1. Adler N, Dvash J, Shamay-Tsoory SG. {{Empathic Embarrassment Accuracy in Autism Spectrum Disorder}}. {Autism Res};2015 (Mar 2)
Empathic accuracy refers to the ability of perceivers to accurately share the emotions of protagonists. Using a novel task assessing embarrassment, the current study sought to compare levels of empathic embarrassment accuracy among individuals with autism spectrum disorders (ASD) with those of matched controls. To assess empathic embarrassment accuracy, we compared the level of embarrassment experienced by protagonists to the embarrassment felt by participants while watching the protagonists. The results show that while the embarrassment ratings of participants and protagonists were highly matched among controls, individuals with ASD failed to exhibit this matching effect. Furthermore, individuals with ASD rated their embarrassment higher than controls when viewing themselves and protagonists on film, but not while performing the task itself. These findings suggest that individuals with ASD tend to have higher ratings of empathic embarrassment, perhaps due to difficulties in emotion regulation that may account for their impaired empathic accuracy and aberrant social behavior. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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2. Al-Amin MM, Rahman MM, Rahman F, Ema FZ, Reza HM. {{Astaxanthin improves behavioural disorder and oxidative stress in prenatal valproic acid-induced mice model of autism}}. {Behav Brain Res};2015 (Feb 27)
Prenatal exposure to valproic acid on gestational day 12.5 may lead to the impaired behaviour in the offspring, which is similar to the human autistic symptoms. To the contrary, astaxanthin shows neuroprotective effect by its antioxidant mechanism. We aimed to (i) develop mice model of autism and (ii) investigate the effect of astaxanthin on such model animals. Valproic acid (600mg/kg) was administered intraperitoneally to the pregnant mice on gestational day 12.5. Prenatal valproic acid-exposed mice were divided into 2 groups on postnatal day 25 and astaxanthin (2mg/kg) was given to the experimental group (VPA_AST, n=10) while saline was given to the control group (VPA, n=10) for 4 weeks. Behavioural test including social interaction, open field and hot-plate were conducted on postnatal day 25 and oxidative stress markers such as lipid peroxidation, advanced protein oxidation product, nitric oxide, glutathione, and activity of superoxide dismutase and catalase were estimated on postnatal day 26 to confirm mice model of autism and on postnatal day 56 to assess the effect of astaxanthin. On postnatal day 25, prenatal valproic acid-exposed mice exhibited (i) delayed eye opening (ii) longer latency to respond painful stimuli, (iii) poor sociability and social novelty and (iv) high level of anxiety. In addition, an increased level of oxidative stress was found by determining different oxidative stress markers. Treatment with astaxanthin significantly (p<0.05) improved the behavioural disorder and reduced the oxidative stress in brain and liver. In conclusion, prenatal exposure to valproic day in pregnant mice leads to the development of autism-like features. Astaxanthin improves the impaired behaviour in animal model of autism presumably by its antioxidant activity.
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3. Bang J, Nadig A. {{Learning Language in Autism: Maternal Linguistic Input Contributes to Later Vocabulary}}. {Autism Res};2015 (Mar 2)
It is well established that children with typical development (TYP) exposed to more maternal linguistic input develop larger vocabularies. We know relatively little about the linguistic environment available to children with autism spectrum disorders (ASD), and whether input contributes to their later vocabulary. Children with ASD or TYP and their mothers from English and French-speaking families engaged in a 10 min free-play interaction. To compare input, children were matched on language ability, sex, and maternal education (ASD n = 20, TYP n = 20). Input was transcribed, and the number of word tokens and types, lexical diversity (D), mean length of utterances (MLU), and number of utterances were calculated. We then examined the relationship between input and children’s spoken vocabulary 6 months later in a larger sample (ASD: n = 19, 50-85 months; TYP: n = 44, 25-58 months). No significant group differences were found on the five input features. A hierarchical multiple regression model demonstrated input MLU significantly and positively contributed to spoken vocabulary 6 months later in both groups, over and above initial language levels. No significant difference was found between groups in the slope between input MLU and later vocabulary. Our findings reveal children with ASD and TYP of similar language levels are exposed to similar maternal linguistic environments regarding number of word tokens and types, D, MLU, and number of utterances. Importantly, linguistic input accounted for later vocabulary growth in children with ASD. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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4. Chromik LC, Quintin EM, Lepage JF, Hustyi KM, Lightbody AA, Reiss AL. {{The Influence of Hyperactivity, Impulsivity, and Attention Problems on Social Functioning in Adolescents and Young Adults With Fragile X Syndrome}}. {J Atten Disord};2015 (Mar 2)
OBJECTIVE: Individuals with fragile X syndrome (FXS) present primarily with cognitive and social deficits in addition to symptoms of ADHD. The relationship between symptoms of ADHD, cognitive functioning, and social skills has never been explicitly studied. METHOD: Here, we analyzed both longitudinal (n = 70; Time 1: ages 6-18; Time 2: ages 15-26) and cross-sectional (n = 73; Time 2 only) data using hierarchical linear regression to assess how global intellectual functioning (IQ) and symptoms of ADHD influence social functioning in individuals with FXS. RESULTS: We found that ADHD symptoms at Times 1 and 2 consistently predict social functioning in both males and females with FXS at Time 2. CONCLUSION: Our results suggest that addressing ADHD symptoms in childhood may have positive, long-term effects on the social functioning of adolescents and young adults with FXS.
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5. Colvert E, Tick B, McEwen F, Stewart C, Curran SR, Woodhouse E, Gillan N, Hallett V, Lietz S, Garnett T, Ronald A, Plomin R, Rijsdijk F, Happe F, Bolton P. {{Heritability of Autism Spectrum Disorder in a UK Population-Based Twin Sample}}. {JAMA Psychiatry};2015 (Mar 4)
Importance: Most evidence to date highlights the importance of genetic influences on the liability to autism and related traits. However, most of these findings are derived from clinically ascertained samples, possibly missing individuals with subtler manifestations, and obtained estimates may not be representative of the population. Objectives: To establish the relative contributions of genetic and environmental factors in liability to autism spectrum disorder (ASD) and a broader autism phenotype in a large population-based twin sample and to ascertain the genetic/environmental relationship between dimensional trait measures and categorical diagnostic constructs of ASD. Design, Setting, and Participants: We used data from the population-based cohort Twins Early Development Study, which included all twin pairs born in England and Wales from January 1, 1994, through December 31, 1996. We performed joint continuous-ordinal liability threshold model fitting using the full information maximum likelihood method to estimate genetic and environmental parameters of covariance. Twin pairs underwent the following assessments: the Childhood Autism Spectrum Test (CAST) (6423 pairs; mean age, 7.9 years), the Development and Well-being Assessment (DAWBA) (359 pairs; mean age, 10.3 years), the Autism Diagnostic Observation Schedule (ADOS) (203 pairs; mean age, 13.2 years), the Autism Diagnostic Interview-Revised (ADI-R) (205 pairs; mean age, 13.2 years), and a best-estimate diagnosis (207 pairs). Main Outcomes and Measures: Participants underwent screening using a population-based measure of autistic traits (CAST assessment), structured diagnostic assessments (DAWBA, ADI-R, and ADOS), and a best-estimate diagnosis. Results: On all ASD measures, correlations among monozygotic twins (range, 0.77-0.99) were significantly higher than those for dizygotic twins (range, 0.22-0.65), giving heritability estimates of 56% to 95%. The covariance of CAST and ASD diagnostic status (DAWBA, ADOS and best-estimate diagnosis) was largely explained by additive genetic factors (76%-95%). For the ADI-R only, shared environmental influences were significant (30% [95% CI, 8%-47%]) but smaller than genetic influences (56% [95% CI, 37%-82%]). Conclusions and Relevance: The liability to ASD and a more broadly defined high-level autism trait phenotype in this large population-based twin sample derives primarily from additive genetic and, to a lesser extent, nonshared environmental effects. The largely consistent results across different diagnostic tools suggest that the results are generalizable across multiple measures and assessment methods. Genetic factors underpinning individual differences in autismlike traits show considerable overlap with genetic influences on diagnosed ASD.
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6. Crafa D, Warfa N. {{Maternal migration and autism risk: Systematic analysis}}. {Int Rev Psychiatry};2015 (Mar 4):1-8.
Autism (AUT) is one of the most prevalent developmental disorders emerging during childhood, and can be amongst the most incapacitating mental disorders. Some individuals with AUT require a lifetime of supervised care. Autism Speaks reported estimated costs for 2012 at pound34 billion in the UK; and $3.2 million-$126 billion in the US, Australia and Canada. Ethnicity and migration experiences appear to increase risks of AUT and relate to underlying biological risk factors. Sociobiological stress factors can affect the uterine environment, or relate to stress-induced epigenetic changes during pregnancy and delivery. Epigenetic risk factors associated with AUT also include poor pregnancy conditions, low birth weight, and congenital malformation. Recent studies report that children from migrant communities are at higher risk of AUT than children born to non-migrant mothers, with the exception of Hispanic children. This paper provides the first systematic review into prevalence and predictors of AUT with a particular focus on maternal migration stressors and epigenetic risk factors. AUT rates appear higher in certain migrant communities, potentially relating to epigenetic changes after stressful experiences. Although AUT remains a rare disorder, failures to recognize its public health urgency and local community needs continue to leave certain cultural groups at a disadvantage.
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7. Damaj L, Lupien-Meilleur A, Lortie A, Riou E, Ospina LH, Gagnon L, Vanasse C, Rossignol E. {{CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms}}. {Eur J Hum Genet};2015 (Mar 4)
CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of CaV2.1 channels function, presumably affecting cerebellar, cortical and limbic networks.European Journal of Human Genetics advance online publication, 4 March 2015; doi:10.1038/ejhg.2015.21.
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8. Field C, Allen ML, Lewis C. {{Attentional Learning Helps Language Acquisition Take Shape for Atypically Developing Children, Not Just Children with Autism Spectrum Disorders}}. {J Autism Dev Disord};2015 (Mar 3)
The shape bias-generalising labels to same shaped objects-has been linked to attentional learning or referential intent. We explore these origins in children with typical development (TD), autism spectrum disorders (ASD) and other developmental disorders (DD). In two conditions, a novel object was presented and either named or described. Children selected another from a shape, colour or texture match. TD children choose the shape match in both conditions, children with DD and ‘high-verbal mental age’ (VMA) children with ASD (language age > 4.6) did so in the name condition and ‘low-VMA’ children with ASD never showed the heuristic. Thus, the shape bias arises from attentional learning in atypically developing children and is delayed in ASD.
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9. Gao R, Penzes P. {{Common Mechanisms of Excitatory and Inhibitory Imbalance in Schizophrenia and Autism Spectrum Disorders}}. {Curr Mol Med};2015 (Mar 2)
Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are cognitive disorders with complex genetic architectures but overlapping behavioral phenotypes, which suggests common pathway perturbations. Multiple lines of evidence implicate imbalances in excitatory and inhibitory activity (E/I imbalance) as a shared pathophysiological mechanism. Thus, understanding the molecular underpinnings of E/I imbalance may provide essential insight into the etiology of these disorders and may uncover novel targets for future drug discovery. Here, we review key genetic, physiological, neuropathological, functional, and pathway studies that suggest alterations to excitatory/inhibitory circuits are keys to ASD and SCZ pathogenesis.
10. Ghilan M, Hryciw BN, Brocardo PS, Bostrom CA, Gil-Mohapel J, Christie BR. {{Enhanced Corticosteroid Signaling Alters Synaptic Plasticity in the Dentate Gyrus in Mice Lacking the Fragile X Mental Retardation Protein}}. {Neurobiol Dis};2015 (Feb 27)
The fragile X mental retardation protein (FMRP) is an important regulator of protein translation, and a lack of FMRP expression leads to a cognitive disorder known as fragile X syndrome (FXS). Clinical symptoms characterizing FXS include learning impairments and heightened anxiety in response to stressful situations. Here, we report that, in response to acute stress, mice lacking FMRP show a faster elevation of corticosterone and a more immediate impairment in N-methyl-D-aspartate receptor (NMDAR) dependent long-term potentiation (LTP) in the dentate gyrus (DG). These stress-induced LTP impairments were rescued by administering the glucocorticoid receptor (GR) antagonist RU38486. Administration of RU38486 also enhanced LTP in Fmr1-/y mice in the absence of acute stress to wild-type levels, and this enhancement was blocked by application of the NMDAR antagonist 2-amino-5-phosphonopentanoic acid. These results suggest that a loss of FMPR results in enhanced GR signaling that may adversely affect NMDAR dependent synaptic plasticity in the DG.
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11. Hedley D, Nevill RE, Monroy-Moreno Y, Fields N, Wilkins J, Butter E, Mulick JA. {{Efficacy of the ADEC in Identifying Autism Spectrum Disorder in Clinically Referred Toddlers in the US}}. {J Autism Dev Disord};2015 (Mar 4)
The Autism Detection in Early Childhood (ADEC) is a brief, play-based screening tool for the assessment of autism spectrum disorder (ASD) in children aged 12-36 months. We examined the psychometric properties of the ADEC in a clinical sample of toddlers (n = 114) referred to a US pediatric hospital for assessment due to concerns of developmental delay or ASD. The ADEC (cutoff = 11) returned good sensitivity (.93-.94) but poorer specificity (.62-.64) for best estimate clinical diagnosis of ASD, and compared favorably with the ADOS-2. Internal consistency was acceptable, alpha = .80, and inter-rater reliability was high, ICC = .95. Results support the use of the ADEC as a clinical screen for ASD.
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12. Hill-Yardin EL, Argyropoulos A, Hosie S, Rind G, Anderson P, Hannan AJ, O’Brien TJ. {{Reduced susceptibility to induced seizures in the Neuroligin-3(R451C) mouse model of autism}}. {Neurosci Lett};2015 (Mar 4);589:57-61.
Epilepsy is a common comorbidity in patients with autism spectrum disorder (ASD) and several gene mutations are associated with both of these disorders. In order to determine whether a point mutation in the gene for the synaptic protein, Neuroligin-3 (Nlgn3, R451C), identified in patients with ASD alters seizure susceptibility, we administered the proconvulsant pentylenetetrazole (PTZ) to adult male Neuroligin-3(R451C) (NL3(R451C)) and wild type (WT) mice. It has previously been reported that NL3(R451C) mice show altered inhibitory GABAergic activity in brain regions relevant to epilepsy, including the hippocampus and somatosensory cortex. PTZ administration induces absence-seizures at low dose, and generalised convulsive seizures at higher dose. Susceptibility to absence seizures was examined by analysing the frequency and duration of spike-and-wave discharge (SWD) events and accompanying motor seizure activity induced by subcutaneous administration of low dosage (20 or 30mg/kg) PTZ. Susceptibility to generalised convulsive seizures was tested by measuring the response to high dosage (60mg/kg) PTZ using a modified Racine scale. There was no change in the number of SWD events exhibited by NL3(R451C) compared to WT mice following administration of both 20mg/kg PTZ (1.17+/-0.31 compared to 16.0+/-11.16 events/30min, NL3(R451C) versus WT, respectively) and 30mg/kg PTZ (7.5+/-6.54 compared with 27.8+/-19.9 events/30min, NL3(R451C) versus WT, respectively). NL3(R451C) mice were seizure resistant to generalised convulsive seizures induced by high dose PTZ compared to WT littermates (median latency to first >3s duration clonic seizure; 14.5min versus 7.25min, 95% CI: 1.625-2.375, p=0.0009, NL3(R451C) versus WT, respectively). These results indicate that the R451C mutation in the Nlgn3 gene, associated with ASD in humans, confers resistance to induced seizures, suggesting dysfunction of PTZ-sensitive GABAergic signalling in this mouse model of ASD.
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13. Kim E, Camacho J, Combs Z, Ariza J, Lechpammer M, Noctor SC, Martinez-Cerdeno V. {{Preliminary findings suggest the number and volume of supragranular and infragranular pyramidal neurons are similar in the anterior superior temporal area of control subjects and subjects with autism}}. {Neurosci Lett};2015 (Mar 4);589:98-103.
We investigated the cytoarchitecture of the anterior superior temporal area (TA2) of the postmortem cerebral cortex in 9 subjects with autism and 9 age-matched typically developing subjects between the ages of 13 and 56 years. The superior temporal gyrus is involved in auditory processing and social cognition and its pathology has been correlated with autism. We quantified the number and soma volume of pyramidal neurons in the supragranular layers and pyramidal neurons in the infragranular layers in each subject. We did not find significant differences in the number or volume of supragranular or infragranular neurons in the cerebral cortex of subjects with autism compared to typically developing subjects. This report does not support an alteration of supragranular to infragranular neurons in autism. However, further stereological analysis of the number of cells and cell volumes in specific cortical areas is needed to better establish the cellular phenotype of the autistic cerebral cortex and to understand its clinical relevance in autism.
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14. Lazaro MT, Golshani P. {{The utility of rodent models of autism spectrum disorders}}. {Curr Opin Neurol};2015 (Apr);28(2):103-109.
PURPOSE OF REVIEW: This review discusses the ways that rodent models of autism spectrum disorders (ASDs) have been used to gain critical information about convergent molecular pathways, the mechanisms underlying altered microcircuit structure and function, and as a screen for potential cutting edge-treatments for ASDs. RECENT FINDINGS: There is convergent evidence that impaired developmental pruning of connections may be a common finding among several mouse models of ASDs. Recent studies have uncovered impaired autophagy by pathological mTOR activation as a potential contributor to microcircuit dysfunction and behavior. ASD-related disinhibition and exaggerated synaptic plasticity in multiple distinct circuits in cortex and reward circuits in striatum also contribute to social dysfunction and repetitive behaviors. New exciting molecular therapeutic techniques have reversed cognitive deficits in models of ASD, indicating that mouse models could be used for preclinical translational studies of new treatments. SUMMARY: Rodent models of ASDs coupled to new emerging technologies for genome editing, cell-specific functional and structural imaging, and neuronal activity manipulation will yield critical insights into ASD pathogenesis and fuel the emergence of new treatments.
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15. Lehti V, Hinkka-Yli-Salomaki S, Cheslack-Postava K, Gissler M, Brown AS, Sourander A. {{Maternal socio-economic status based on occupation and autism spectrum disorders: A national case-control study}}. {Nord J Psychiatry};2015 (Mar 3):1-8.
Background: The association between parental socio-economic status (SES) and autism spectrum disorders (ASD) has been studied in several countries, but the results have been contradictory. Aims: The aim of this study was to examine the association between maternal SES and subtypes of ASD in Finland. Methods: A national case-control study was conducted. Children born in 1991-2005 and diagnosed with ASD by the year 2007 were identified from the Finnish Hospital Discharge Register (FHDR). Their matched controls were selected from the Finnish Medical Birth Register (FMBR). There were 3468 cases and 13,868 controls. The information on maternal SES was collected from the FMBR and categorized into upper white-collar workers (referent), lower white-collar workers, blue-collar workers and « others », consisting of students, housewives and other groups with unknown SES. The statistical test used was conditional logistic regression. Results: The likelihood of ASD was increased among offspring of mothers who belong to the group « others » (adjusted OR = 1.2, 95% CI 1.009-1.3). The likelihood of Asperger’s syndrome was decreased among offspring of lower white-collar workers (adjusted OR = 0.8, 95% CI 0.6-0.9) and blue-collar workers (adjusted OR = 0.6, 95% CI 0.5-0.7). The likelihood of pervasive developmental disorder not otherwise specified (PDD-NOS) was increased among offspring of blue-collar workers (adjusted OR = 1.5, 1.2-1.9) and « others » (adjusted OR = 1.3, 1.1-1.7). No association was found between maternal SES and childhood autism. Conclusions: The association between maternal SES and ASD differs by ASD subtype. Socio-economic groups might differ from each other by risk factors for ASD subtypes or by their service use.
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16. Leung RC, Vogan VM, Powell TL, Anagnostou E, Taylor MJ. {{The role of executive functions in social impairment in Autism Spectrum Disorder}}. {Child Neuropsychol};2015 (Mar 3):1-9.
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by socio-communicative impairments. Executive dysfunction may explain some key characteristics of ASD, both social and nonsocial hallmarks. Limited research exists exploring the relations between executive function and social impairment in ASD and few studies have used a comparison control group. Thus, the objective of the present study was to investigate the relations between executive functioning using the Behavioral Rating Inventory of Executive Functioning (BRIEF), social impairment as measured by the Social Responsiveness Scale (SRS), and overall autistic symptomology as measured by the Autism Diagnostic Observation Schedule (ADOS) in children and adolescents with and without ASD. Seventy children and adolescents diagnosed with ASD and 71 typically developing controls were included in this study. Findings showed that behavioral regulation executive processes (i.e., inhibition, shifting, and emotional control) predicted social function in all children. However, metacognitive executive processes (i.e., initiation, working memory, planning, organization, and monitoring) predicted social function only in children with ASD and not in typically developing children. Our findings suggest a distinct metacognitive executive function-social symptom link in ASD that is not present in the typical population. Understanding components of executive functioning that contribute to the autistic symptomology, particularly in the socio-communicative domain, is crucial for developing effective interventions that target key executive processes as well as underlying behavioral symptoms.
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17. Lyst MJ, Bird A. {{Rett syndrome: a complex disorder with simple roots}}. {Nat Rev Genet};2015 (Mar 3)
Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the X-linked gene MECP2 (methyl-CpG-binding protein 2). Two decades of research have fostered the view that MeCP2 is a multifunctional chromatin protein that integrates diverse aspects of neuronal biology. More recently, studies have focused on specific RTT-associated mutations within the protein. This work has yielded molecular insights into the critical functions of MeCP2 that promise to simplify our understanding of RTT pathology.
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18. Matthews NL, Smith CJ, Pollard E, Ober-Reynolds S, Kirwan J, Malligo A. {{Adaptive Functioning in Autism Spectrum Disorder During the Transition to Adulthood}}. {J Autism Dev Disord};2015 (Mar 3)
There is a dearth of research regarding adaptive functioning during the transition to adulthood in autism spectrum disorder (ASD). Profiles on the Vineland Adaptive Behavior Scales, Second Edition were examined by age and intellectual ability in 75 participants with ASD (16-58 years). Results extend previous reports of a cognitive advantage over adaptive functioning in children by demonstrating a similar pattern in an older sample. Daily living skills were a relative strength compared to communication and socialization in adults, but not adolescents. In general, highest subdomain scores were observed in writing skills and lowest scores were observed in interpersonal skills. Regardless of cognitive ability, all standard scores were well below average, indicating a need for lifelong intervention that targets adaptive functioning.
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19. Pramparo T, Pierce K, Lombardo MV, Carter Barnes C, Marinero S, Ahrens-Barbeau C, Murray SS, Lopez L, Xu R, Courchesne E. {{Prediction of Autism by Translation and Immune/Inflammation Coexpressed Genes in Toddlers From Pediatric Community Practices}}. {JAMA Psychiatry};2015 (Mar 4)
Importance: The identification of genomic signatures that aid early identification of individuals at risk for autism spectrum disorder (ASD) in the toddler period remains a major challenge because of the genetic and phenotypic heterogeneity of the disorder. Generally, ASD is not diagnosed before the fourth to fifth birthday. Objective: To apply a functional genomic approach to identify a biologically relevant signature with promising performance in the diagnostic classification of infants and toddlers with ASD. Design, Setting, and Participants: Proof-of-principle study of leukocyte RNA expression levels from 2 independent cohorts of children aged 1 to 4 years (142 discovery participants and 73 replication participants) using Illumina microarrays. Coexpression analysis of differentially expressed genes between Discovery ASD and control toddlers were used to define gene modules and eigengenes used in a diagnostic classification analysis. Independent validation of the classifier performance was tested on the replication cohort. Pathway enrichment and protein-protein interaction analyses were used to confirm biological relevance of the functional networks in the classifier. Participant recruitment occurred in general pediatric clinics and community settings. Male infants and toddlers (age range, 1-4 years) were enrolled in the study. Recruitment criteria followed the 1-Year Well-Baby Check-Up Approach. Diagnostic judgment followed DSM-IV-TR and Autism Diagnostic Observation Schedule criteria for autism. Participants with ASD were compared with control groups composed of typically developing toddlers as well as toddlers with global developmental or language delay. Main Outcomes and Measures: Logistic regression and receiver operating characteristic curve analysis were used in a classification test to establish the accuracy, specificity, and sensitivity of the module-based classifier. Results: Our signature of differentially coexpressed genes was enriched in translation and immune/inflammation functions and produced 83% accuracy. In an independent test with approximately half of the sample and a different microarray, the diagnostic classification of ASD vs control samples was 75% accurate. Consistent with its ASD specificity, our signature did not distinguish toddlers with global developmental or language delay from typically developing toddlers (62% accuracy). Conclusions and Relevance: This proof-of-principle study demonstrated that genomic biomarkers with very good sensitivity and specificity for boys with ASD in general pediatric settings can be identified. It also showed that a blood-based clinical test for at-risk male infants and toddlers could be refined and routinely implemented in pediatric diagnostic settings.
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20. Robertson RE. {{The Acquisition of Problem Behavior in Individuals With Developmental Disabilities as a Behavioral Cusp}}. {Behav Modif};2015 (Mar 1)
A behavioral cusp has been defined as a behavior change that produces contact with new contingencies with important and far-reaching consequences. The concept of behavioral cusps has most frequently been used to select target skills taught to learners and to evaluate the importance of those skills; however, the concept is equally applicable to behavior changes that bring about important and far-reaching negative consequences. Although it has been acknowledged that socially undesirable behavior change can also qualify as a behavioral cusp, this area of the cusp concept has been under-examined. In this article, an undesirable behavior change, the acquisition of problem behavior in individuals with developmental disabilities, is compared with criteria for behavioral cusps previously identified in the literature. The advantages of viewing problem behavior as a behavioral cusp are outlined, and implications for practice and research from a behavioral cusp approach to problem behavior are provided.
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21. Salazar F, Baird G, Chandler S, Tseng E, O’Sullivan T, Howlin P, Pickles A, Simonoff E. {{Co-occurring Psychiatric Disorders in Preschool and Elementary School-Aged Children with Autism Spectrum Disorder}}. {J Autism Dev Disord};2015 (Mar 4)
We employed a clinical sample of young children with ASD, with and without intellectual disability, to determine the rate and type of psychiatric disorders and possible association with risk factors. We assessed 101 children (57 males, 44 females) aged 4.5-9.8 years. 90.5 % of the sample met the criteria. Most common diagnoses were: generalized anxiety disorder (66.5 %), specific phobias (52.7 %) and attention deficit hyperactivity disorder (59.1 %). Boys were more likely to have oppositional defiant disorder (OR 3.9). Higher IQ was associated with anxiety disorders (OR 2.9) and older age with agoraphobia (OR 5.8). Night terrors was associated with parental psychological distress (OR 14.2). Most young ASD children met the criteria for additional psychopathology.
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22. Schreibman L, Dawson G, Stahmer AC, Landa R, Rogers SJ, McGee GG, Kasari C, Ingersoll B, Kaiser AP, Bruinsma Y, McNerney E, Wetherby A, Halladay A. {{Naturalistic Developmental Behavioral Interventions: Empirically Validated Treatments for Autism Spectrum Disorder}}. {J Autism Dev Disord};2015 (Mar 4)
Earlier autism diagnosis, the importance of early intervention, and development of specific interventions for young children have contributed to the emergence of similar, empirically supported, autism interventions that represent the merging of applied behavioral and developmental sciences. « Naturalistic Developmental Behavioral Interventions (NDBI) » are implemented in natural settings, involve shared control between child and therapist, utilize natural contingencies, and use a variety of behavioral strategies to teach developmentally appropriate and prerequisite skills. We describe the development of NDBIs, their theoretical bases, empirical support, requisite characteristics, common features, and suggest future research needs. We wish to bring parsimony to a field that includes interventions with different names but common features thus improving understanding and choice-making among families, service providers and referring agencies.
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23. Tang AH, Alger BE. {{Homer Protein-Metabotropic Glutamate Receptor Binding Regulates Endocannabinoid Signaling and Affects Hyperexcitability in a Mouse Model of Fragile X Syndrome}}. {J Neurosci};2015 (Mar 4);35(9):3938-3945.
The Fmr1 knock-out mouse model of fragile X syndrome (Fmr1-/y) has an epileptogenic phenotype that is triggered by group I metabotropic glutamate receptor (mGluR) activation. We found that a membrane-permeable peptide that disrupts mGluR5 interactions with long-form Homers enhanced mGluR-induced epileptiform burst firing in wild-type (WT) animals, replicating the early stages of hyperexcitability in Fmr1-/y. The peptide enhanced mGluR-evoked endocannabinoid (eCB)-mediated suppression of inhibitory synapses, decreased it at excitatory synapses in WTs, but had no effect on eCB actions in Fmr1-/y. At a low concentration, the mGluR agonist did not generate eCBs at excitatory synapses but nevertheless induced burst firing in both Fmr1-/y and peptide-treated WT slices. This burst firing was suppressed by a cannabinoid receptor antagonist. We suggest that integrity of Homer scaffolds is essential for normal mGluR-eCB functioning and that aberrant eCB signaling resulting from disturbances of this molecular structure contributes to the epileptic phenotype of Fmr1-/y.
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24. Zalla T. {{The experience of regret and the self-relevant emotions in autism spectrum disorders: A reply to Nicolle et al}}. {Cortex};2015 (Feb 11)
