1. Behnia F, Parets SE, Kechichian T, Yin H, Dutta EH, Saade GR, Smith AK, Menon R. {{Fetal DNA Methylation of Autism Spectrum Disorders (ASD) Candidate Genes: Association with Spontaneous Preterm Birth}}. {Am J Obstet Gynecol}. 2015.
OBJECTIVE: Autism Spectrum Disorder (ASD) is associated with preterm birth (PTB); though the reason underlying this relationship is still unclear. Our objective was to examine DNA methylation patterns of four ASD candidate genes in human fetal membranes from spontaneous PTB and uncomplicated term birth (TB). STUDY DESIGN: A literature search for genes implicated in ASD yielded 14 candidate genes (OXTR, SHANK3, BCL2, RORA, EN2, RELN, MECP2, AUTS2, NLGN3, NRXN1, SLC6A4, UBE3A, GABA, AFF2) that were epigenetically modified in relation to ASD. DNA methylation in fetal leukocyte DNA in four of these genes (OXTR, SHANK3, BCL2 and RORA) associated with PTB in a previous study. This study evaluated DNA methylation, transcription (qPCR) and translation patterns (immunostaining and western blot) in fetal membrane from term labor (TL; n=14), term not in labor (TNIL; n=29) and spontaneous preterm birth (PTB; n=27). Statistical analysis was performed using ANOVA and a p-value of < 0.05 was significant. RESULTS: Higher methylation of the OXTR promoter was seen in fetal membranes from PTB compared to TL or TNIL. No other gene showed any methylation differences between groups. Expression of OXTR was not different between groups but the 70 kDa OXTR protein was seen only in PTB, and immunostaining was more intense in PTB amniocytes than TL or TNIL. CONCLUSION: Among the four genes studied, fetal membranes from PTB demonstrate differences in OXTR methylation and regulation and expression, suggesting that epigenetic alteration of this gene in fetal membrane may likely be indicating an in utero programing of this gene and serve as a surrogate in a subset of PTB. The usefulness of OXTR hypermethylation as a surrogate for link to ASD should be further evaluated in longitudinal and in vitro studies.
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2. Berko ER, Greally JM. {{How might epigenetic dysregulation in early embryonic life contribute to autism spectrum disorder?}}. {Epigenomics}. 2015; 7(1): 1-4.
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3. Bukala M, Hu MY, Lee R, Ward-Horner JC, Fienup DM. {{The effects of work-reinforcer schedules on performance and preference in students with autism}}. {J Appl Behav Anal}. 2015.
This study investigated performance under and preference for continuous and discontinuous work-reinforcer schedules in 3 students who had been diagnosed with autism. Under continuous schedules, participants completed all work and consumed all reinforcers in contiguous units. Under discontinuous schedules, work and reinforcer access were broken up into smaller units. During the alternating-schedules phase, session duration was shorter in the continuous schedule for 2 participants. During free choice, all 3 participants preferred the continuous work schedule.
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4. Chang YC, Shih W, Kasari C. {{Friendships in preschool children with autism spectrum disorder: What holds them back, child characteristics or teacher behavior?}}. {Autism}. 2015.
Children begin to show preferences for specific playmates as early as the first 2 years of life. Children with autism spectrum disorder have difficulty making friends, even in elementary and middle school. However, very little is known about earlier friendships in children with autism such as preschool friendships. This study examined friendships in preschool children with autism and explored how joint attention contributes to these friendships in mainstream settings. A secondary aim was to determine the extent to which teachers used strategies to facilitate friendship development. The participants were 31 mainstreamed preschool children (ages 2-5 years) with autism spectrum disorder. School observations were conducted individually to capture participants’ interactions with peers and adults during free play. The results indicated that 20% of the participants had friendships at school. Children with friends were more likely than children without friends to be jointly engaged with their peers during free play, and they used higher joint attention skills. Teachers used few friendship facilitating strategies, and more often used behavioral management strategies within the classrooms. Future studies may want to examine the effects of early interventions and/or teacher training on the development of friendships in preschool children with autism spectrum disorder within the school setting.
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5. DeQuinzio JA, Taylor BA. {{Teaching children with autism to discriminate the reinforced and nonreinforced responses of others: Implications for observational learning}}. {J Appl Behav Anal}. 2015.
We taught 4 participants with autism to discriminate between the reinforced and nonreinforced responses of an adult model and evaluated the effectiveness of this intervention using a multiple baseline design. During baseline, participants were simply exposed to adult models’ correct and incorrect responses and the respective consequences of each. During discrimination training, in the presence of target pictures, we taught participants to imitate the reinforced responses of an adult model and to say « I don’t know » when an adult model’s response was not reinforced. Test sessions were conducted after baseline, discrimination training, and generalization sessions to measure responding to target pictures in the absence of the model, prompts, and reinforcement. All 4 participants showed acquisition in the discrimination of reinforced and nonreinforced responses of the adult model during test sessions. Generalization to stimuli not associated with training was variable across the 4 participants. Implications for teaching observational learning responses to children with autism are discussed.
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6. Eye PG, Hawley JS. {{Pearls & Oy-sters: Fragile X tremor/ataxia syndrome: A diagnostic dilemma}}. {Neurology}. 2015; 84(7): e43-5.
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7. Garbacz SA, McIntyre LL. {{Conjoint Behavioral Consultation for Children With Autism Spectrum Disorder}}. {Sch Psychol Q}. 2015.
The present study examined the efficacy of Conjoint Behavioral Consultation (CBC) for children with Autism Spectrum Disorder (ASD) in early elementary school. In addition, the parent-teacher relationship, parent and teacher competence in problem solving, and CBC acceptability were examined. Participants included 3 children with ASD in early elementary school, and their parents and teachers. Findings suggested (a) CBC was efficacious for treating children’s social behavior in classrooms, (b) 2 of 3 parent-teacher dyads reported improvements in the parent-teacher relationship, (c) all parents and teacher reported increases in their problem-solving competences, and (d) CBC was highly acceptable to parents and teachers. Implications for CBC research and interventions for children with ASD are discussed. (PsycINFO Database Record (c) 2015 APA, all rights reserved).
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8. Lim CM. {{Accommodating Autistics and Treating Autism: Can We Have Both?}}. {Bioethics}. 2015.
One of the central claims of the neurodiversity movement is that society should accommodate the needs of autistics, rather than try to treat autism. People have variously tried to reject this accommodation thesis as applicable to all autistics. One instance is Pier Jaarsma and Stellan Welin, who argue that the thesis should apply to some but not all autistics. They do so via separating autistics into high- and low-functioning, on the basis of IQ and social effectiveness or functionings. I reject their grounds for separating autistics. IQ is an irrelevant basis for separating autistics. Charitably rendering it as referring to more general capacities still leaves us mistaken about the roles they play in supporting the accommodation thesis. The appeal to social effectiveness or functionings relies on standards that are inapplicable to autistics, and which risks being deaf to the point of their claims. I then consider if their remaining argument concerning autistic culture may succeed independently of the line they draw. I argue that construing autistics’ claims as beginning from culture mistakes their status, and may even detract from their aims. Via my discussion of Jaarsma and Welin, I hope to point to why the more general strategy of separating autistics, in response to the accommodation thesis, does not fully succeed. Finally, I sketch some directions for future discussions, arguing that we should instead shift our attention to consider another set of questions concerning the costs and extent of change required to accommodate all autistics.
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9. MacMullin JA, Lunsky Y, Weiss JA. {{Plugged in: Electronics use in youth and young adults with autism spectrum disorder}}. {Autism}. 2015.
Although electronic technology currently plays an integral role for most youth, there are growing concerns of its excessive and compulsive use. This study documents patterns and impact of electronics use in individuals with autism spectrum disorder compared to typically developing peers. Participants included 172 parents of typically developing individuals and 139 parents of individuals with an autism spectrum disorder diagnosis, ranging in age from 6 to 21 years. Parents completed an online survey of demographics and the frequency, duration, and problematic patterns of electronics use in their youth and young adults. Individuals with autism spectrum disorder were reported to use certain electronics more often in the last month and on an average day, and had greater compulsive Internet and video game use than individuals without autism spectrum disorder. Across both samples, males used video games more often than females. Compared to parents of individuals without autism spectrum disorder, parents of individuals with autism spectrum disorder were significantly more likely to report that electronics use was currently having a negative impact. The implications of problematic electronics use for individuals with autism spectrum disorder are discussed.
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10. Newschaffer CJ. {{Regarding Mandell and Lecavalier’s editorial « Should we believe the Centers for Disease Control and Prevention’s autism spectrum disorders prevalence estimates » and subsequent exchange with Durkin et al}}. {Autism}. 2015.
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11. Ouellette-Kuntz H, Coo H, Cobigo V, Wilton AS. {{Uptake of Colorectal Cancer Screening among Ontarians with Intellectual and Developmental Disabilities}}. {PLoS One}. 2015; 10(2): e0118023.
Under-screening for cancer may contribute to a greater disease burden in individuals with intellectual and developmental disabilities (IDD) as their life expectancy increases. In 2008, the province of Ontario launched Canada’s first population-based colorectal cancer screening program. Our objectives were to compare the proportions of Ontarians with and without IDD who have undergone colorectal cancer screening and to examine factors associated with screening uptake among Ontarians with IDD. Records for Ontario residents 50-64 years of age were linked across various administrative health and social services datasets to identify individuals with IDD and to select a random sample of the age-equivalent Ontario population without IDD as a comparison group. Logistic regression models were fit to examine the odds of screening uptake among individuals with IDD while controlling for age, sex, urban or rural residence, neighbourhood income quintile, expected use of health care resources, and being enrolled with or seeing a physician in a patient enrolment model (any of several primary care practice models designed to improve patient access and quality of care in Ontario), and to examine the association between these variables and colorectal cancer screening in the IDD population. The odds of having had a fecal occult blood test in the previous two years and being up-to-date with colorectal tests were 32% and 46% lower, respectively, for Ontarians with IDD compared to those without IDD. Being older, female, having a greater expected use of health care resources, and being enrolled with or seeing a physician in a primary care patient enrolment model were all significantly associated with higher odds of having been screened for colorectal cancer in the IDD population. These findings underscore the need for targeted interventions aimed at making colorectal cancer screening more equitable.
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12. Parlade MV, Iverson JM. {{The Development of Coordinated Communication in Infants at Heightened Risk for Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2015.
This study evaluated the extent to which developmental change in coordination of social communication in early infancy differentiates children eventually diagnosed with ASD from those not likely to develop the disorder. A prospective longitudinal design was used to compare nine infants at heightened risk for ASD (HR) later diagnosed with ASD, to 13 HR infants with language delay, 28 HR infants with no diagnosis, and 30 low risk infants. Hierarchical linear modeling analyses revealed that ASD infants exhibited significantly slower growth in coordinations overall and in gestures coordinated with vocalizations, even relative to HR infants with language delay. Disruption in the development of gesture-vocalization coordinations may result in negative cascading effects that adversely impact later social and linguistic development.
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13. Pucilowska J, Vithayathil J, Tavares EJ, Kelly C, Karlo JC, Landreth GE. {{The 16p11.2 Deletion Mouse Model of Autism Exhibits Altered Cortical Progenitor Proliferation and Brain Cytoarchitecture Linked to the ERK MAPK Pathway}}. {J Neurosci}. 2015; 35(7): 3190-200.
Autism spectrum disorders are complex, highly heritable neurodevelopmental disorders affecting approximately 1 in 100 children. Copy number variations of human chromosomal region 16p11.2 are genetically linked to 1% of autism-related disorders. This interval contains the MAPK3 gene, which encodes the MAP kinase, ERK1. Mutations in upstream elements regulating the ERK pathway are genetically linked to autism and other disorders of cognition including the neuro-cardio-facial cutaneous syndromes and copy number variations. We report that a murine model of human 16p11.2 deletion exhibits a reduction in brain size and perturbations in cortical cytoarchitecture. We observed enhanced progenitor proliferation and premature cell cycle exit, which are a consequence of altered levels of downstream ERK effectors cyclin D1 and p27(Kip1) during mid-neurogenesis. The increased progenitor proliferation and cell cycle withdrawal resulted in premature depletion of progenitor pools, altering the number and frequency of neurons ultimately populating cortical lamina. Specifically, we found a reduced number of upper layer pyramidal neurons and an increase in layer VI corticothalamic projection neurons, reflecting the altered cortical progenitor proliferation dynamics in these mice. Importantly, we observed a paradoxical increase in ERK signaling in mid-neurogenesis in the 16p11.2del mice, which is coincident with the development of aberrant cortical cytoarchitecture. The 16p11.2del mice exhibit anxiety-like behaviors and impaired memory. Our findings provide evidence of ERK dysregulation, developmental abnormalities in neurogenesis, and behavioral impairment associated with the 16p11.2 chromosomal deletion.
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14. Ratni H, Rogers-Evans M, Bissantz C, Grundschober C, Moreau JL, Schuler F, Fischer H, Alvarez Sanchez R, Schnider P. {{Discovery of Highly Selective Brain-Penetrant Vasopressin 1a Antagonists for the Potential Treatment of Autism via a Chemogenomic and Scaffold Hopping Approach}}. {J Med Chem}. 2015.
From a micromolar high throughput screening hit 7, the successful complementary application of a chemogenomic approach and of a scaffold hopping exercise rapidly led to a low single digit nanomolar human vasopressin 1a (hV1a) receptor antagonist 38. Initial optimization of the mouse V1a activities delivered suitable tool compounds which demonstrated a V1a mediated central in vivo effect. This novel series was further optimized through parallel synthesis with a focus on balancing lipophilicity to achieve robust aqueous solubility while avoiding P-gp mediated efflux. These efforts led to the discovery of the highly potent and selective brain-penetrant hV1a antagonist RO5028442 (8) suitable for human clinical studies in people with autism.
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15. Rose S, Wynne R, Frye RE, Melnyk S, James SJ. {{Increased susceptibility to ethylmercury-induced mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines}}. {J Toxicol}. 2015; 2015: 573701.
The association of autism spectrum disorders with oxidative stress, redox imbalance, and mitochondrial dysfunction has become increasingly recognized. In this study, extracellular flux analysis was used to compare mitochondrial respiration in lymphoblastoid cell lines (LCLs) from individuals with autism and unaffected controls exposed to ethylmercury, an environmental toxin known to deplete glutathione and induce oxidative stress and mitochondrial dysfunction. We also tested whether pretreating the autism LCLs with N-acetyl cysteine (NAC) to increase glutathione concentrations conferred protection from ethylmercury. Examination of 16 autism/control LCL pairs revealed that a subgroup (31%) of autism LCLs exhibited a greater reduction in ATP-linked respiration, maximal respiratory capacity, and reserve capacity when exposed to ethylmercury, compared to control LCLs. These respiratory parameters were significantly elevated at baseline in the ethylmercury-sensitive autism subgroup as compared to control LCLs. NAC pretreatment of the sensitive subgroup reduced (normalized) baseline respiratory parameters and blunted the exaggerated ethylmercury-induced reserve capacity depletion. These findings suggest that the epidemiological link between environmental mercury exposure and an increased risk of developing autism may be mediated through mitochondrial dysfunction and support the notion that a subset of individuals with autism may be vulnerable to environmental influences with detrimental effects on development through mitochondrial dysfunction.
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16. Wang HG, Jeffries JJ, Wang TF. {{Genetic and Developmental Perspective of Language Abnormality in Autism and Schizophrenia: One Disease Occurring at Different Ages in Humans?}}. {Neuroscientist}. 2015.
Language and communication through it are two of the defining features of normally developed human beings. However, both these functions are often impaired in autism and schizophrenia. In the former disorder, the problem usually emerges in early childhood (~2 years old) and typically includes a lack of communication. In the latter condition, the language problems usually occur in adolescence and adulthood and presents as disorganized speech. What are the fundamental mechanisms underlying these two disorders? Is there a shared genetic basis? Are the traditional beliefs about them true? Are there any common strategies for their prevention and management? To answer these questions, we searched PubMed by using autism, schizophrenia, gene, and language abnormality as keywords, and we reconsidered the basic concepts about these two diseases or syndromes. We found many functional genes, for example, FOXP2, COMT, GABRB3, and DISC1, are actually implicated in both of them. After observing the symptoms, genetic correlates, and temporal progression of these two disorders as well as their relationships more carefully, we now infer that the occurrence of these two diseases is likely developmentally regulated via interaction between the genome and the environment. Furthermore, we propose a unified view of autism and schizophrenia: a single age-dependently occurred disease that is newly named as Systemic Integral Disorder: if occurring in children before age 2, it is called autism; if in adolescence or a later age, it is called schizophrenia.
