1. Baig DN, Yanagawa T, Tabuchi K. {{Distortion of the normal function of synaptic cell adhesion molecules by genetic variants as a risk for autism spectrum disorders}}. {Brain Res Bull};2016 (Oct 12)
Synaptic cell adhesion molecules (SCAMs) are a functional category of cell adhesion molecules that connect pre- and postsynapses by the protein-protein interaction via their extracellular cell adhesion domains. Countless numbers of common genetic variants and rare mutations in SCAMs have been identified in the patients with autism spectrum disorders (ASDs). Among these, NRXN and NLGN family proteins cooperatively function at synaptic terminals both of which genes are strongly implicated as risk genes for ASDs. Knock-in mice carrying a single rare point mutation of NLGN3 (NLGN3 R451C) discovered in the patients with ASDs display a deficit in social interaction and an enhancement of spatial learning and memory ability reminiscent of the clinical phenotype of ASDs. NLGN4 knockout (KO) and NRXN2alpha KO mice also show a deficit in sociability as well as some specific neuropsychiatric behaviors. In this review, we selected NRXNs/NLGNs, CNTNAP2/CNTNAP4, CNTN4, ITGB3, and KIRREL3 as strong ASD risk genes based on SFARI score and summarize the protein structures, functions at synapses, representative discoveries in human genetic studies, and phenotypes of the mutant model mice in light of the pathophysiology of ASDs.
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2. Bryn V, Aass HC, Skjeldal OH, Isaksen J, Saugstad OD, Ormstad H. {{Cytokine Profile in Autism Spectrum Disorders in Children}}. {J Mol Neurosci};2016 (Oct 12)
The pathogenesis of autism spectrum disorders (ASD) is not completely understood, but there is evidence of associations with altered immune responses. The aim of this study was to determine the serum levels of various cytokines in children with ASD and in healthy controls, in order to determine their role in ASD and its diagnostic subgroups. Sixty-five ASD patients were enrolled from an epidemiological survey in Norway, of which 30 were diagnosed with childhood autism, 16 with Asperger syndrome, 12 with atypical autism, 1 with Rett syndrome, and 6 with another ASD diagnosis. The serum levels of 12 cytokines were measured in all of the patients and in 30 healthy children. The cytokine levels did not differ significantly between the ASD group and the healthy controls. However, the interleukin-8 (IL-8) level was significantly higher (6.82 vs 4.58 pg/ml, p = 0.017) while that of IL-10 was significantly lower (2.24 vs 6.49 pg/ml, p = 0.009) in patients with childhood autism than in controls. Furthermore, the IL-8 level was significantly higher in childhood autism than in Asperger syndrome (6.82 vs 4.05 pg/ml, p = 0.013). Our study shows that the cytokine profile of children diagnosed with ASD, regardless of the subdiagnosis, does not differ from healthy controls. However, differentiation into different diagnostic subgroups reveals significantly different levels of IL-8 and IL-10. This indicates that different mechanisms may underlie the different ASD subdiagnoses. Future research into the pathophysiological mechanisms of ASD should pay more attention to the different subdiagnoses of ASD.
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3. Butwicka A, Langstrom N, Larsson H, Lundstrom S, Serlachius E, Almqvist C, Frisen L, Lichtenstein P. {{Increased Risk for Substance Use-Related Problems in Autism Spectrum Disorders: A Population-Based Cohort Study}}. {J Autism Dev Disord};2016 (Oct 12)
Despite limited and ambiguous empirical data, substance use-related problems have been assumed to be rare among patients with autism spectrum disorders (ASD). Using Swedish population-based registers we identified 26,986 individuals diagnosed with ASD during 1973-2009, and their 96,557 non-ASD relatives. ASD, without diagnosed comorbidity of attention deficit hyperactivity disorder (ADHD) or intellectual disability, was related to a doubled risk of substance use-related problems. The risk of substance use-related problems was the highest among individuals with ASD and ADHD. Further, risks of substance use-related problems were increased among full siblings of ASD probands, half-siblings and parents. We conclude that ASD is a risk factor for substance use-related problems. The elevated risks among relatives of probands with ASD suggest shared familial (genetic and/or shared environmental) liability.
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4. D’Cruz AM, Mosconi MW, Ragozzino ME, Cook EH, Sweeney JA. {{Alterations in the functional neural circuitry supporting flexible choice behavior in autism spectrum disorders}}. {Transl Psychiatry};2016 (Oct 11);6(10):e916.
Restricted and repetitive behaviors, and a pronounced preference for behavioral and environmental consistency, are distinctive characteristics of autism spectrum disorder (ASD). Alterations in frontostriatal circuitry that supports flexible behavior might underlie this behavioral impairment. In an functional magnetic resonance imaging study of 17 individuals with ASD, and 23 age-, gender- and IQ-matched typically developing control participants, reversal learning tasks were used to assess behavioral flexibility as participants switched from one learned response choice to a different response choice when task contingencies changed. When choice outcome after reversal was uncertain, the ASD group demonstrated reduced activation in both frontal cortex and ventral striatum, in the absence of task performance differences. When the outcomes of novel responses were certain, there was no difference in brain activation between groups. Reduced activation in frontal cortex and ventral striatum suggest problems in decision-making and response planning, and in processing reinforcement cues, respectively. These processes, and their integration, are essential for flexible behavior. Alterations in these systems may therefore contribute to a rigid adherence to preferred behavioral patterns in individuals with an ASD. These findings provide an additional impetus for the use of reversal learning paradigms as a translational model for treatment development targeting the domain of restricted and repetitive behaviors in ASD.
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5. Locke J, Beidas RS, Marcus S, Stahmer A, Aarons GA, Lyon AR, Cannuscio C, Barg F, Dorsey S, Mandell DS. {{A mixed methods study of individual and organizational factors that affect implementation of interventions for children with autism in public schools}}. {Implement Sci};2016 (Oct 10);11(1):135.
BACKGROUND: The significant lifelong impairments associated with autism spectrum disorder (ASD), combined with the growing number of children diagnosed with ASD, have created urgency in improving school-based quality of care. Although many interventions have shown efficacy in university-based research, few have been effectively implemented and sustained in schools, the primary setting in which children with ASD receive services. Individual- and organizational-level factors have been shown to predict the implementation of evidence-based interventions (EBIs) for the prevention and treatment of other mental disorders in schools, and may be potential targets for implementation strategies in the successful use of autism EBIs in schools. The purpose of this study is to examine the individual- and organizational-level factors associated with the implementation of EBIs for children with ASD in public schools. METHODS: We will apply the Domitrovich and colleagues (2008) framework that examines the influence of contextual factors (i.e., individual- and organizational-level factors) on intervention implementation in schools. We utilize mixed methods to quantitatively test whether the factors identified in the Domitrovich and colleagues (2008) framework are associated with the implementation of autism EBIs, and use qualitative methods to provide a more comprehensive understanding of the factors associated with successful implementation and sustainment of these interventions with the goal of tailoring implementation strategies. DISCUSSION: The results of this study will provide an in-depth understanding of individual- and organizational-level factors that influence the successful implementation of EBIs for children with ASD in public schools. These data will inform potential implementation targets and tailoring of strategies that will help schools overcome barriers to implementation and ultimately improve the services and outcomes for children with ASD.
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6. Miller M, Iosif AM, Young GS, Hill MM, Ozonoff S. {{Early Detection of ADHD: Insights From Infant Siblings of Children With Autism}}. {J Clin Child Adolesc Psychol};2016 (Oct 12):1-8.
Converging evidence suggests shared genetic underpinnings of attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Studies of infants at risk for ASD have proliferated over the past decade; the few studies that have followed these infants beyond age 3 report a range of difficulties facing a subset of these infants as they reach school age, including elevated levels of attention problems and externalizing behavior. Given this, we aimed to identify early predictors of school-age ADHD outcomes in a sample of infant siblings at risk for ASD. This study reports on a sample of 59 infants at high and low risk for ASD who had been followed for more than a decade, collecting data at regular intervals from 3 to 36 months and then determining diagnostic outcome at 8-10 years of age. Seventeen participants were diagnosed with Diagnostic and Statistical Manual of Mental Disorders (5th ed.) ADHD at school age (n = 14 high risk, 3 low risk). As infants, the ADHD outcome group demonstrated atypical longitudinal patterns of sustained visual attention. A significantly larger proportion of their parents reported behavior/temperament problems at 36 months of age, and examiners noted the presence of inattentive, hyperactive, and/or impulsive behaviors in this group by 18 months of age. These data suggest that behavioral indicators of risk for later ADHD may be present early in development, which may improve earlier detection and treatment of the disorder.
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7. Panahi Y, Salasar Moghaddam F, Ghasemi Z, Hadi Jafari M, Shervin Badv R, Eskandari MR, Pedram M. {{Selection of Suitable Reference Genes for Analysis of Salivary Transcriptome in Non-Syndromic Autistic Male Children}}. {Int J Mol Sci};2016 (Oct 12);17(10)
Childhood autism is a severe form of complex genetically heterogeneous and behaviorally defined set of neurodevelopmental diseases, collectively termed as autism spectrum disorders (ASD). Reverse transcriptase quantitative real-time PCR (RT-qPCR) is a highly sensitive technique for transcriptome analysis, and it has been frequently used in ASD gene expression studies. However, normalization to stably expressed reference gene(s) is necessary to validate any alteration reported at the mRNA level for target genes. The main goal of the present study was to find the most stable reference genes in the salivary transcriptome for RT-qPCR analysis in non-syndromic male childhood autism. Saliva samples were obtained from nine drug naive non-syndromic male children with autism and also sex-, age-, and location-matched healthy controls using the RNA-stabilizer kit from DNA Genotek. A systematic two-phased measurement of whole saliva mRNA levels for eight common housekeeping genes (HKGs) was carried out by RT-qPCR, and the stability of expression for each candidate gene was analyzed using two specialized algorithms, geNorm and NormFinder, in parallel. Our analysis shows that while the frequently used HKG ACTB is not a suitable reference gene, the combination of GAPDH and YWHAZ could be recommended for normalization of RT-qPCR analysis of salivary transcriptome in non-syndromic autistic male children.
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8. Purpura G, Fulceri F, Puglisi V, Masoni P, Contaldo A. {{Motor coordination impairment in children with autism spectrum disorder: a pilot study using Movement Assessment Battery for Children-2 Checklist}}. {Minerva Pediatr};2016 (Oct 12)
BACKGROUND: Some research suggests that children with autism spectrum disorder (ASD) experience diverse motor difficulties that appear closely related to the severity of symptomatology, including repetitive behaviors. Therefore, motor assessment in ASD has crucial relevance in order to plan a specific intervention. The aim of this study is to assess and describe the motor functioning in school-aged children with ASD and to evaluate the relationship between their motor profile and clinical features. METHOD: The Movement Assessment Battery for Children-2nd edition (M-ABC2) Checklist was administered to twenty children with ASD, aged between 5 and 13.5 years. The motor profile of the sample was analyzed and then the relationship between the motor functioning and the clinical characteristics of subjects (age, treatment duration, intellectual functioning and repetitive behaviors) was investigated. RESULTS: 70% of our sample has motor difficulties, especially in aiming and catching skills, balance and manual dexterity. Poorer performance was related to a higher frequency and intensity of repetitive and stereotyped behaviors. CONCLUSIONS: Motor difficulties in children with ASD affect specific skills that imply the ability to integrate the perception with the action for anticipating and controlling the movement in a well-coordinated way. This result, along with the finding of an increased severity of repetitive and stereotyped behaviors in these children, emphasizes the close link between motor and « core » symptoms in ASD.
9. Puscian A, Leski S, Kasprowicz G, Winiarski M, Borowska J, Nikolaev T, Boguszewski PM, Lipp HP, Knapska E. {{Eco-HAB as a fully automated and ecologically relevant assessment of social impairments in mouse models of autism}}. {Elife};2016 (Oct 12);5
Eco-HAB is an open source, RFID-based system for automated measurement and analysis of social preference and in-cohort sociability in mice. The system closely follows murine ethology. It requires no contact between a human experimenter and tested animals, overcoming the confounding factors that lead to irreproducible assessment of murine social behavior between laboratories. In Eco-HAB, group-housed animals live in a spacious, four-compartment apparatus with shadowed areas and narrow tunnels, resembling natural burrows. Eco-HAB allows for assessment of the tendency of mice to voluntarily spend time together in ethologically relevant mouse group sizes. Custom-made software for automated tracking, data extraction, and analysis enables quick evaluation of social impairments. The developed protocols and standardized behavioral measures demonstrate high replicability. Unlike classic three-chambered sociability tests, Eco-HAB provides measurements of spontaneous, ecologically relevant social behaviors in group-housed animals. Results are obtained faster, with less manpower, and without confounding factors.
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10. Sivanesan S, Tan A, Jeyaraj R, Lam J, Gole M, Hardan A, Ashkan K, Rajadas J. {{Pharmaceuticals and Stem Cells in Autism Spectrum Disorders: Wishful Thinking?}}. {World Neurosurg};2016 (Oct 7)
Autism Spectrum Disorders (ASDs) are a group of complex neurodevelopmental conditions characterized by abnormal patterns of attention, and impaired social and communication skills. ASDs are also associated with a number of functional challenges and potentially harmful deficits, including restricted and repetitive behaviors, anxiety, irritability, seizures, and self-harm. Although the exact causes of ASDs are currently unknown, it is suggested that genetic, epigenetic and environmental factors play critical roles. Recent findings support evidence for synaptic defects and impairments in brain information processing that are linked to social and perceptual skills. Owing to the clinical heterogeneity and lack of precise diagnostic tools, current therapeutic approaches aimed at managing ASD-associated conditions are not definitive. In this review, we seek to provide a contemporary account of the key pathological events pertaining to autism: the theory of oxidative stress and inflammatory causes; ideas of immune dysfunction; the probable biomarkers that can be used for diagnostics – and the use of pharmaceuticals and stem cells as possible candidates for the treatment of ASDs.
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11. Tanet A, Hubert-Barthelemy A, Crespin GC, Bodeau N, Cohen D, Saint-Georges C. {{A Developmental and Sequenced One-to-One Educational Intervention for Autism Spectrum Disorder: A Randomized Single-Blind Controlled Trial}}. {Front Pediatr};2016;4:99.
INTRODUCTION: Individuals with autism spectrum disorder (ASD) who also exhibit severe-to-moderate ranges of intellectual disability (ID) still face many challenges (i.e., less evidence-based trials, less inclusion in school with peers). METHODS: We implemented a novel model called the « Developmental and Sequenced One-to-One Educational Intervention » (DS1-EI) in 5- to 9-year-old children with co-occurring ASD and ID. The treatment protocol was adapted for school implementation by designing it using an educational agenda. The intervention was based on intensity, regular assessments, updating objectives, encouraging spontaneous communication, promoting skills through play with peers, supporting positive behaviors, providing supervision, capitalizing on teachers’ unique skills, and providing developmental and sequenced learning. Developmental learning implies that the focus of training is what is close to the developmental expectations given a child’s development in a specific domain. Sequenced learning means that the teacher changes the learning activities every 10-15 min to maintain the child’s attention in the context of an anticipated time agenda. We selected 11 French institutions in which we implemented the model in small classrooms. Each institution recruited participants per dyads matched by age, sex, and developmental quotient. Patients from each dyad were then randomized to a DS1-EI group or a Treatment as usual (TAU) group for 36 months. The primary variables – the Childhood Autism Rating scale (CARS) and the psychoeducational profile (PEP-3) – will be blindly assessed by independent raters at the 18-month and 36-month follow-up. DISCUSSION AND BASELINE DESCRIPTION: We enrolled 75 participants: 38 were randomized to the DS1-EI and 37 to the TAU groups. At enrollment, we found no significant differences in participants’ characteristics between groups. As expected, exposure to school was the only significant difference [9.4 (+/-4.1) h/week in the DS1-EI group vs. 3.4 (+/-4.5) h/week in the TAU group, Student’s t-test, t = 5.83, p < 0.001]. ETHICS AND DISSEMINATION: The protocol was authorized by the competent national regulatory authority (Agence nationale de securite du medicament et des produits de sante) and approved by the local Ethics Committee (Comite de Protection des Personnes) at the University Hospital Saint-Antoine (May 7, 2013). The findings will be disseminated through peer-reviewed journals and national and international conferences. TRIAL REGISTRATION NUMBERS: ANSM130282B-31 (April 16 2013) and ACTRN12616000592448 (May 6 2016).
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12. Vo LC, Snyder C, McCracken C, McDougle CJ, McCracken JT, Aman MG, Tierney E, Arnold LE, Levi D, Kelleman M, Carroll D, Morrissey J, Vitiello B, Scahill L. {{No Apparent Cardiac Conduction Effects of Acute Treatment with Risperidone in Children with Autism Spectrum Disorder}}. {J Child Adolesc Psychopharmacol};2016 (Oct 11)
OBJECTIVES: Risperidone is approved for the treatment of serious behavioral problems in children with autism spectrum disorder (ASD). This study examined the effects of risperidone on cardiac conduction in children with ASD. METHODS: Data were collected from an 8-week, five-site trial conducted by the Research Units on Pediatric Psychopharmacology Autism Network. Children (age 5-17 years) were randomly assigned to risperidone (n = 49) or placebo (n = 52) under double-blind conditions. Risperidone was superior to placebo in reducing serious behavioral problems. A standard 12-lead, electrocardiogram (ECG) was obtained in most subjects at screening and week 8. A pediatric electrophysiologist blind to treatment assignment reviewed all available ECGs for readability, abnormalities, and cardiac conduction parameters, including QTc. The electrophysiologist measurements were compared to machine readings. A second blinded electrophysiologist examined all available ECGs for abnormalities and a 20% random sample for QTc. RESULTS: Of the 101 randomized subjects in the trial, complete pretreatment and week 8 data were available on 65 subjects (placebo n = 30; risperidone n = 35). The electrophysiologist did not identify any cardiac conduction adverse effects of risperidone and there was no difference in mean change on the QTc compared to placebo. The Bland-Altman plot showed a systematic bias in QTc measurements by the electrophysiologist and machine. Machine readings produced higher values than the electrophysiologist for shorter QTc intervals and machine scoring was lower than electrophysiologist readings for longer QTc values (p = 0.001). Two electrophysiologists had overall percent agreements of 82.9% (95% CI: 76.3 to 89.6) on qualitative assessment and 88.6% (95% CI: 79.3 to 98.0) on QTc interval. CONCLUSION: Using conventional doses during acute treatment in children with ASD and serious behavioral problems, there was no difference in the mean change in QTc between risperidone and placebo. Compared to the electrophysiologist, the machine readings may miss elevated QTc measurements.
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13. Weber RJ, Gadow KD. {{Relation of Psychiatric Symptoms with Epilepsy, Asthma, and Allergy in Youth with ASD vs. Psychiatry Referrals}}. {J Abnorm Child Psychol};2016 (Oct 11)
The present study aimed to characterize the association of psychopathology with the clinical correlates of epilepsy, asthma, and allergy within and between neurobehavioral syndromes. Participants were consecutively evaluated youth (6-18 years, 75 % male) with autism spectrum disorder (ASD; n = 589) and non-ASD outpatient psychiatry referrals (n = 653). Informants completed a background questionnaire (parents) and a psychiatric symptom severity rating scale (parents, teachers). Youth with ASD had higher rates of epilepsy and allergy but not asthma than psychiatry referrals, even when analyses were limited to youth with IQ >/= 70. Somatic conditions evidenced variable associations with medical services utilization, educational interventions, family income, and maternal education. Youth with ASD with versus without epilepsy had more severe ASD social deficits (parents’ ratings) and less severe ASD repetitive behaviors (teachers’ ratings). Epilepsy was associated with more severe depression, mania, and schizophrenia symptoms in youth with ASD. Youth with allergy (psychiatry referrals only) had more severe anxiety and depression symptoms (parents’ ratings) but less severe aggression (teachers’ ratings) thus providing evidence of both context- and diagnostic-specificity. Youth with ASD versus non-ASD psychiatry referrals evidence a variable pattern of relations between somatic conditions and a range of clinical correlates, which suggests that the biologic substrates and psychosocial concomitants of neurodevelopmental disorders and their co-occurring somatic conditions may interact to produce unique clinical phenotypes.
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14. Zhang B, Seigneur E, Wei P, Gokce O, Morgan J, Sudhof TC. {{Developmental plasticity shapes synaptic phenotypes of autism-associated neuroligin-3 mutations in the calyx of Held}}. {Mol Psychiatry};2016 (Oct 11)
Neuroligins are postsynaptic cell-adhesion molecules that bind to presynaptic neurexins. Mutations in neuroligin-3 predispose to autism, but how such mutations affect synaptic function remains incompletely understood. Here we systematically examined the effect of three autism-associated mutations, the neuroligin-3 knockout, the R451C knockin, and the R704C knockin, on synaptic transmission in the calyx of Held, a central synapse ideally suited for high-resolution analyses of synaptic transmission. Surprisingly, germline knockout of neuroligin-3 did not alter synaptic transmission, whereas the neuroligin-3 R451C and R704C knockins decreased and increased, respectively, synaptic transmission. These puzzling results prompted us to ask whether neuroligin-3 mutant phenotypes may be reshaped by developmental plasticity. Indeed, conditional knockout of neuroligin-3 during late development produced a marked synaptic phenotype, whereas conditional knockout of neuroligin-3 during early development caused no detectable effect, mimicking the germline knockout. In canvassing potentially redundant candidate genes, we identified developmentally early expression of another synaptic neurexin ligand, cerebellin-1. Strikingly, developmentally early conditional knockout of cerebellin-1 only modestly impaired synaptic transmission, whereas in contrast to the individual single knockouts, developmentally early conditional double knockout of both cerebellin-1 and neuroligin-3 severely decreased synaptic transmission. Our data suggest an unanticipated mechanism of developmental compensation whereby cerebellin-1 and neuroligin-3 functionally occlude each other during development of calyx synapses. Thus, although acute manipulations more likely reveal basic gene functions, developmental plasticity can be a major factor in shaping the overall phenotypes of genetic neuropsychiatric disorders.Molecular Psychiatry advance online publication, 11 October 2016; doi:10.1038/mp.2016.157.
