1. Coo H, Ouellette-Kuntz H, Lam YM, Brownell M, Flavin MP, Roos LL. {{The association between the interpregnancy interval and autism spectrum disorder in a Canadian cohort}}. {Canadian journal of public health = Revue canadienne de sante publique}. 2015;106(2):e36-42.
OBJECTIVES: Two studies reported an increased risk of autistic disorder in children conceived less than 12 months after a previous birth. Our objective was to examine the association between the interpregnancy interval (IPI) and autism spectrum disorder (ASD) in a Canadian cohort. METHODS: Using administrative datasets housed at the Manitoba Centre for Health Policy, we identified pairs of first- and second-born singleton siblings born between 1988 and 2005. Diagnoses of ASD were ascertained by searching physician billing claims, hospital discharge abstracts, education data, and a database containing information on individuals identified for a 2002-2007 ASD surveillance program in Manitoba. Logistic regression models were fit to examine the association between the IPI and ASD in 41,050 second-born siblings where the first-borns did not have ASD, using IPIs of >/=36 months as the reference category and specifying three case groups. Case Group 1 included individuals with at least one ASD code (n = 490); Case Group 2 included those with two or more ASD codes (n = 375); and Case Group 3 comprised individuals with a record in the ASD surveillance program database (n = 141). RESULTS: The adjusted odds ratios (ORs) for IPIs shorter than 12 months ranged from 1.22 (95% CI: 0.91-1.63) for Case Group 1 to 1.72 (95% CI: 0.96-3.06) for Case Group 3. When the case groups were restricted to individuals with more severe ASD, the ORs increased and were significant for Case Groups 1 and 2. CONCLUSION: Our findings also support an association between short IPIs and more severe ASD.
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2. Engchuan W, Dhindsa K, Lionel AC, Scherer SW, Chan JH, Merico D. {{Performance of case-control rare copy number variation annotation in classification of autism}}. {BMC medical genomics}. 2015 Jan 15;8 Suppl 1:S7.
BACKGROUND: A substantial proportion of Autism Spectrum Disorder (ASD) risk resides in de novo germline and rare inherited genetic variation. In particular, rare copy number variation (CNV) contributes to ASD risk in up to 10% of ASD subjects. Despite the striking degree of genetic heterogeneity, case-control studies have detected specific burden of rare disruptive CNV for neuronal and neurodevelopmental pathways. Here, we used machine learning methods to classify ASD subjects and controls, based on rare CNV data and comprehensive gene annotations. We investigated performance of different methods and estimated the percentage of ASD subjects that could be reliably classified based on presumed etiologic CNV they carry. RESULTS: We analyzed 1,892 Caucasian ASD subjects and 2,342 matched controls. Rare CNVs (frequency 1% or less) were detected using Illumina 1M and 1M-Duo BeadChips. Conditional Inference Forest (CF) typically performed as well as or better than other classification methods. We found a maximum AUC (area under the ROC curve) of 0.533 when considering all ASD subjects with rare genic CNVs, corresponding to 7.9% correctly classified ASD subjects and less than 3% incorrectly classified controls; performance was significantly higher when considering only subjects harboring de novo or pathogenic CNVs. We also found rare losses to be more predictive than gains and that curated neurally-relevant annotations (brain expression, synaptic components and neurodevelopmental phenotypes) outperform Gene Ontology and pathway-based annotations. CONCLUSIONS: CF is an optimal classification approach for case-control rare CNV data and it can be used to prioritize subjects with variants potentially contributing to ASD risk not yet recognized. The neurally-relevant annotations used in this study could be successfully applied to rare CNV case-control data-sets for other neuropsychiatric disorders.
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3. Gozes I. {{The cytoskeleton as a drug target for neuroprotection: the case of the autism-mutated ADNP}}. {Biological chemistry}. 2015 May 8.
15 years ago we discovered activity-dependent neuroprotective protein (ADNP), and showed that it is essential for brain formation/ function. Our protein interaction studies identified ADNP as a member of the chromatin remodelling complex, SWI/SNF also associated with alternative splicing of tau and prediction of tauopathy. Recently, we have identified cytoplasmic ADNP interactions with the autophagy regulating microtubule-associated protein 1 light chain 3 (LC3) and with microtubule end binding (EB) proteins. The ADNPEB- binding SIP domain is shared with the ADNP snippet drug candidate, NAPVSIPQ termed NAP (davunetide). Thus, we identified a precise target for ADNP/NAP (davunetide) neuroprotection toward improved drug development.
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4. Kaushik G, Thomas MA, Aho KA. {{Psychoactive pharmaceuticals as environmental contaminants may disrupt highly inter-connected nodes in an Autism-associated protein-protein interaction network}}. {BMC bioinformatics}. 2015 Apr 23;16 Suppl 7:S3.
BACKGROUND: Most cases of idiopathic autism spectrum disorder (ASD) likely result from unknown environmental triggers in genetically susceptible individuals. These triggers may include maternal exposure of a fetus to minute concentrations of pharmaceuticals, such as carbamazepine (CBZ), venlafaxine (VNX) and fluoxetine (FLX). Unmetabolized pharmaceuticals reach drinking water through a variety of routes, including ineffectively treated sewage. Previous studies in our laboratory examined the extent to which gene sets were enriched in minnow brains treated with pharmaceuticals. Here, we tested the hypothesis that genes in fish brains and human cell cultures, significantly enriched by pharmaceuticals, would have distinct characteristics in an ASD-associated protein interaction network. We accomplished this by comparing these groups using 10 network indices. RESULTS: A network of 7212 proteins and 33,461 interactions was generated. We found that network characteristics for enriched gene sets for particular pharmaceuticals were distinct from each other, and were different from non-enriched ASD gene sets. In particular, genes in fish brains, enriched by CBZ and VNX 1) had higher network importance than that in the overall network, and those enriched by FLX, and 2) were distinct from FLX and non-enriched ASD genes in multivariate network space. Similarly, genes in human cell cultures enriched by pharmaceutical mixtures (at environmental concentrations) and valproate (at clinical dosages) had similar network signatures, and had greater network importance than genes in the overall ASD network. CONCLUSIONS: The results indicate that important gene sets in the ASD network are particularly susceptible to perturbation by pharmaceuticals at environmental concentrations.
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5. Mohammadzaheri F, Koegel LK, Rezaei M, Bakhshi E. {{A Randomized Clinical Trial Comparison Between Pivotal Response Treatment (PRT) and Adult-Driven Applied Behavior Analysis (ABA) Intervention on Disruptive Behaviors in Public School Children with Autism}}. {J Autism Dev Disord}. 2015 May 8.
Children with autism often demonstrate disruptive behaviors during demanding teaching tasks. Language intervention can be particularly difficult as it involves social and communicative areas, which are challenging for this population. The purpose of this study was to compare two intervention conditions, a naturalistic approach, Pivotal Response Treatment (PRT) with an adult-directed ABA approach on disruptive behavior during language intervention in the public schools. A randomized clinical trial design was used with two groups of children, matched according to age, sex and mean length of utterance. The data showed that the children demonstrated significantly lower levels of disruptive behavior during the PRT condition. The results are discussed with respect to antecedent manipulations that may be helpful in reducing disruptive behavior.
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6. Oh SY, He F, Krans A, Frazer M, Taylor JP, Paulson HL, Todd PK. {{RAN translation at CGG repeats induces ubiquitin proteasome system impairment in models of fragile X-associated tremor ataxia syndrome}}. {Human molecular genetics}. 2015 May 7.
Fragile X-associated Tremor Ataxia Syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG trinucleotide repeat expansion in the 5’UTR of the Fragile X gene, FMR1. FXTAS is thought to arise primarily from an RNA gain-of-function toxicity mechanism. However, recent studies demonstrate that the repeat also elicits production of a toxic polyglycine protein, FMRpolyG, via Repeat-Associated Non-AUG (RAN) initiated translation. Pathologically, FXTAS is characterized by ubiquitin positive intranuclear neuronal inclusions, raising the possibility that failure of protein quality control pathways could contribute to disease pathogenesis. To test this hypothesis, we used Drosophila and cell based models of CGG-repeat associated toxicity. In Drosophila, ubiquitin proteasome system (UPS) impairment led to enhancement of CGG-repeat induced degeneration whereas overexpression of the chaperone protein HSP70 suppressed this toxicity. In transfected mammalian cells, CGG-repeat expression triggered accumulation of a GFP-UPS reporter in a length-dependent fashion. To delineate the contributions from CGG repeats as RNA from RAN translation associated toxicity, we enhanced or impaired the production of FMRpolyG in these models. Driving expression of FMRpolyG enhanced induction of UPS impairment in cell models while prevention of RAN translation attenuated UPS impairment in cells and suppressed the genetic interaction with UPS manipulation in Drosophila. Taken together, these findings suggest that CGG repeats induce ubiquitin proteasome system impairment at least in part through activation of RAN translation.
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7. Potrzeba ER, Fein D, Naigles L. {{Investigating the shape bias in typically developing children and children with autism spectrum disorders}}. {Frontiers in psychology}. 2015;6:446.
Young typically developing (TD) children have been observed to utilize word learning strategies such as the noun bias and shape bias; these improve their efficiency in acquiring and categorizing novel terms. Children using the shape bias extend object labels to new objects of the same shape; thus, the shape bias prompts the categorization of object words based on the global characteristic of shape over local, discrete details. Individuals with autism spectrum disorders (ASDs) frequently attend to minor details of objects rather than their global structure. Therefore, children with ASD may not use shape bias to acquire new words. Previous research with children with ASD has provided evidence that they parallel TD children in showing a noun bias, but not a shape bias (Tek et al., 2008). However, this sample was small and individual and item differences were not investigated in depth. In an extension of Tek et al. (2008) with twice the sample size and a wider developmental timespan, we tested 32 children with ASD and 35 TD children in a longitudinal study across 20 months using the intermodal preferential looking paradigm. Children saw five triads of novel objects (target, shape-match, color-match) in both NoName and Name trials; those who looked longer at the shape-match during the Name trials than the NoName trials demonstrated a shape bias. The TD group showed a significant shape bias at all visits, beginning at 20 months of age while the language-matched ASD group did not show a significant shape bias at any visit. Within the ASD group, though, some children did show a shape bias; these children had larger vocabularies concurrently and longitudinally. Degree of shape bias elicitation varied by item, but did not seem related to perceptual complexity. We conclude that shape does not appear to be an organizing factor for word learning by children with ASD.
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8. Ring M, Gaigg SB, Bowler DM. {{Relational Memory Processes in Adults with Autism Spectrum Disorder}}. {Autism research : official journal of the International Society for Autism Research}. 2015 May 7.
Research into memory in Autism Spectrum Disorder (ASD) suggests intact item memory but difficulties in forming relations between items (Bowler, Gaigg, & Lind, 2011). In this study, we tested memory for items as well as for sequential, spatial, and associative relations between items with the same paradigm using abstract shapes in ASD and typically developing (TD) individuals. Participants studied shape triplets on a computer screen and memory was subsequently tested either for the individual items making up the triplets, the screen-locations, the order or the combinations of items presented at study. Contrary to our predictions, performance was significantly lower in the ASD group on all four tasks. The result raises questions about how intact item memory is in ASD, which role task complexity plays, and how item-specific versus relational processing affect task performance. One possibility is that TD individuals relied more on relational processing in the current study and might have therefore had an advantage over ASD individuals. This idea is supported by the result of a preliminary analysis of age-related differences in memory across the midadult lifespan in both groups. Age seems to affect order memory less in ASD compared with TD individuals where it leads to a significant decrease in performance. This might indicate a decrease in relational processing in TD but not ASD individuals with increasing age. More research is needed to answer questions about the change in cognition in ASD individuals across the lifespan. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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9. Salmasi A, Harrison R, Brondani MA. {{They stole her teeth! An exploration of adults with developmental disability experiences with dental care}}. {Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry}. 2015 May 7.
PURPOSE: The aim of this paper was to explore the experiences of adults with developmental disabilities (AWDD) in accessing and utilizing dental services in Vancouver, BC. METHODS: Participants were either self-advocates or parents/caregivers who discussed their experiences in five focus group discussions with 20 participants in total (age range 17-60 years, 2 males). Each focus group lasted on average 40 minutes. Transcripts were coded for thematic analysis; the codes were organized into themes and finally into domains. RESULTS: Seven domains relating to the participants’ experiences with dental care were identified, and included communication, trust, and respect as provided-based domains to the quality of the dental experience for AWDD and their parents, while financial issues, transitional services, and waiting times were system-based barriers to access to dental care for theses AWDD. Finally, what makes for a positive dental experience was shared in terms of acknowledging parent’s role as advocates and making simple accommodations to see AWDD by the dental office. CONCLUSIONS: Access to a care provider did not necessarily equate to satisfaction with quality of experience. Efforts have to focus on establishing communication and trust with AWDD patients as key to a positive dental experience. We encourage a global discussion on the need to better incorporate dental care for special needs individuals within dental school curricula.
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10. Sun X, Allison C, Matthews FE, Zhang Z, Auyeung B, Baron-Cohen S, Brayne C. {{Exploring the Underdiagnosis and Prevalence of Autism Spectrum Conditions in Beijing}}. {Autism research : official journal of the International Society for Autism Research}. 2015 May 6.
Previous studies reported that the prevalence of Autism Spectrum Conditions (ASC) in mainland China is much lower than estimates from developed countries (around 1%). The aim of the study is to apply current screening and standardized diagnostic instruments to a Chinese population to establish a prevalence estimate of ASC in an undiagnosed population in mainland China. We followed the design development used previously in the UK published in 2009 by Baron-Cohen and colleagues. The Mandarin Childhood Autism Spectrum Test (CAST) was validated by screening primary school pupils (n = 737 children age 6-10 years old) in Beijing and by conducting diagnostic assessments using the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised. The prevalence estimate was generated after adjusting and imputing for missing values using the inverse probability weighting. Response was high (97%). Using the UK cutoff (>/=15), CAST performance has 84% sensitivity and 96% specificity (95% confidence interval [CI]: 46, 98, and 96, 97, respectively). Six out of 103 children, not previously diagnosed, were found to the meet diagnostic criteria (8.5 after adjustment, 95% CI: 1.6, 15.4). The preliminary prevalence in an undiagnosed primary school population in mainland China was 119 per 10,000 (95% CI: 53, 265). The utility of CAST is acceptable as a screening instrument for ASC in large epidemiological studies in China. Using a comparable method, the preliminary prevalence estimate of ASC in mainland China is similar to that of those from developed countries. Autism Res 2015, : -. (c) 2015 The Authors. Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.
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11. Tsuji S, Yuhi T, Furuhara K, Ohta S, Shimizu Y, Higashida H. {{Salivary oxytocin concentrations in seven boys with autism spectrum disorder received massage from their mothers: a pilot study}}. {Frontiers in psychiatry}. 2015;6:58.
Seven male children with autism spectrum disorder (ASD), aged 8-12 years, attending special education classrooms for ASD and disabled children, were assigned to receive touch therapy. Their mothers were instructed to provide gentle touch in the massage style of the International Liddle Kidz Association. The mothers gave massages to their child for 20 min every day over a period of 3 months, followed by no massage for 4 months. To assess the biological effects of such touch therapy, saliva was collected before and 20 min after a single session of massage for 20 min from the children and mothers every 3 weeks during the massage period and every 4 weeks during the non-massage period, when they visited a community meeting room. Salivary oxytocin levels were measured using an enzyme immunoassay kit. During the period of massage therapy, the children and mothers exhibited higher oxytocin concentrations compared to those during the non-massage period. The changes in oxytocin levels before and after a single massage session were not significantly changed in children and mothers. The results suggested that the ASD children (massage receivers) and their mothers (massage givers) show touch therapy-dependent changes in salivary oxytocin concentrations.
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12. Verdyck P, Berckmoes V, De Vos A, Verpoest W, Liebaers I, Bonduelle M, De Rycke M. {{Chromosome fragility at FRAXA in human cleavage stage embryos at risk for fragile X syndrome}}. {American journal of medical genetics Part A}. 2015 May 7.
Fragile X syndrome (FXS), the most common inherited intellectual disability syndrome, is caused by expansion and hypermethylation of the CGG repeat in the 5′ UTR of the FMR1 gene. This expanded repeat, also known as the rare fragile site FRAXA, causes X chromosome fragility in cultured cells from patients but only when induced by perturbing pyrimidine synthesis. We performed preimplantation genetic diagnosis (PGD) on 595 blastomeres biopsied from 442 cleavage stage embryos at risk for FXS using short tandem repeat (STR) markers. In six blastomeres, from five embryos an incomplete haplotype was observed with loss of all alleles telomeric to the CGG repeat. In all five embryos, the incomplete haplotype corresponded to the haplotype carrying the CGG repeat expansion. Subsequent analysis of additional blastomeres from three embryos by array comparative genomic hybridization (aCGH) confirmed the presence of a terminal deletion with a breakpoint close to the CGG repeat in two blastomeres from one embryo. A blastomere from another embryo showed the complementary duplication. We conclude that a CGG repeat expansion at FRAXA causes X chromosome fragility in early human IVF embryos at risk for FXS. (c) 2015 Wiley Periodicals, Inc.
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13. Yatziv T, Jacobson H. {{Understanding visual consciousness in autism spectrum disorders}}. {Front Hum Neurosci}. 2015;9:204.
The paper focuses on the question of what the (visual) perceptual differences are between individuals with autism spectrum disorders (ASD) and typically developing (TD) individuals. We argue against the view that autistic subjects have a deficiency in the most basic form of perceptual consciousness-namely, phenomenal consciousness. Instead, we maintain, the perceptual atypicality of individuals with autism is of a more conceptual and cognitive sort-their perceptual experiences share crucial aspects with TD individuals. Our starting point is Ben Shalom’s (2005, 2009) three-level processing framework for explaining atypicality in several domains of processing among autistics, which we compare with two other tripartite models of perception-Jackendoff’s (1987) and Prinz’s (2000, 2005a, 2007) Intermediate Level Hypothesis and Lamme’s (2004, 2006, 2010) neural account of consciousness. According to these models, whereas the second level of processing is concerned with viewer-centered visual representations of basic visual properties and incorporates some early forms of integration, the third level is more cognitive and conceptual. We argue that the data suggest that the atypicality in autism is restricted mainly to the third level. More specifically, second-level integration, which is the mark of phenomenal consciousness, is typical, yet third-level integration of perceptual objects and concepts is atypical. Thus, the basic experiences of individuals with autism are likely to be similar to typical subjects’ experiences; the main difference lies in the sort of cognitive access the subjects have to their experiences. We conclude by discussing implications of the suggested analysis of experience in autism for conceptions of phenomenal consciousness.
