1. Berry-Kravis E. {{Mechanism Based Treatments in Neurodevelopmental Disorders: Fragile X Syndrome}}. {Pediatr Neurol};2013 (Dec 4)
BACKGROUND: Fragile X syndrome (FXS) is the most common identifiable genetic cause of intellectual disability and autistic spectrum disorders. Recent major advances have been made in the understanding of the neurobiology and functions of fragile X mental retardation protein, the FMR1 gene product, which is absent or reduced in FXS, largely based on work in the fmr1 knockout mouse model. FXS has emerged as a disorder of synaptic plasticity associated with abnormalities of long-term depression and long-term potentiation and immature dendritic spine architecture, related to dysregulation of dendritic translation typically activated by group I mGluR and other receptors. This work has led to efforts to develop treatments for FXS with neuroactive molecules targeted to pathways dysregulated in the absence of fragile X mental retardation protein. CONCLUSION: These agents have been shown to rescue molecular, spine, and behavioral phenotypes in the FXS mouse model, and clinical trials are underway to translate findings in animal models of FXS to humans, raising complex issues about trial design and outcome measures to assess disease-modifying changes that might be associated with treatment. Genes known to be causes of autistic spectrum disorders interact with the translational pathway defective in FXS and it is likely that there will be substantial overlap in molecular pathways and mechanisms of synaptic dysfunction. Thus targeted treatment and clinical trial strategies in FXS may serve as a model for ASD and other cognitive disorders.
Lien vers le texte intégral (Open Access ou abonnement)
2. Bruining H, Eijkemans MJ, Kas MJ, Curran SR, Vorstman JA, Bolton PF. {{Behavioral signatures related to genetic disorders in autism}}. {Mol Autism};2014 (Feb 11);5(1):11.
BACKGROUND: Autism spectrum disorder (ASD) is well recognized to be genetically heterogeneous. It is assumed that the genetic risk factors give rise to a broad spectrum of indistinguishable behavioral presentations. METHODS: We tested this assumption by analyzing the Autism Diagnostic Interview-Revised (ADI-R) symptom profiles in samples comprising six genetic disorders that carry an increased risk for ASD (22q11.2 deletion, Down’s syndrome, Prader-Willi, supernumerary marker chromosome 15, tuberous sclerosis complex and Klinefelter syndrome; total n = 322 cases, groups ranging in sample sizes from 21 to 90 cases). We mined the data to test the existence and specificity of ADI-R profiles using a multiclass extension of support vector machine (SVM) learning. We subsequently applied the SVM genetic disorder algorithm on idiopathic ASD profiles from the Autism Genetics Resource Exchange (AGRE). RESULTS: Genetic disorders were associated with behavioral specificity, indicated by the accuracy and certainty of SVM predictions; one-by-one genetic disorder stratifications were highly accurate leading to 63% accuracy of correct genotype prediction when all six genetic disorder groups were analyzed simultaneously. Application of the SVM algorithm to AGRE cases indicated that the algorithm could detect similarity of genetic behavioral signatures in idiopathic ASD subjects. Also, affected sib pairs in the AGRE were behaviorally more similar when they had been allocated to the same genetic disorder group. CONCLUSIONS: Our findings provide evidence for genotype-phenotype correlations in relation to autistic symptomatology. SVM algorithms may be used to stratify idiopathic cases of ASD according to behavioral signature patterns associated with genetic disorders. Together, the results suggest a new approach for disentangling the heterogeneity of ASD.
Lien vers le texte intégral (Open Access ou abonnement)
3. Cannell JJ. {{Paracetamol, oxidative stress, vitamin D and autism spectrum disorders}}. {Int J Epidemiol};2014 (Feb 11)
Lien vers le texte intégral (Open Access ou abonnement)
4. Choi J, Ababon MR, Soliman M, Lin Y, Brzustowicz LM, Matteson PG, Millonig JH. {{Autism Associated Gene, ENGRAILED2, and Flanking Gene Levels Are Altered in Post-Mortem Cerebellum}}. {PLoS One};2014;9(2):e87208.
BACKGROUND: Previous genetic studies demonstrated association between the transcription factor ENGRAILED2 (EN2) and Autism Spectrum Disorder (ASD). Subsequent molecular analysis determined that the EN2 ASD-associated haplotype (rs1861972-rs1861973 A-C) functions as a transcriptional activator to increase gene expression. EN2 is flanked by 5 genes, SEROTONIN RECEPTOR5A (HTR5A), INSULIN INDUCED GENE1 (INSIG1), CANOPY1 HOMOLOG (CNPY1), RNA BINDING MOTIF PROTEIN33 (RBM33), and SONIC HEDGEHOG (SHH). These flanking genes are co-expressed with EN2 during development and coordinate similar developmental processes. To investigate if mRNA levels for these genes are altered in individuals with autism, post-mortem analysis was performed. METHODS: qRT-PCR quantified mRNA levels for EN2 and the 5 flanking genes in 78 post-mortem cerebellar samples. mRNA levels were correlated with both affection status and rs1861972-rs1861973 genotype. Molecular analysis investigated whether EN2 regulates flanking gene expression. RESULTS: EN2 levels are increased in affected A-C/G-T individuals (p = .0077). Affected individuals also display a significant increase in SHH and a decrease in INSIG1 levels. Rs1861972-rs1861973 genotype is correlated with significant increases for SHH (A-C/G-T) and CNPY1 (G-T/G-T) levels. Human cell line over-expression and knock-down as well as mouse knock-out analysis are consistent with EN2 and SHH being co-regulated, which provides a possible mechanism for increased SHH post-mortem levels. CONCLUSIONS: EN2 levels are increased in affected individuals with an A-C/G-T genotype, supporting EN2 as an ASD susceptibility gene. SHH, CNPY1, and INSIG1 levels are also significantly altered depending upon affection status or rs1861972-rs1861973 genotype. Increased EN2 levels likely contribute to elevated SHH expression observed in the post-mortem samples.
Lien vers le texte intégral (Open Access ou abonnement)
5. Harper-Hill K, Copland D, Arnott W. {{Efficiency of Lexical Access in Children with Autism Spectrum Disorders: Does Modality Matter?}}. {J Autism Dev Disord};2014 (Feb 12)
The provision of visual support to individuals with an autism spectrum disorder (ASD) is widely recommended. We explored one mechanism underlying the use of visual supports: efficiency of language processing. Two groups of children, one with and one without an ASD, participated. The groups had comparable oral and written language skills and nonverbal cognitive abilities. In two semantic priming experiments, prime modality and prime-target relatedness were manipulated. Response time and accuracy of lexical decisions on the spoken word targets were measured. In the first uni-modal experiment, both groups demonstrated significant priming effects. In the second experiment which was cross-modal, no effect for relatedness or group was found. This result is considered in the light of the attentional capacity required for access to the lexicon via written stimuli within the developing semantic system. These preliminary findings are also considered with respect to the use of visual support for children with ASD.
Lien vers le texte intégral (Open Access ou abonnement)
6. Jameel L, Vyas K, Bellesi G, Roberts V, Channon S. {{Going ‘Above and Beyond’: Are Those High in Autistic Traits Less Pro-social?}}. {J Autism Dev Disord};2014 (Feb 13)
Few studies have explored how the cognitive differences associated with autistic spectrum disorder translate into everyday social behaviour. This study investigated pro-social behaviour in students scoring high and low on the autism-spectrum quotient (AQ), using a novel scenario task: ‘Above and Beyond’. Each scenario involved an opportunity to behave pro-socially, and thus required balancing the needs of a character against participants’ own interests. High AQ participants both generated responses and selected courses of action that were less pro-social than those of the low AQ group. For actions of low pro-social value they gave higher self-satisfaction ratings; conversely, they gave lower self-satisfaction ratings for high pro-social actions. The implications for everyday functioning are considered for those with high autistic traits.
Lien vers le texte intégral (Open Access ou abonnement)
7. Kas MJ, Modi ME, Saxe MD, Smith DG. {{Advancing the discovery of medications for autism spectrum disorder using new technologies to reveal social brain circuitry in rodents}}. {Psychopharmacology (Berl)};2014 (Feb 13)
INTRODUCTION: Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by core differences and impairments in social behavioral functioning. There are no approved medications for improving social cognition and behavior in ASD, and the underlying mechanisms needed to discover safer, more effective medications are unclear. DISCUSSION: In this review, we diagram the basic neurocircuitry governing social behaviors in order to provide a neurobiological framework for the origins of the core social behavioral symptoms of ASD. In addition, we discuss recent technological innovations in research tools that provide unprecedented observation of cellular morphology and activity deep within the intact brain and permit the precise control of discrete brain regions and specific cell types at distinct developmental stages. CONCLUSIONS: The use of new technologies to reveal the neural circuits underlying social behavioral impairments associated with ASD is advancing our understanding of the brain changes underlying ASD and enabling the discovery of novel and effective therapeutic interventions.
Lien vers le texte intégral (Open Access ou abonnement)
8. Kirby AV, Dickie VA, Baranek GT. {{Sensory experiences of children with autism spectrum disorder: In their own words}}. {Autism};2014 (Feb 11)
First-person perspectives of children with autism spectrum disorder are rarely included in research, yet their voices may help more clearly illuminate their needs. This study involved phenomenological interviews with children with autism spectrum disorder (n = 12, ages 4-13) used to gain insights about their sensory experiences. This article addresses two study aims: determining the feasibility of interviewing children with autism spectrum disorder and exploring how they share information about their sensory experiences during the qualitative interview process. With the described methods, children as young as 4 years old and across a broad range of autism severity scores successfully participated in the interviews. The manner with which children shared information about their sensory experiences included themes of normalizing, storytelling, and describing responses. The interviews also revealed the importance of context and the multisensory nature of children’s experiences. These findings contribute strategies for understanding the sensory experiences of children with autism spectrum disorder with implications for practice and future research.
Lien vers le texte intégral (Open Access ou abonnement)
9. Lyall K, Schmidt RJ, Hertz-Picciotto I. {{Maternal lifestyle and environmental risk factors for autism spectrum disorders}}. {Int J Epidemiol};2014 (Feb 11)
BACKGROUND:: Over the past 10 years, research into environmental risk factors for autism has grown dramatically, bringing evidence that an array of non-genetic factors acting during the prenatal period may influence neurodevelopment. METHODS:: This paper reviews the evidence on modifiable preconception and/or prenatal factors that have been associated, in some studies, with autism spectrum disorder (ASD), including nutrition, substance use and exposure to environmental agents. This review is restricted to human studies with at least 50 cases of ASD, having a valid comparison group, conducted within the past decade and focusing on maternal lifestyle or environmental chemicals. RESULTS:: Higher maternal intake of certain nutrients and supplements has been associated with reduction in ASD risk, with the strongest evidence for periconceptional folic acid supplements. Although many investigations have suggested no impact of maternal smoking and alcohol use on ASD, more rigorous exposure assessment is needed. A number of studies have demonstrated significant increases in ASD risk with estimated exposure to air pollution during the prenatal period, particularly for heavy metals and particulate matter. Little research has assessed other persistent and non-persistent organic pollutants in association with ASD specifically. CONCLUSIONS:: More work is needed to examine fats, vitamins and other maternal nutrients, as well as endocrine-disrupting chemicals and pesticides, in association with ASD, given sound biological plausibility and evidence regarding other neurodevelopmental deficits. The field can be advanced by large-scale epidemiological studies, attention to critical aetiological windows and how these vary by exposure, and use of biomarkers and other means to understand underlying mechanisms.
Lien vers le texte intégral (Open Access ou abonnement)
10. Mortimer R, Privopoulos M, Kumar S. {{The effectiveness of hydrotherapy in the treatment of social and behavioral aspects of children with autism spectrum disorders: a systematic review}}. {J Multidiscip Healthc};2014;7:93-104.
BACKGROUND: Autism spectrum disorders (ASDs) are increasing in prevalence. Children with ASDs present with impairments in social interactions; communication; restricted, repetitive, and stereotyped patterns of behavior, interests, or activities; as well as motor delays. Hydrotherapy is used as a treatment for children with disabilities and motor delays. There have been no systematic reviews conducted on the effectiveness of hydrotherapy in children with ASDs. AIM: We aimed to examine the effectiveness of hydrotherapy on social interactions and behaviors in the treatment of children with ASDs. METHODS: A systematic search of Cochrane, CINAHL, PsycINFO, Embase, MEDLINE(R), and Academic Search Premier was conducted. Studies of participants, aged 3-18 years, with ASDs at a high-functioning level were included if they utilized outcome measures assessing social interactions and behaviors through questionnaire or observation. A critical appraisal, using the McMaster Critical Review Form for Quantitative Studies, was performed to assess methodological quality. RESULTS: Four studies of varying research design and quality met the inclusion criteria. The participants in these studies were aged between 3-12 years of age. The duration of the intervention ranged from 10-14 weeks, and each study used varied measures of outcome. Overall, all the studies showed some improvements in social interactions or behaviors following a Halliwick-based hydrotherapy intervention. INTERPRETATION: Few studies have investigated the effect of hydrotherapy on the social interactions and behaviors of children with ASDs. While there is an increasing body of evidence for hydrotherapy for children with ASDs, this is constrained by small sample size, lack of comparator, crude sampling methods, and the lack of standardized outcome measures. Hydrotherapy shows potential as a treatment method for social interactions and behaviors in children with ASDs.
Lien vers le texte intégral (Open Access ou abonnement)
11. Rossignol DA, Genuis SJ, Frye RE. {{Environmental toxicants and autism spectrum disorders: a systematic review}}. {Transl Psychiatry};2014;4:e360.
Although the involvement of genetic abnormalities in autism spectrum disorders (ASD) is well-accepted, recent studies point to an equal contribution by environmental factors, particularly environmental toxicants. However, these toxicant-related studies in ASD have not been systematically reviewed to date. Therefore, we compiled publications investigating potential associations between environmental toxicants and ASD and arranged these publications into the following three categories: (a) studies examining estimated toxicant exposures in the environment during the preconceptional, gestational and early childhood periods; (b) studies investigating biomarkers of toxicants; and (c) studies examining potential genetic susceptibilities to toxicants. A literature search of nine electronic scientific databases through November 2013 was performed. In the first category examining ASD risk and estimated toxicant exposures in the environment, the majority of studies (34/37; 92%) reported an association. Most of these studies were retrospective case-control, ecological or prospective cohort studies, although a few had weaker study designs (for example, case reports or series). Toxicants implicated in ASD included pesticides, phthalates, polychlorinated biphenyls (PCBs), solvents, toxic waste sites, air pollutants and heavy metals, with the strongest evidence found for air pollutants and pesticides. Gestational exposure to methylmercury (through fish exposure, one study) and childhood exposure to pollutants in water supplies (two studies) were not found to be associated with ASD risk. In the second category of studies investigating biomarkers of toxicants and ASD, a large number was dedicated to examining heavy metals. Such studies demonstrated mixed findings, with only 19 of 40 (47%) case-control studies reporting higher concentrations of heavy metals in blood, urine, hair, brain or teeth of children with ASD compared with controls. Other biomarker studies reported that solvent, phthalate and pesticide levels were associated with ASD, whereas PCB studies were mixed. Seven studies reported a relationship between autism severity and heavy metal biomarkers, suggesting evidence of a dose-effect relationship. Overall, the evidence linking biomarkers of toxicants with ASD (the second category) was weaker compared with the evidence associating estimated exposures to toxicants in the environment and ASD risk (the first category) because many of the biomarker studies contained small sample sizes and the relationships between biomarkers and ASD were inconsistent across studies. Regarding the third category of studies investigating potential genetic susceptibilities to toxicants, 10 unique studies examined polymorphisms in genes associated with increased susceptibilities to toxicants, with 8 studies reporting that such polymorphisms were more common in ASD individuals (or their mothers, 1 study) compared with controls (one study examined multiple polymorphisms). Genes implicated in these studies included paraoxonase (PON1, three of five studies), glutathione S-transferase (GSTM1 and GSTP1, three of four studies), delta-aminolevulinic acid dehydratase (one study), SLC11A3 (one study) and the metal regulatory transcription factor 1 (one of two studies). Notably, many of the reviewed studies had significant limitations, including lack of replication, limited sample sizes, retrospective design, recall and publication biases, inadequate matching of cases and controls, and the use of nonstandard tools to diagnose ASD. The findings of this review suggest that the etiology of ASD may involve, at least in a subset of children, complex interactions between genetic factors and certain environmental toxicants that may act synergistically or in parallel during critical periods of neurodevelopment, in a manner that increases the likelihood of developing ASD. Because of the limitations of many of the reviewed studies, additional high-quality epidemiological studies concerning environmental toxicants and ASD are warranted to confirm and clarify many of these findings.
Lien vers le texte intégral (Open Access ou abonnement)
12. Sun X, Allison C, Auyeung B, Matthews FE, Norton S, Baron-Cohen S, Brayne C. {{Psychometric Properties of the Mandarin Version of the Childhood Autism Spectrum Test (CAST): An Exploratory Study}}. {J Autism Dev Disord};2014 (Feb 13)
Limited studies have investigated the latent autistic traits in the mainland Chinese population for autism spectrum conditions (ASC). This study explored the psychometric properties of a Mandarin Chinese version of the CAST in a sample consisting of 737 children in mainstream schools and 50 autistic cases. A combination of categorical data factor analysis and item response theory suggested a good-fit model of a two-factor solution for 28 items on the Mandarin CAST including social and communication, and inflexible/stereotyped language and behaviours (Goodness-of-fit indices: RMSEA = 0.029, CFI = 0.957, TLI = 0.950, SRMR = 0.064). The correlation between the two factors was moderate (GFC = 0.425). This study provided evidence for the CAST as a multidimensional measure for ASC screening in a Chinese population and also showed that the symptom manifestation of ASC in Chinese children shares similarity with western populations.
