1. Banerjee A, Castro J, Sur M. {{Rett syndrome: genes, synapses, circuits, and therapeutics}}. {Front Psychiatry};2012;3:34.
Development of the nervous system proceeds through a set of complex checkpoints which arise from a combination of sequential gene expression and early neural activity sculpted by the environment. Genetic and environmental insults lead to neurodevelopmental disorders which encompass a large group of diseases that result from anatomical and physiological abnormalities during maturation and development of brain circuits. Rett syndrome (RTT) is a neurological disorder of genetic origin, caused by mutations in the X-linked gene methyl-CpG binding protein 2 (MeCP2). It features a range of neuropsychiatric abnormalities including motor dysfunctions and mild to severe cognitive impairment. Here, we discuss key questions and recent studies describing animal models, cell-type specific functions of methyl-CpG binding protein 2 (MeCP2), defects in neural circuit plasticity, and attempts to evaluate possible therapeutic strategies for RTT. We also discuss how genes, proteins, and overlapping signaling pathways affect the molecular etiology of apparently unrelated neuropsychiatric disorders, an understanding of which can offer novel therapeutic strategies for a range of autism spectrum disorders (ASDs).
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2. Ching H, Pringsheim T. {{Aripiprazole for autism spectrum disorders (ASD)}}. {Cochrane Database Syst Rev};2012;5:CD009043.
BACKGROUND: Autism spectrum disorders (ASD) include Autistic Disorder, Asperger’s Disorder and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). Irritability related to ASD has been treated with antipsychotics. Aripiprazole, a third generation atypical antipsychotic, is a relatively new drug that has a unique mechanism of action different from other antipsychotics. OBJECTIVES: To determine the safety and efficacy of aripiprazole for individuals with ASD. SEARCH METHODS: We searched the following databases on 4th May 2011: Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 2), MEDLINE (1948 to April Week 3 2011), EMBASE (1980 to 2011 Week 17), PsycINFO (1887 to current), CINAHL (1937 to current), WorldCat, ZETOC, Autism Data, Conference Proceedings Index-S, Conference Proceedings Index -SSH, ClinicalTrials.gov, and WHO ICTRP. We searched for records published in 1990 or later, as this was the year aripiprazole became available. SELECTION CRITERIA: Randomized controlled trials of aripiprazole versus placebo for the treatment of individuals with a diagnosis of ASD. DATA COLLECTION AND ANALYSIS: Two review authors independently collected, evaluated, and analyzed data. We performed meta-analysis for primary and secondary outcomes, when possible. MAIN RESULTS: Two randomized controlled trials with similar methodology have evaluated the use of aripiprazole for a duration of eight weeks in 316 children with ASD. The included trials had a low risk of bias. Although we searched for studies across age groups, only studies in children and youths were found. Meta-analysis of study results revealed a mean improvement of 6.17 points on the Aberrant Behavior Checklist (ABC) irritability subscale, 7.93 points on the ABC hyperactivity subscale, and 2.66 points in the stereotypy subscale in children treated with aripiprazole relative to children treated with a placebo. In terms of adverse side effects, children treated with aripiprazole had a greater increase in weight with a mean increase of 1.13 kg relative to placebo, and had a higher risk ratio for sedation (RR 4.28) and tremor (RR 10.26). AUTHORS’ CONCLUSIONS: Evidence from two randomized controlled trials suggests that aripiprazole can be effective in treating some behavioral aspects of ASD in children. After treatment with aripiprazole, children showed less irritability, hyperactivity, and stereotypies (repetitive, purposeless actions). Notable side effects must be considered, however, such as weight gain, sedation, drooling, and tremor. Longer studies of aripiprazole in individuals with ASD would be useful to gain information on long-term safety and efficacy.
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3. Davis LK, Gamazon ER, Kistner-Griffin E, Badner JA, Liu C, Cook EH, Sutcliffe JS, Cox NJ. {{Loci nominally associated with autism from genome-wide analysis show enrichment of brain expression quantitative trait loci but not lymphoblastoid cell line expression quantitative trait loci}}. {Mol Autism};2012 (May 16);3(1):3.
ABSTRACT: BACKGROUND: Autism spectrum disorder is a severe early onset neurodevelopmental disorder with high heritability but significant heterogeneity. Traditional genome-wide approaches to test for an association of common variants with autism susceptibility risk have met with limited success. However, novel methods to identify moderate risk alleles in attainable sample sizes are now gaining momentum. METHODS: In this study, we utilized publically available genome-wide association study data from the Autism Genome Project and annotated the results (P <0.001) for expression quantitative trait loci present in the parietal lobe (GSE35977), cerebellum (GSE35974) and lymphoblastoid cell lines (GSE7761). We then performed a test of enrichment by comparing these results to simulated data conditioned on minor allele frequency to generate an empirical P-value indicating statistically significant enrichment of expression quantitative trait loci in top results from the autism genome-wide association study. RESULTS: Our findings show a global enrichment of brain expression quantitative trait loci, but not lymphoblastoid cell line expression quantitative trait loci, among top single nucleotide polymorphisms from an autism genome-wide association study. Additionally, the data implicates individual genes SLC25A12, PANX1 and PANX2 as well as pathways previously implicated in autism. CONCLUSIONS: These findings provide supportive rationale for the use of annotation-based approaches to genome-wide association studies.
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4. Falkmer M, Granlund M, Nilholm C, Falkmer T. {{From my perspective – Perceived participation in mainstream schools in students with autism spectrum conditions}}. {Dev Neurorehabil};2012;15(3):191-201.
Objectives: To examine perceived participation in students with ASC and their classmates in mainstream schools and to investigate correlations between activities the students wanted to do and actually participated in. Methods: Twenty-two students with ASC and their 382 classmates responded to a 46-item questionnaire regarding perceived participation in mainstream schools. Results: On 57% of the items, students with ASC perceived lower participation than their classmates. These results emphasize the importance of knowledge about students’ perceived participation. However, positive correlations between what the students wanted to do and actually did indicate that students with ASC may be participating to the extent that they wanted. Conclusion: Students with ASC perceived lower overall participation in mainstream school than their classmates. The correlations between « I want to » and « I do » statements in students with ASC indicated that aspects of autonomy are important to incorporate when studying, and interpreting, self-rated participation in mainstream schools.
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5. Griesi-Oliveira K, Moreira DD, Davis-Wright N, Sanders S, Mason C, Orabona GM, Vadasz E, Bertola DR, State MW, Passos-Bueno MR. {{A complex chromosomal rearrangement involving chromosomes 2, 5, and X in autism spectrum disorder}}. {Am J Med Genet B Neuropsychiatr Genet};2012 (May 16)
Here, we describe a female patient with autism spectrum disorder and dysmorphic features that harbors a complex genetic alteration, involving a de novo balanced translocation t(2;X)(q11;q24), a 5q11 segmental trisomy and a maternally inherited isodisomy on chromosome 5. All the possibly damaging genetic effects of such alterations are discussed. In light of recent findings on ASD genetic causes, the hypothesis that all these alterations might be acting in orchestration and contributing to the phenotype is also considered. (c) 2012 Wiley Periodicals, Inc.
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6. Hattier MA, Matson JL, May AC, Whiting SE. {{Repetitive/restricted behaviours and interests in children with cerebral palsy and autism spectrum disorder}}. {Dev Neurorehabil};2012;15(3):178-184.
Objective: To inspect the presence and severity of deficits in restricted and/or repetitive behaviours and interests (RRBIs) in children with cerebral palsy (CP) and autism spectrum disorders (ASDs). Methods: Children studied (18-35 months of age) belonged to one of three diagnostic groups: children with CP and autism (n = 11), children with CP and Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS; n = 10) and children with a sole diagnosis of CP (n = 15). A one-way, between subjects ANOVA was conducted on the Repetitive Behaviour/Restricted Interests domain of the Baby and Infant Screen for aUtIsm Traits-Part 1 (BISCUIT-Part 1) and followed up with post-hoc tests. Percentage endorsements were also calculated for each item of this domain. Results: Children with CP + autism had significantly greater impairment. No significant differences were found between the CP + PDD-NOS and the CP alone groups. Conclusion: The implications of these findings are discussed.
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7. Jahromi LB, Meek SE, Ober-Reynolds S. {{Emotion regulation in the context of frustration in children with high functioning autism and their typical peers}}. {J Child Psychol Psychiatry};2012 (May 16)
Background: It is well accepted that emotion regulation difficulties are a serious concern for children with ASD, yet empirical studies of this construct are limited for this population. The present study describes group differences between high functioning children with autism and their typical peers in frustration and discrete coping strategies for emotion regulation. We also use sequential analyses to test differences in the efficacy of individual coping strategies at regulating children’s frustration. Methods: Subjects were 20 children with autism (M = 59 months) and 20 developmentally matched typically developing children (M = 50 months). Measures of children’s frustration (negative facial expressions and behaviors, negative vocalizations, resignation) and emotion regulation coping strategies were observationally coded from structured video recordings. Results: Children with autism displayed a higher intensity and duration of resignation, and the group difference became most pronounced when children worked alone during the parent-absent segment of the locked box task. Children with autism used significantly more avoidance and venting strategies, and fewer constructive strategies than typical children. Sequential analyses revealed that social support strategies (orienting and verbalizing to the experimenter) were ineffective for children with autism, while these behaviors, vocal venting, and distraction strategies were all effective for typically developing children. Conclusions: The results go beyond the recent literature by offering a rich description of children’s efforts to regulate their frustration when faced with challenge, and point to important contextual differences in the efficacy of children’s coping strategies.
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8. Lawton K, Kasari C. {{Teacher-Implemented Joint Attention Intervention: Pilot Randomized Controlled Study for Preschoolers With Autism}}. {J Consult Clin Psychol};2012 (May 14)
Objective: The vast majority of children with an autism spectrum disorder (ASD) attend public preschools at some point in their childhood. Community preschool practices often are not evidence based, and almost none target the prelinguistic core deficits of ASD. This study investigated the effectiveness of public preschool teachers implementing a validated intervention (the Joint Attention and Symbolic Play/Engagement and Regulation intervention; JASP/ER) on a core deficit of autism, initiating joint attention. Method: Sixteen dyads (preschoolers with ASD and the public school teachers who worked in the child’s classroom) were randomly assigned to the 6-week JASP/ER intervention or a control group. Results: At the end of the intervention, JASP/ER teachers used more JASP/ER strategies than the control teachers, and JASP/ER preschoolers used more joint attention in their classroom than control children. Additionally, JASP/ER children spent more time in supported engagement and less time in object engagement than control preschoolers on a taped play interaction. Conclusions: Findings suggest that teachers were able to improve a core deficit of children with ASD in a public preschool context. (PsycINFO Database Record (c) 2012 APA, all rights reserved).
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9. Matson JL, Kozlowski AM, Hattier MA, Horovitz M, Sipes M. {{DSM-IV vs DSM-5 diagnostic criteria for toddlers with Autism}}. {Dev Neurorehabil};2012;15(3):185-190.
Purpose: To evaluate prevalence rates of autism and autism symptomatology in toddlers using DSM-IV vs DSM-5 criteria. Method: Two thousand seven hundred and twenty-one toddlers at risk for a developmental disability participated. DSM-IV and DSM-5 criteria were applied and overall prevalence using each set of criteria was established. Groups were also compared on BISCUIT-Part 1 scores to determine if groups differed on autism symptomatology. Results: DSM-5 resulted in 47.79% fewer toddlers being diagnosed with ASD compared to those on the DSM-IV. Toddlers diagnosed according to DSM-5 exhibited greater levels of autism symptomatology than those diagnosed with DSM-IV, but the latter group still exhibited significant levels of autism symptomatology. Conclusion: The proposed DSM-5 will result in far fewer persons being diagnosed with ASD. These results replicate findings from two previous studies, with older children/adolescents and adults. As a result of these new criteria, far fewer people will qualify for needed autism services.
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10. Muers M. {{Human genetics: Fruits of exome sequencing for autism}}. {Nat Rev Genet};2012 (May 15)
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11. Shattuck PT, Narendorf SC, Cooper B, Sterzing PR, Wagner M, Taylor JL. {{Postsecondary Education and Employment Among Youth With an Autism Spectrum Disorder}}. {Pediatrics};2012 (May 14)
OBJECTIVES:We examined the prevalence and correlates of postsecondary education and employment among youth with an autism spectrum disorder (ASD).METHODS:Data were from a nationally representative survey of parents, guardians, and young adults with an ASD. Participation in postsecondary employment, college, or vocational education and lack of participation in any of these activities were examined. Rates were compared with those of youth in 3 other eligibility categories: speech/language impairment, learning disability, and mental retardation. Logistic regression was used to examine correlates of each outcome.RESULTS:For youth with an ASD, 34.7% had attended college and 55.1% had held paid employment during the first 6 years after high school. More than 50% of youth who had left high school in the past 2 years had no participation in employment or education. Youth with an ASD had the lowest rates of participation in employment and the highest rates of no participation compared with youth in other disability categories. Higher income and higher functional ability were associated with higher adjusted odds of participation in postsecondary employment and education.CONCLUSIONS:Youth with an ASD have poor postsecondary employment and education outcomes, especially in the first 2 years after high school. Those from lower-income families and those with greater functional impairments are at heightened risk for poor outcomes. Further research is needed to understand how transition planning before high school exit can facilitate a better connection to productive postsecondary activities.
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12. White SJ. {{The Triple I Hypothesis: Taking Another(‘s) Perspective on Executive Dysfunction in Autism}}. {J Autism Dev Disord};2012 (May 15)
The executive dysfunction theory attempts to explain not only the repetitive behaviours but also the socio-communicative difficulties in autism. While it is clear that some individuals with autism perform poorly on certain executive function tasks, it remains unclear what underlies these impairments. The most consistent and striking difficulties are seen on tasks that are open-ended in structure, lack explicit instructions and involve arbitrary rules. I propose that impairment on such tasks is not due to executive dysfunction; instead, poor performance results from difficulties forming an implicit understanding of the experimenter’s expectations for the task, resulting in egocentric and idiosyncratic behaviour. These difficulties in taking another’s perspective may be explained parsimoniously by the mentalising difficulties robustly demonstrated to exist in autism.
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13. Yu Z, Fan D, Gui B, Shi L, Xuan C, Shan L, Wang Q, Shang Y, Wang Y. {{Neurodegeneration-associated TDP-43 Interacts with Fragile X Mental Retardation Protein (FMRP)/Staufen (STAU1) and Regulates SIRT1 Expression in Neuronal Cells}}. {J Biol Chem};2012 (May 14)
Despite the identification of the 43kDa transactive response DNA-binding protein (TDP-43) as a major pathological signatory protein in a wide range of neurodegenerative diseases, the mechanistic role of TDP-43 in neurodegenerative disorders is still poorly understood. Here, we report that TDP-43 is physically associated with fragile X mental retardation protein (FMRP) and Staufen (STAU1) to form a functional complex. Differential microarray analysis revealed that the expression of a collection of functionally important genes including Sirtuin (SIRT1) is regulated by this complex. RNA-immunoprecipitation (RIP) assays demonstrated that TDP-43/FMRP/STAU1 could specifically bind to the 3’UTR of SIRT1 mRNA, and that knockdown the expression of any one of these three proteins resulted in the reduction of SIRT1 mRNA and protein. SIRT1 is implicated in double-stranded DNA break repair and is required for cell survival. Indeed, depletion of TDP-43/FMRP/STAU1 sensitizes cells to apoptosis and DNA damages. Collectively, our results revealed a molecular mechanism for the cellular function of TDP-43 and might shed new light on the understanding of the mechanistic role of TDP-43 in neurodegenerative diseases.
