic characteristics of a sound in the subcortical auditory system, to compare repetition-related effects in children with ASD and typically developing children. Results revealed an increase of the FFR with stimulus repetition in children with ASD compared to their peers. Moreover, such defective early sensory encoding of stimulus redundancy was associated with sensory overload. These results highlight that auditory sensitivities in ASD emerge already at the level of the subcortical auditory system.

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12. Fornaro M, Sassi T, Novello S, Anastasia A, Fusco A, Senatore I, de Bartolomeis A. Prominent autistic traits and subthreshold bipolar/mixed features of depression in severe anorexia nervosa. Braz J Psychiatry ;2019 (Nov 4)

OBJECTIVE : Autistic traits are associated with a burdensome clinical presentation of anorexia nervosa (AN), as is AN with concurrent depression. The aim of the present study was to explore the intertwined association between complex psychopathology combining autistic traits, subthreshold bipolarity, and mixed depression among people with AN. METHOD : Sixty patients with AN and concurrent major depressive episode (mean age, 22.2+/-7 years) were cross-sectionally assessed using the Autism-Spectrum Quotient test (AQ-test), the Hamilton depression scales for depression and anxiety, the Young Mania Rating Scale (YMRS), the Hypomania-Checklist-32 (HCL-32), second revision (for subthreshold bipolarity), the Brown Assessment and Beliefs Scale (BABS), the Yale-Brown-Cornell Eating Disorders Scale (YBC-EDS), and the Eating Disorder Examination Questionnaire (EDE-Q). Cases were split into two groups depending on body mass index (BMI) : severe AN (AN+) if BMI < 16, not severe (AN-) if BMI >/= 16. RESULTS : The "subthreshold bipolarity with prominent autistic traits" pattern correctly classified 83.6% of AN patients (AN+ = 78.1% ; AN- = 91.3%, Exp(B) = 1.391). AN+ cases showed higher rates of positive scores for YMRS items 2 (increased motor activity-energy) and 5 (irritability) compared to AN- cases. CONCLUSIONS : In our sample, depressed patients with severe AN had more pronounced autistic traits and subtly mixed bipolarity. Further studies with larger samples and prospective follow-up of treatment outcomes are warranted to replicate these findings.

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13. Forrest DL, Kroeger RA, Stroope S. Autism Spectrum Disorder Symptoms and Bullying Victimization Among Children with Autism in the United States. J Autism Dev Disord ;2019 (Nov 5)

Children with autism spectrum disorder (ASD) experience more frequent bullying victimization compared to their neurotypical peers. This study used the 2011 Survey of Pathways to Diagnosis and Services to examine associations between six Children’s Social Behavior Questionnaire (CSBQ) subscales and bullying victimization among 1057 children with ASD. Bivariate results showed significant correlations between each CSBQ subscale and more frequent bullying victimization. Yet results from multinomial logistic regression models indicated that after adjusting for all CSBQ subscales and covariates, two of the CSBQ subscales remained significantly associated with greater risk of bullying victimization : not being optimally tuned to the social situation, and resistance to changes. Implications for future research and efforts toward reducing bullying victimization among children with ASD are discussed.

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14. Hara Y. [Chronic Activation of the Dopaminergic Neuronal Pathway Improves Behavioral Abnormalities in the Prenatal Valproic Acid Exposure Mouse Model of Autism Spectrum Disorder]. Yakugaku Zasshi ;2019 ;139(11):1391-1396.

Over the last decade there has been an increase in the prevalence of autism spectrum disorder (ASD) ; however, its pathogenic mechanisms remain unclear. To date, no effective drug has been developed to treat the core symptoms of ASD, especially social interaction deficits. Previous studies have mainly focused on the glutamatergic, GABAergic, and serotonergic signaling pathways ; however, a growing number of studies have reported abnormalities in the dopaminergic pathway, such as mutations and functional alterations of dopamine-related molecules, in ASD patients. Furthermore, atypical antipsychotic drugs risperidone and aripiprazole are prescribed for the treatment of non-core symptoms, such as irritability, in patients with ASD. These observations suggest that the dopaminergic pathway is involved in the pathogenesis of ASD. Previously, we have established a mouse model of ASD based on clinical research, which shows that exposure to valproic acid, an antiepileptic drug, during pregnancy causes an increase in the risk of developing ASD in children. This review summarizes our recent studies, which have assessed alterations in the prefrontal dopaminergic pathway. In addition, we discuss the effects of treatment with attention deficit/hyperactivity disorder drugs and atypical antipsychotic drugs, which activate the prefrontal dopaminergic pathway, on ASD-like behavioral abnormalities in the valproic acid exposure mouse model of ASD.

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15. Harle B. Intensive early screen exposure as a causal factor for symptoms of autistic spectrum disorder : The case for <>. Trends Neurosci Educ ;2019 (Dec) ;17:100119.

Intensive Early Screen Exposure (IESE) has been associated with detrimental outcomes on different variables including attention, language, emotion regulation and socialisation, some of which are central to the diagnosis of neurodevelopmental disorders, such as ADHD and learning disorders. Following Bradford-Hill’s recommendations, we argue that there is growing clinical and empirical evidence supporting a causal relationship between intensive early screen exposure (more than 4 h a day) and subsequent symptoms of Autism Spectrum Disorders in some possibly vulnerable younger children (less than 6 years old). Clinicians should also be aware of the existence of cases of recovery or dramatic improvement after parents accept to stop screen exposure for a few months, associated with daily moments of dyadic interaction, since this intervention has repeatedly been found to be effective with no known side-effects.

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16. Heimer G, van Woerden GM, Barel O, Marek-Yagel D, Kol N, Munting BJ, Borghei M, Atawneh OM, Nissenkorn A, Rechavi G, Anikster Y, Elgersma Y, Kushner SA, Ben Zeev B. Netrin-G2 dysfunction causes a Rett-like phenotype with areflexia. Hum Mutat ;2019 (Nov 6)

We describe the underlying genetic cause of a novel Rett-like phenotype accompanied by areflexia in three MECP2-negative individuals from two unrelated families. Discovery analysis was performed using whole exome sequencing followed by Sanger sequencing for validation and segregation. Functional studies using short-hairpin RNA (shRNA) for targeted gene knockdown were implemented by transfection of mouse cultured primary hippocampal neurons and in vivo by in utero electroporation. All patients shared a common homozygous frameshift mutation (Chr 9:135073515, c.376dupT, p.(Ser126PhefsTer241)) in netrin-G2 (NTNG2, NM_032536.3) with predicted nonsense-mediated decay. The mutation fully segregated with the disease in both families. Knockdown of either NTNG2 or the related netrin-G family member NTNG1 resulted in severe neurodevelopmental defects of neuronal morphology and migration. While NTNG1 has previously been linked to a RTT-like phenotype, this is the first description of a RTT-like phenotype caused by NTNG2 mutation. Netrin-G proteins have been shown to be required for proper axonal guidance during early brain development and involved in NMDA-mediated synaptic transmission. Our results demonstrating that knockdown of murine NTNG2 causes severe impairments of neuronal morphology and cortical migration are consistent with those of RTT animal models and the shared neurodevelopmental phenotypes between the individuals described here and typical RTT patients. This article is protected by copyright. All rights reserved.

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17. Iacobucci G. All inpatients with learning disabilities or autism to have case review in next 12 months, says health secretary. Bmj ;2019 (Nov 5) ;367:l6380.

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18. Jacobs D, Steyaert J, Dierickx K, Hens K. Parents’ views and experiences of the autism spectrum disorder diagnosis of their young child : a longitudinal interview study. Eur Child Adolesc Psychiatry ;2019 (Nov 4)

Parents are valuable stakeholders in research, clinical practice and policy development concerning autism spectrum disorder (ASD). Little is known, however, about how parents view and experience an ASD diagnosis. We investigated the evolution of parents’ views and experiences of the ASD diagnosis before, right after and 12 months after their child was diagnosed. Seventeen Flemish parents waiting for their young child’s diagnostic ASD assessment participated in a longitudinal study consisting of three in-depth interviews. They described their views and experiences concerning their child’s ASD diagnosis at three separate moments : (T1) prior to a diagnostic ASD assessment ; (T2) immediately after their final feedback session at the end of the assessment ; and (T3) 12 months later. Interviews were digitally recorded, transcribed and analysed in Nvivo 11 according to the procedures of interpretative phenomenological analysis. We extracted three themes from the interview material throughout the parental journey : (T1) expecting certainty and exculpation ; (T2) vulnerabilisation of the child ; and (T3) pragmatic attitude and some disappointment. At T3, the parents overall had come to value the diagnosis because of two reasons : they were satisfied with their child’s entitlement to ASD-related support at school, and with the diagnosis’ impact on the child’s relationships with parents and teachers. Many parents experienced their child with an ASD diagnosis as vulnerable, and themselves as acutely responsible for his development and future. Our findings may lead to a higher satisfaction with the clinical trajectory in both clinician and parents by inspiring a conversation between them about parents’ evolving views, hopes and concerns related to their child’s ASD diagnosis.

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19. Johansen Taber K, Lim-Harashima J, Naemi H, Goldberg J. Fragile X syndrome carrier screening accompanied by genetic consultation has clinical utility in populations beyond those recommended by guidelines. Mol Genet Genomic Med ;2019 (Nov 6):e1024.

BACKGROUND : Fragile X syndrome (FXS) is the most common inherited form of intellectual disability. Many providers offer preconception or prenatal FXS carrier screening. However, guidelines recommend screening only for those with a family history or undergoing fertility evaluation. Wider screening has been resisted because of concerns about patient understanding of FXS-associated inheritance patterns and phenotypes. Additionally, the clinical utility has been questioned. METHODS : We addressed these concerns by analyzing reproductive decision-making and pregnancy management informed by post-test genetic consultation among 122 FMR1 premutation carriers identified by expanded carrier screening. RESULTS : Sixty-three percent of those screened met guidelines screening criteria ; the remaining 37% did not. Ninety-eight percent had undergone post-test genetic consultation. Of respondents screened preconceptionally, 74% reported planning or pursuing actions to reduce the risk of an affected pregnancy ; the extent to which couples planned/pursued these actions was not significantly different between those meeting either screening criterion (76%) versus those meeting neither criterion (55%). Of respondents screened prenatally, 41% pursued prenatal diagnostic testing ; the extent to which couples pursued prenatal diagnosis was not significantly different between those who met either screening criterion (37%) versus those who met neither criterion (31%). CONCLUSION : These results support the expansion of FXS screening criteria in guidelines.

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20. Kowallik AE, Schweinberger SR. Sensor-Based Technology for Social Information Processing in Autism : A Review. Sensors (Basel) ;2019 (Nov 4) ;19(21)

The prevalence of autism spectrum disorders (ASD) has increased strongly over the past decades, and so has the demand for adequate behavioral assessment and support for persons affected by ASD. Here we provide a review on original research that used sensor technology for an objective assessment of social behavior, either with the aim to assist the assessment of autism or with the aim to use this technology for intervention and support of people with autism. Considering rapid technological progress, we focus (1) on studies published within the last 10 years (2009-2019), (2) on contact- and irritation-free sensor technology that does not constrain natural movement and interaction, and (3) on sensory input from the face, the voice, or body movements. We conclude that sensor technology has already demonstrated its great potential for improving both behavioral assessment and interventions in autism spectrum disorders. We also discuss selected examples for recent theoretical questions related to the understanding of psychological changes and potentials in autism. In addition to its applied potential, we argue that sensor technology-when implemented by appropriate interdisciplinary teams-may even contribute to such theoretical issues in understanding autism.

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21. Kuper GE, Ksobiech K, Wickert J, Leighton F, Frederick E. An Exploratory Analysis of Increasing Self-Efficacy of Adults with Autism Spectrum Disorder Through the Use of Multimedia Training Stimuli. Cyberpsychol Behav Soc Netw ;2019 (Nov 6)

While some evidence-based vocational studies exist for adults with Autism Spectrum Disorder (ASD), most focus on social interaction. This mixed methods exploratory study investigated a multimedia approach to training ASD adults as a strategy for increasing self-efficacy and producing positive training outcomes during the anticipatory socialization and encounter phases of organizational assimilation. Ten ASD adults, seven men and three women, 19 to 42 years of age, participated in the study, which utilized video and virtual reality to instruct participants on how to wire an electrical socket. Significant increases in the participant’s self-efficacy were found using a modified version of the New General Self-Efficacy (NGSE) scale. In addition, a thematic analysis of post-training comments showed that participants, overall, were engaged and had fun during the training. These findings suggest that a multimedia approach may be an effective strategy for achieving positive outcomes by increasing self-efficacy and engagement when training newly hired employees diagnosed with ASD to perform vocational tasks.

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22. Lee BK, Eyles DW, Magnusson C, Newschaffer CJ, McGrath JJ, Kvaskoff D, Ko P, Dalman C, Karlsson H, Gardner RM. Developmental vitamin D and autism spectrum disorders : findings from the Stockholm Youth Cohort. Mol Psychiatry ;2019 (Nov 6)

Animal studies indicate that early life vitamin D is crucial for proper neurodevelopment. Few studies have examined whether maternal and neonatal vitamin D concentrations influence risk of autism spectrum disorders (ASD). Participants were sampled from the Stockholm Youth Cohort, a register-based cohort in Sweden. Concentrations of total 25-hydroxyvitamin D (25OHD) were assessed from maternal and neonatal biosamples using a highly sensitive liquid chromatography tandem mass spectrometry method. The maternal sample consisted of 449 ASD cases and 574 controls, the neonatal sample : 1399 ASD cases and 1607 controls ; and the paired maternal-neonatal sample : 340 ASD cases and 426 controls. Maternal 25OHD was not associated with child ASD in the overall sample. However, in Nordic-born mothers, maternal 25OHD insufficiency (25 - <50 nmol/L) at 11 weeks gestation was associated with 1.58 times higher odds of ASD (95% CI : 1.00, 2.49) as compared with 25OHD sufficiency (>/=50 nmol/L). Neonatal 25OHD < 25 nmol/L was associated with 1.33 times higher odds of ASD (95% CI : 1.02, 1.75) as compared with 25OHD >/= 50 nmol/L. Sibling-matched control analyses indicated these associations were not likely due to familial confounding. Children with both maternal 25OHD and neonatal 25OHD below the median had 1.75 (95% CI : 1.08, 2.86) times the odds of ASD compared with children with maternal and neonatal 25OHD both below the median. Our results are consistent with an increasing body of evidence suggesting that vitamin D concentrations in early life may be associated with increased risk of neurodevelopmental disorders including ASD.

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23. Marland C, Lubke G, Degl’Innocenti A, Rastam M, Gillberg C, Nilsson T, Lundstrom S. The development of a brief screener for autism using item response theory. BMC Psychiatry ;2019 (Nov 4) ;19(1):337.

BACKGROUND : Brief screening instruments focusing on autism spectrum disorder (ASD) that can be administered in primary care are scarce ; there is a need for shorter and more precise instruments. The Autism-Tics, AD/HD and other Comorbidities inventory (A-TAC) has previously been validated for ASD reporting excellent validity. This study aims to determine the psychometric properties of each item in the ASD domain (17 items) in the A-TAC using item response theory (IRT), and thereby construct and validate a short form that could be used as a screening instrument in the general population. METHODS : Since 2004, parents of all 9-year-old Swedish twins have been invited to participate in a telephone interview in the Child and Adolescent Twin Study in Sweden (CATSS). The CATSS is linked to the National Patient Register (NPR), which includes data from in- and outpatient care. Data on ASD (A-TAC) collected in CATSS were compared with diagnoses from the NPR. Diagnoses that had been made both before (previous validity) and after (predictive validity) the interviews were included. The sample was divided into a developmental sample and a validation sample. An IRT model was fitted to the developmental sample and item parameters were used to select a subset of items for the short form. The performance of the proposed short form was examined in the validation sample by the use of receiver operation characteristic curves. RESULTS : Four items which were able to discriminate among individuals with more autism traits were deemed sufficient for use in the short form. The values of the area under the receiver operating characteristic curve for a clinical diagnosis of ASD was .95 (previous validity) and .72 (predictive validity). CONCLUSIONS : The proposed short form with 4 out of the original 17 items from A-TAC, showed excellent previous validity while the predictive validity was fair. The validity of the short form was in agreement with previous validations of the full ASD domain. The short form can be a valuable screening instrument in primary care settings in order to identify individuals in need for further assessment and for use in epidemiological studies.

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24. McTee HM, Mood D, Fredrickson T, Thrasher A, Bonino AY. Using Visual Supports to Facilitate Audiological Testing for Children With Autism Spectrum Disorder. Am J Audiol ;2019 (Nov 5):1-11.

Purpose One in 59 children is diagnosed with autism spectrum disorder (ASD). Due to overlapping symptoms between hearing loss and ASD, children who are suspected of having ASD require an audiological evaluation to determine their hearing status for the purpose of differential diagnosis. The purpose of this article is twofold : (a) to increase audiologists’ knowledge of ASD by discussing the challenges associated with testing and interpreting clinical data for children with ASD or suspected ASD and (b) to provide visual supports that can be used to facilitate audiological assessment. Method Eight children (ages 4-12 years) were recruited as video model participants. Videos were filmed using scripts that used concise and concrete language while portraying common clinical procedures. Using the video models, corresponding visual schedules were also created. Conclusion Although obtaining reliable hearing data from children with ASD is challenging, incorporating visual supports may facilitate testing. Video models and visual schedules have been created and made freely available for download online under a Creative Commons License (Creative Commons-Attribution-NonCommercial-ShareAlike 4.0 International License). Incorporating visual supports during clinical testing has the potential to reduce the child’s and family’s stress, as well as to increase the probability of obtaining a reliable and comprehensive audiological evaluation. Future research is warranted to determine the effectiveness and feasibility of implementing these tools in audiology clinics. Supplemental Material

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25. Menon V, Andrade C, Thennarasu K. Polycystic ovarian syndrome and autism spectrum disorder in the offspring : Should the primary outcome have been different ?. Mol Psychiatry ;2019 (Nov 5)

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26. Mu C, Corley MJ, Lee RWY, Wong M, Pang A, Arakaki G, Miyamoto R, Rho JM, Mickiewicz B, Dowlatabadi R, Vogel HJ, Korchemagin Y, Shearer J. Metabolic framework for the improvement of autism spectrum disorders by a modified ketogenic diet : a pilot study. J Proteome Res ;2019 (Nov 7)

The ketogenic diet (KD) can improve the core features of autism spectrum disorders (ASD) in some children, but the effects on overall metabolism remain unclear. This pilot study investigated behavioural parameters in relation to blood metabolites and trace elements in a cohort of 10 typically developed controls (TC) and 17 children with ASD at baseline and following a 3-month treatment with a modified KD regimen. A non-targeted, multiplatform metabolomics approach was employed, including Gas Chromatography-Mass Spectrometry, 1H Nuclear Magnetic Resonance Spectroscopy, and Inductively Coupled Plasma-Mass Spectrometry. Associations between plasma metabolites, trace elements, and behavior scores were investigated. Employing a combination of metabolomics platforms, 118 named metabolites and 73 trace elements were assessed. Relative to TC, a combination of glutamate, galactonate, and glycerol discriminated ASD with 88% accuracy. ASD had higher concentrations of galactose intermediates, gut microbe-derived trimethylamine N-oxide and N-acetylserotonin, and lower concentrations of 3-hydroxybutyrate and selenium at baseline. Following 3mo KD intervention, levels of circulating ketones and acetylcarnitine were increased. KD restored lower selenium levels in ASD to that of controls and correlation analysis identified a novel negative correlation between changes in selenium and behaviour scores. Based on the different behavior responses to the KD, we found that high responders had greater concentrations of 3-hydroxybutyrate and ornithine, with lower galactose. These findings enhance our current understanding of metabolic derangements present in ASD and may be of utility in predicting favorable responses to KD intervention.

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27. Panjwani AA, Ji Y, Fahey JW, Palmer A, Wang G, Hong X, Zuckerman B, Wang X. Maternal Dyslipidemia, Plasma Branched-Chain Amino Acids, and the Risk of Child Autism Spectrum Disorder : Evidence of Sex Difference. J Autism Dev Disord ;2019 (Nov 4)

In contrast to the well-observed associations between obesity, diabetes, and autism spectrum disorder (ASD), the roles of maternal dyslipidemia and sex disparity in ASD have not been well-studied. We examined the joint associations of maternal plasma cholesterols, branched-chain amino acids (BCAAs) and child sex on child ASD risk. We analyzed data from 756 mother-infant pairs (86 ASD) from the Boston Birth Cohort. Maternal plasma cholesterols and BCAAs were measured in samples collected 24-72 h postpartum. We found that in this urban, low-income prospective birth cohort, low maternal high-density lipoprotein cholesterol (HDL-C), above-median maternal plasma BCAA concentrations, and male sex additively or synergistically increased risk of ASD. Additional studies are necessary to confirm our findings.

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28. Peled J, Cassuto H, Berger I. Processing speed as a marker to stimulant effect in clinical sample of children with high functioning autism spectrum disorder. Nord J Psychiatry ;2019 (Nov 5):1-5.

Background : Patients with co-occurring Attention-Deficit/Hyperactivity Disorder (ADHD) and ASD might benefit from stimulants. There is a progressive increase in prescribing ADHD aimed medications for children diagnosed with Autism Spectrum Disorder (ASD), despite scarce knowledge and no distinct clinical guidelines for that matter.Aim : This study aims to analyze the effect of stimulant on processing speed performance and attention indices in children with ASD and ADHD.Methods : Forty children aged 6-18 years diagnosed with ASD who also met the criteria for ADHD were recruited. All children performed a computerized performance test for the assessment of cognitive attention performance three times : twice while they are drug naive and once an hour after taking a single dose of 10 mg. methylphenidate (MPH). This performance was compared to a group of children diagnosed with ’ADHD only’ without ASD.Results : A significant difference (p < 0.001) was found only in the parameter of measuring cognitive processing speed. This effect is significantly different from the response of the ’ADHD only’ group.Conclusions : The reaction to MPH among ASD children is different than among ADHD children. In ASD, MPH significantly improved cognitive processing speed without changing other measured attention parameters. Improving processing speed, might improve every day functioning in children with ASD who also met the criteria for ADHD, in other means than expected. This unique response suggests new research targets for treatment with stimulants in ASD and ADHD children and its influence on cognitive parameters.

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29. Seo M, Anderson G. Gut-Amygdala Interactions in Autism Spectrum Disorders : Developmental Roles via regulating Mitochondria, Exosomes, Immunity and microRNAs. Curr Pharm Des ;2019 (Nov 4)

BACKGROUND : Autism Spectrum Disorder (ASD) have long been conceived as a developmental disorder. A growing body of data highlights a role for alterations in the gut in the pathoetiology and/or pathophysiology of ASD. Recent work shows alterations in the gut microbiome to have a significant impact on amygdala development in infancy, suggesting that the alterations in the gut microbiome may act to modulate not only amygdala development but how the amygdala modulates the development of the frontal cortex and other brain regions. METHODS : This article reviews wide bodies of data pertaining to the developmental roles of the maternal and foetal gut and immune systems in the regulation of offspring brain development. RESULTS : A number of processes seem to be important in mediating how genetic, epigenetic and environmental factors interact in early development to regulate such gut-mediated changes in the amygdala, wider brain functioning and inter-area connectivity, including via regulation of microRNA (miR)-451, 14-3-3 proteins, cytochrome P450 (CYP)1B1 and the melatonergic pathways. As well as a decrease in the activity of monoamine oxidase, heightened levels of in miR-451 and CYP1B1, coupled to decreased 14-3-3 act to inhibit the synthesis of N-acetylserotonin and melatonin, contributing to the hyperserotonemia that is often evident in ASD, with consequences for mitochondria functioning and the content of released exosomes. These same factors are likely to play a role in regulating placental changes that underpin the association of ASD with preeclampsia and other perinatal risk factors, including exposure to heavy metals and air pollutants. Such alterations in placental and gut processes act to change the amygdala-driven biological underpinnings of affect-cognitive and affect-sensory interactions in the brain. CONCLUSION : Such a perspective readily incorporates previously disparate bodies of data in ASD, including the role of the mu-opioid receptor, dopamine signalling and dopamine receptors, as well as the changes occurring to oxytocin and taurine levels. This has a number of treatment implications, the most readily applicable being the utilization of sodium butyrate and melatonin.

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30. Skafle I, Nordahl-Hansen A, Oien RA. Short Report : Social Perception of High School Students with ASD in Norway. J Autism Dev Disord ;2019 (Nov 6)

An increasing number of students with autism spectrum disorder (ASD) enroll in inclusive schools and classrooms. The aim of this study was to research how students with ASD experience the social aspect of inclusive high schools. Five adolescences with Asperger syndrome were interviewed, and the results show that high school was perceived as an important platform for social training, and an equally important place to find new friends and acquaintances. A majority of the participants had experienced loneliness and bullying in junior high school. However, they experienced high school as a new start, with a more open and inclusive environment. Nevertheless, several of the participants expressed that they used quite a lot of energy on social settings, such as interpreting social situations and on being amongst a larger group of students. In order to support this group of adolescents in their schooling, it is important to look at their strength and resources, and not only focus on the challenges and difficulties.

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31. Song J, Yang X, Zhou Y, Chen L, Zhang X, Liu Z, Niu W, Zhan N, Fan X, Khan AA, Kuang Y, Song L, He G, Li W. Dysregulation of neuron differentiation in an autistic savant with exceptional memory. Mol Brain ;2019 (Nov 7) ;12(1):91.

Autism spectrum disorder (ASD) is a heterogeneous group of complex neurodevelopmental disorders without a unique or definite underlying pathogenesis. Although savant syndrome is common in ASD, few models are available for studying the molecular and cellular mechanisms of this syndrome. In this study, we generated urinary induced pluripotent stem cells (UiPSCs) from a 13-year-old male autistic savant with exceptional memory. The UiPSC-derived neurons of the autistic savant exhibited upregulated expression levels of ASD genes/learning difficulty-related genes, namely PAX6, TBR1 and FOXP2, accompanied by hypertrophic neural somas, enlarged spines, reduced spine density, and an increased frequency of spontaneous excitatory postsynaptic currents. Although this study involved only a single patient and a single control because of the rarity of such cases, it provides the first autistic savant UiPSC model that elucidates the potential cellular mechanisms underlying the condition.

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32. Stirling M, Linton J, Ouellette-Kuntz H, Shooshtari S, Hallet J, Kelly C, Dawe D, Kristjanson M, Decker K, Mahar A. Scoping review protocol documenting cancer outcomes and inequalities for adults living with intellectual and/or developmental disabilities. BMJ Open ;2019 (Nov 3) ;9(11):e032772.

INTRODUCTION : There is increasing attention on the cancer burden for adults with intellectual and developmental disabilities (IDD). Emerging evidence suggests there are differences in cancer experiences and outcomes for individuals living with IDD, from risk through survivorship. These differences may be attributed to features of the IDD, such as cognitive deficits and communication, as well as social determinants of health-like lower education levels and ableism. However, there is no comprehensive overview of the literature quantifying these potential disparities and describing the influencing factors. In this paper, we describe a scoping review protocol to systematically review published literature on cancer for adults with IDD. The purpose of this review is to identify differences in cancer risk, stage at diagnosis, treatment and survival along the cancer continuum for adults with IDD and outline potential contributing factors creating these disparities. METHODS AND ANALYSIS : We will follow Arksey and O’Malley’s expanded framework for scoping reviews to conduct this review. We will systematically search electronic databases for peer-reviewed, published journal articles to identify appropriate studies in collaboration with a health science librarian. Two reviewers will independently review titles and abstracts followed by a full-text review to determine whether it meets inclusion criteria. A data chart for collecting and sorting information will be developed in consultation with the team. Results will be collated and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews : PRISMA-Scoping Reviews. Extracted information will be summarised quantitatively and qualitatively to meet review objectives. ETHICS AND DISSEMINATION : This scoping review will employ a methodology to identify literature related to cancer outcomes and experiences for adults with IDD. Results will be disseminated to relevant stakeholders who care for and support individuals with IDD at local, provincial and national levels and through publishing findings. By highlighting the disparities in the cancer system and gaps in the research, this scoping review can provide direction for future action.

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33. Vasu MM, Sumitha PS, Rahna P, Thanseem I, Anitha A. MicroRNAs in Autism Spectrum Disorders. Curr Pharm Des ;2019 (Nov 5)

BACKGROUND : Efforts to unravel the extensive impact of the non-coding elements of the human genome on cell homeostasis and pathological processes have gained momentum over the last couple of decades. miRNAs refer to short, often 18-25 nucleotides long, non-coding RNA molecules which can regulate gene expression. Each miRNA can regulate several mRNAs. METHODS : This article reviews the literature on the roles of miRNAs in autism. RESULTS : Considering the fact that 1% of the human DNA encodes different families of miRNAs, their overall impact as critical regulators of gene expression in the mammalian brain should be immense. Though the autism spectrum disorders (ASDs) are predominantly genetic in nature and several candidate genes are already identified, the highly heterogeneous and multifactorial nature of the disorder makes it difficult to identify common genetic risk factors. Several studies have suggested that the environmental factors may interact with the genetic factors to increase the risk. miRNAs could possibly be one of those factors which explain this link between genetics and environment. CONCLUSION : In the present review, we have summarized our current knowledge on miRNAs and their complex roles in ASD, and also on their therapeutic applications.

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34. Walker M, Nixon S, Haines J, McPherson A. I Work Out, Who Cares if I’m Bigger : What Matters to Youth with ASD regarding Weight and Their Bodies ?. Dev Neurorehabil ;2019 (Nov 5):1-8.

Background : Childhood overweight and obesity, in addition to weight stigma, can result in numerous physical and psychosocial conditions. Children with Autism Spectrum Disorder (ASD) are at a higher risk of developing overweight/obesity than their typically developing peers, yet we know little about what matters to them with regards to weight and their bodies.Methods : Eight semi-structured interviews were conducted with youth with ASD. Interviews were transcribed and analyzed using a phenomenological approach within an interpretive paradigm.Results : Participants mostly showed little concern about their weight. Participants highly valued moving their bodies and reported feeling good about their bodies.Discussion : Findings suggest that children with ASD may be more engaged in healthcare discussions focusing on growth and health rather than size and weight. This approach can also reduce stigmatizing discussions.

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35. Wang X, Lu J, Xie W, Lu X, Liang Y, Li M, Wang Z, Huang X, Tang M, Pfaff DW, Tang YP, Yao P. Maternal diabetes induces autism-like behavior by hyperglycemia-mediated persistent oxidative stress and suppression of superoxide dismutase 2. Proc Natl Acad Sci U S A ;2019 (Nov 4)

Epidemiological studies show that maternal diabetes is associated with an increased risk of autism spectrum disorders (ASDs), although the detailed mechanisms remain unclear. The present study aims to investigate the potential effect of maternal diabetes on autism-like behavior in offspring. The results of in vitro study showed that transient hyperglycemia induces persistent reactive oxygen species (ROS) generation with suppressed superoxide dismutase 2 (SOD2) expression. Additionally, we found that SOD2 suppression is due to oxidative stress-mediated histone methylation and the subsequent dissociation of early growth response 1 (Egr1) on the SOD2 promoter. Furthermore, in vivo rat experiments showed that maternal diabetes induces SOD2 suppression in the amygdala, resulting in autism-like behavior in offspring. SOD2 overexpression restores, while SOD2 knockdown mimics, this effect, indicating that oxidative stress and SOD2 expression play important roles in maternal diabetes-induced autism-like behavior in offspring, while prenatal and postnatal treatment using antioxidants permeable to the blood-brain barrier partly ameliorated this effect. We conclude that maternal diabetes induces autism-like behavior through hyperglycemia-mediated persistent oxidative stress and SOD2 suppression. Here we report a potential mechanism for maternal diabetes-induced ASD.

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