1. Agarwal N, Becker A, Jost KL, Haase S, Thakur BK, Brero A, Hardt T, Kudo S, Leonhardt H, Cardoso MC. {{MeCP2 Rett mutations affect large scale chromatin organization}}. {Hum Mol Genet};2011 (Aug 10)
Rett syndrome is a neurological, X chromosomal-linked disorder associated with mutations in the MECP2 gene. MeCP2 protein has been proposed to play a role in transcriptional regulation as well as in chromatin architecture. Since MeCP2 mutant cells exhibit surprisingly mild changes in gene expression, we have now explored the possibility that Rett mutations may affect the ability of MeCP2 to bind and organize chromatin. We found that all but one of the 21 missense MeCP2 mutants analyzed accumulated at heterochromatin and about half of them were significantly affected. Furthermore, two thirds of all mutants showed a significantly decreased ability to cluster heterochromatin. Three mutants containing different proline substitutions (P101H, P101R and P152R) were severely affected only in heterochromatin clustering and located far away from the DNA interface in the MeCP2 methyl binding domain structure. MeCP2 mutants affected in heterochromatin accumulation further exhibited the shortest residence time on heterochromatin, followed by intermediate binding kinetics for clustering impaired mutants. We propose that different interactions of MeCP2 with methyl cytosines, DNA and likely other heterochromatin proteins are required for MeCP2 function and their dysfunction lead to Rett syndrome.
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2. Barton ML, Dumont-Mathieu T, Fein D. {{Screening Young Children for Autism Spectrum Disorders in Primary Practice}}. {J Autism Dev Disord};2011 (Aug 13)
The increasing prevalence of autism spectrum disorders as well as emerging evidence of the efficacy of early intervention has focused attention on the need for early identification of young children suspected of having an ASSD. Several studies have suggested that while parents report concerns early in development, it may be months before children can be evaluated and services provided, and these delays may be even more marked in under-served populations. The American Academy of Pediatrics recently recommended universal screening for autism spectrum disorders at the 18- and 24-month well-child pediatric visit. The authors review several early screening tools currently in use and offer recommendations for integrating autism specific screening into primary care practice.
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3. Bennett T, Boyle M, Georgiades K, Georgiades S, Thompson A, Duku E, Bryson S, Fombonne E, Vaillancourt T, Zwaigenbaum L, Smith I, Mirenda P, Roberts W, Volden J, Waddell C. {{Influence of reporting effects on the association between maternal depression and child autism spectrum disorder behaviors}}. {J Child Psychol Psychiatry};2011 (Aug 10)
Background: Maximizing measurement accuracy is an important aim in child development assessment and research. Parents are essential informants in the diagnostic process, and past research suggests that certain parental characteristics may influence how they report information about their children. This has not been studied in autism spectrum disorders (ASD) to date. We aimed, therefore, to investigate the possible effect that maternal depression might have on a mother’s reports of her child’s ASD behaviors. Using structural equation modeling, we disaggregated shared from unique variation in the association between latent variable measures of maternal depression and ASD behaviors. Methods: Data were obtained from a study of preschoolers aged 2-4 newly diagnosed with ASD (n = 214). Information from a parent questionnaire, a semi-structured parent interview, and a semi-structured observational assessment was used to develop a latent variable measure of child ASD behaviors. Mothers reported on their own depression symptoms. We first modeled the covariance between maternal depression and child ASD behavior. Then, to quantify unique variation, we added covariance terms between maternal depression and the residual variation associated with the individual measures of child ASD behaviors. Results: The model demonstrated excellent fit to the underlying data. Maternal self-report of depression symptoms exhibited a significant association with the unique variance of the questionnaire report but not with the latent variable measure of child ASD behavior. A gradient pattern of association was demonstrated between maternal depression and the unique variance of the ASD measures: most strongly for the maternal questionnaire report, more weakly for the maternal semi-structured interview, and to a trivial extent for the observational interview. Conclusions: Parental depression may influence reporting of ASD behaviors in preschoolers. Shared method effects may also contribute to bias. This finding highlights the importance of obtaining multimethod reports of child ASD symptoms.
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4. Cook JL, Bird G. {{Atypical Social Modulation of Imitation in Autism Spectrum Conditions}}. {J Autism Dev Disord};2011 (Aug 11)
Appropriate modulation of imitation according to social context is important for successful social interaction. In the present study we subliminally primed high-functioning adults with ASC and age- and IQ-matched controls with either a pro- or non- social attitude. Following priming, an automatic imitation paradigm was used to acquire an index of imitation. Whereas imitation levels were higher for pro-socially primed relative to non-socially primed control participants, there was no difference between pro- and non- socially primed individuals with ASC. We conclude that high-functioning adults with ASC demonstrate atypical social modulation of imitation. Given the importance of imitation in social interaction we speculate that difficulties with the modulation of imitation may contribute to the social problems characteristic of ASC.
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5. De Rubeis S, Bagni C. {{Regulation of molecular pathways in the Fragile X Syndrome: insights into Autism Spectrum Disorders}}. {J Neurodev Disord};2011 (Aug 13)
The Fragile X syndrome (FXS) is a leading cause of intellectual disability (ID) and autism. The disease is caused by mutations or loss of the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein playing multiple functions in RNA metabolism. The expression of a large set of neuronal mRNAs is altered when FMRP is lost, thus causing defects in neuronal morphology and physiology. FMRP regulates mRNA stability, dendritic targeting, and protein synthesis. At synapses, FMRP represses protein synthesis by forming a complex with the Cytoplasmic FMRP Interacting Protein 1 (CYFIP1) and the cap-binding protein eIF4E. Here, we review the clinical, genetic, and molecular aspects of FXS with a special focus on the receptor signaling that regulates FMRP-dependent protein synthesis. We further discuss the FMRP-CYFIP1 complex and its potential relevance for ID and autism.
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6. Eric Barnes R, McCabe H. {{Should we welcome a cure for autism? A survey of the arguments}}. {Med Health Care Philos};2011 (Aug 12)
Substantial research efforts have been devoted to developing a cure for autism, but some advocates of people with autism claim that these efforts are misguided and even harmful. They claim that there is nothing wrong with people with autism, so there is nothing to cure. Others argue that autism is a serious and debilitating disorder and that a cure for autism would be a wonderful medical breakthrough. Our goal in this essay is to evaluate what assumptions underlie each of these positions. We evaluate the arguments made on each side, reject those that are implausible and then highlight the key assumptions of those that remain.
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7. Harris CD, Lindell AK. {{The influence of autism-like traits on cheek biases for the expression and perception of happiness}}. {Brain Cogn};2011 (Aug 9)
People with autism show attenuated cerebral lateralisation for emotion processing. Given growing appreciation of the notion that autism represents a continuum, the present study aimed to determine whether atypical hemispheric lateralisation is evident in people with normal but above average levels of autism-like traits. One hundred and twenty-seven right-handed participants (M=43, F=84) completed the AQ questionnaire (Baron-Cohen, Wheelwright, Skinner, Martin, & Clubley, 2001), and then (a) posed for a photo expressing happiness, and (b) viewed pairs of left and right cheek poses, making a forced-choice decision indicating which image appeared happier (half the images were mirror-reversed to control for perceptual biases). Results indicated that irrespective of AQ status, people were intuitively aware that the left cheek is more emotionally expressive: participants offered the left cheek when posing to appear happy, and perceived left poses as happier than right poses. As the left cheek is predominantly controlled by the right hemisphere, these findings strongly support the right hemisphere hypothesis. The fact that people with normal but above average levels of autism-like traits did not show a reduced leftward bias for either task indicates that the attenuated emotion lateralisation pattern noted in the clinical population does not extend into the normal spectrum. Instead, the results suggest that people with normal but above average levels of AQ traits are as sensitive to the silent social/emotional cues signalled by a left cheek pose as those with lower AQ scores.
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8. Kuenssberg R, McKenzie K. {{Confirmatory factor analysis of the Adult Asperger Assessment: The association of symptom domains within a clinical population}}. {Res Dev Disabil};2011 (Aug 8)
Autism Spectrum Disorder (ASD) is a behaviourally defined disorder characterised by impairments in three domains of social interaction, communication, and repetitive, stereotyped behaviours and activities. Proposed changes to diagnostic criteria suggest that the diagnostic triad may no longer fit as the best way to conceptualise ASD, and that social and communication impairments should be considered as a single domain. The aim of this study was to examine the structure of symptom domains within the Adult Asperger Assessment (AAA; Baron-Cohen, Wheelwright, Robinson, & Woodbury-Smith, 2005), a diagnostic tool for high functioning adults. As theoretical models already exist, confirmatory factor analysis was used to examine data from a clinical population of adults (n=153) diagnosed with Asperger Syndrome (AS) and High Functioning Autism (HFA). Confirmatory factor analysis was used to fit different models based on the structure proposed by the authors of the AAA, the traditional triad and the newly proposed diagnostic dyad. Analysis suggested that none of the tested models were a good fit on the AAA dataset. However, it did highlight very high correlations between social and communication factors (r>0.9) within unmodified models. The results of the analysis provide tentative support for the move towards considering ASD as a dyad of ‘social-communication’ impairments and repetitive/restricted interests behaviours and activities, rather than the traditional triad.
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9. Lieberman S, Zuckerman S, Levy-Lahad E, Altarescu G. {{Conflicts regarding genetic counseling for fragile X syndrome screening: A survey of clinical geneticists and genetic counselors in Israel}}. {Am J Med Genet A};2011 (Aug 10)
Although fragile X screening has been offered in Israel since 1994, issues related to potential neurological and gynecological symptoms in carriers make counseling for fragile X different from recessive disorders. We evaluated the attitudes of clinical geneticists and genetic counselors regarding genetic counseling given to the women undergoing screening. We performed a self-administered questionnaire including 13 study questions mailed to all clinical geneticists and genetic counselors in Israel. The questions were related to counseling for women pre- and post-screening regarding themselves and the affected fetuses (including the risk for premature ovarian insufficiency; FXPOI and fragile X-associated tremor ataxia syndrome; FXTAS). Out of a total of 80 clinical geneticists and genetic counselors, 34 responded with no additional responses on e-mail re-call. There was no clear consensus for 11/13 (85%) presented questions. The most striking differences in opinion were observed for issues regarding FXTAS risk in pre-screening counseling sessions (P < 0.05). This study demonstrates that, there is no consensus on critical variables implying risk for fetus and mother and that counseling practices are dissimilar even in this small cohort of experts. We demonstrated a conflict between the detailed amount of information, which should be given prior to the test in order to allow informed decisions and the overload of information, which may cause confusion. (c) 2011 Wiley-Liss, Inc.
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10. Mazzucchelli TG, Sanders MR. {{Preventing behavioural and emotional problems in children who have a developmental disability: A public health approach}}. {Res Dev Disabil};2011 (Aug 8)
Children with developmental disabilities are at substantially greater risk of developing emotional and behavioural problems compared to their typically developing peers. While the quality of parenting that children receive has a major effect on their development, empirically supported parenting programs reach relatively few parents. A recent trend in parenting intervention research has been the adoption of a public health approach to improve the quality of parenting at a population level. This has involved delivering parenting interventions on a large scale and in a cost-effective manner. Such trials have been demonstrated to reduce negative parenting practices, prevent child maltreatment, and reduce child behavioural and emotional problems. However, these trials have been restricted to parents of children who are developing typically. This paper explores the rational for the extension of a population health approach to parenting interventions for children with developmental disabilities. It is argued that a population-based implementation and evaluation trial of an empirically supported system of interventions is needed to determine whether this approach is viable and can have a positive impact on parents and their children in a disability context. The Stepping Stones Triple P-Positive Parenting Program is presented as an example of a parenting intervention that satisfies the requirements for such a trial. Tasks and challenges of such a trial are discussed.
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11. Mukamel Z, Konopka G, Wexler E, Osborn GE, Dong H, Bergman MY, Levitt P, Geschwind DH. {{Regulation of MET by FOXP2, Genes Implicated in Higher Cognitive Dysfunction and Autism Risk}}. {J Neurosci};2011 (Aug 10);31(32):11437-11442.
Autism spectrum disorder (ASD) is a highly heritable, behaviorally defined, heterogeneous disorder of unknown pathogenesis. Several genetic risk genes have been identified, including the gene encoding the receptor tyrosine kinase MET, which regulates neuronal differentiation and growth. An ASD-associated polymorphism disrupts MET gene transcription, and there are reduced levels of MET protein expression in the mature temporal cortex of subjects with ASD. To address the possible neurodevelopmental contribution of MET to ASD pathogenesis, we examined the expression and transcriptional regulation of MET by a transcription factor, FOXP2, which is implicated in regulation of cognition and language, two functions altered in ASD. MET mRNA expression in the midgestation human fetal cerebral cortex is strikingly restricted, localized to portions of the temporal and occipital lobes. Within the cortical plate of the temporal lobe, the pattern of MET expression is highly complementary to the expression pattern of FOXP2, suggesting the latter may play a role in repression of gene expression. Consistent with this, MET and FOXP2 also are reciprocally expressed by differentiating normal human neuronal progenitor cells (NHNPs) in vitro, leading us to assess whether FOXP2 transcriptionally regulates MET. Indeed, FOXP2 binds directly to the 5′ regulatory region of MET, and overexpression of FOXP2 results in transcriptional repression of MET. The expression of MET in restricted human neocortical regions, and its regulation in part by FOXP2, is consistent with genetic evidence for MET contributing to ASD risk.
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12. Peters SU, Horowitz L, Barbieri-Welge R, Taylor JL, Hundley RJ. {{Longitudinal follow-up of autism spectrum features and sensory behaviors in Angelman syndrome by deletion class}}. {J Child Psychol Psychiatry};2011 (Aug 10)
Background: Angelman syndrome (AS) is a neurogenetic disorder characterized by severe intellectual disability, lack of speech, and low threshold for laughter; it is considered a ‘syndromic’ form of autism spectrum disorder (ASD). Previous studies have indicated overlap of ASD and AS, primarily in individuals with larger ( approximately 6 Mb) Class I deletions of chromosome 15q11-13. Questions remain regarding whether intellectual disability solely contributes to ASD features in AS and how ASD features in AS change over time. In this study, we used a dimensional approach to examine ASD symptom severity in individuals with AS Class I versus Class II deletions within the context of cognitive development over time. Methods: A total of 17 participants with a larger, Class I deletion and 25 participants with a smaller Class II deletion ( approximately 5 Mb) were enrolled (age range = 2-25 years; 5 years 5 months). Standardized measures of cognition, language, motor skills, adaptive skills, maladaptive behavior, autism, and sensory-seeking behaviors/aversions were given at baseline and after 12 months. Results: Despite equivalent cognition and adaptive behavior, the results of repeated measures analyses of variance indicate that participants with Class I deletions have greater impairment in social affect (F = 8.65; p = .006) and more repetitive behaviors (F = 7.92; p = .008) compared to participants with Class II deletions. Although both groups improve in cognition over time, differences in ASD behaviors persist. Conclusions: Despite a lack of differences in cognition or adaptive behavior, individuals with Class I deletions have greater severity in ASD features and sensory aversions that remain over time. There are four genes (NIPA 1, NIPA 2, CYFIP1, and GCP5) missing in Class I and present in Class Il deletions, one or more of which may have a role in modifying the severity of social affect impairment, and level of restricted/repetitive behaviors in AS. Our results also suggest the utility of a dimensional, longitudinal approach to the assessment of ASD features in populations of individuals who are low functioning.
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13. Stefanatos GA, Baron IS. {{The Ontogenesis of Language Impairment in Autism: A Neuropsychological Perspective}}. {Neuropsychol Rev};2011 (Aug 13)
Autistic Disorder (AD) is a phenotypically heterogeneous condition characterized by impairments in social interaction, communication, and the presence of repetitive behavior and restricted interests. It is a model syndrome to investigate neural interaction and integration at the nexus of language and social cognition. This paper considers the problems of language acquisition in AD from an evolutionary and ontogenetic context. Following a review of normal language development during the formative years of brain development, we examine what is known about infant linguistic and nonlinguistic precursors of language acquisition in AD and examine how anomalies of several processes relate to language abnormalities manifest by the early elementary school years. Population heterogeneity and practical limitations inherent to the study of children currently limit a comprehensive understanding of the significance of specific neurological abnormalities in relation to observed deficits. However, convergent evidence implicates anomalies of a widely distributed neural network, involving superior temporal sulcus, superior temporal gyrus, supramarginal gyrus, insula, inferior frontal gyrus, hippocampus, amygdala and cerebellum. These anomalies reflect the cumulative effects of genetic, epigenetic and environmental influences. Neuropsychological studies of language in AD provide an important means to define the phenotypic variation resulting from alterations in neural architecture. By mapping broad relationships between key symptoms, neuropsychological impairment and neural substrate, information derived from these studies enable a level of analysis that bridges the gap between the genome and the syndrome. Further study of children during the critical first 2 years of life using behavioral, electrophysiological, and functional neuroimaging methods is essential.
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14. Thomas KC, Parish SL, Rose RA, Kilany M. {{Access to care for children with autism in the context of state Medicaid reimbursement}}. {Matern Child Health J};2011 (Aug 11)
This paper examines the role of state residence and Medicaid reimbursement rates in explaining the relationship between having autism and access to care for children. Three questions are addressed: (1) Is there variation across states in the relationship between having autism and access to care? (2) Does taking account of state residence explain a significant amount of the variation in this relationship? (3) Does accounting for Medicaid reimbursement rates enhance our understanding of this relationship? Data from the 2005 National Survey of Children with Special Health Care Needs were combined with state characteristics to estimate a hierarchical generalized linear model of the association between state residence, Medicaid reimbursement rate and problems accessing care for children with special health care needs with and without autism. Findings indicate there is significant variation between states in the relationship between having autism and problems accessing care, and accounting for state residence explains a significant amount of variation in the model. Medicaid reimbursement rates have an independent effect on access to care for children with autism: when families raising children with autism live in states with higher reimbursement rates, they have lower odds of experiencing problems accessing care. The state context in which families live impacts access to care for children with autism. Moreover, when families live in states with higher Medicaid reimbursement rates, they are less likely to experience problems getting care. The value of this analysis is that it helps identify where to look for strategies to improve access.
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15. van Daalen E, Kemner C, Verbeek NE, van der Zwaag B, Dijkhuizen T, Rump P, Houben R, van ‘t Slot R, de Jonge MV, Staal WG, Beemer FA, Vorstman JA, Burbach JP, van Amstel HK, Hochstenbach R, Brilstra EH, Poot M. {{Social responsiveness scale-aided analysis of the clinical impact of copy number variations in autism}}. {Neurogenetics};2011 (Aug 12)
Recent array-based studies have detected a wealth of copy number variations (CNVs) in patients with autism spectrum disorders (ASD). Since CNVs also occur in healthy individuals, their contributions to the patient’s phenotype remain largely unclear. In a cohort of children with symptoms of ASD, diagnosis of the index patient using ADOS-G and ADI-R was performed, and the Social Responsiveness Scale (SRS) was administered to the index patients, both parents, and all available siblings. CNVs were identified using SNP arrays and confirmed by FISH or array CGH. To evaluate the clinical significance of CNVs, we analyzed three families with multiple affected children (multiplex) and six families with a single affected child (simplex) in which at least one child carried a CNV with a brain-transcribed gene. CNVs containing genes that participate in pathways previously implicated in ASD, such as the phosphoinositol signaling pathway (PIK3CA, GIRDIN), contactin-based networks of cell communication (CNTN6), and microcephalin (MCPH1) were found not to co-segregate with ASD phenotypes. In one family, a loss of CNTN5 co-segregated with disease. This indicates that most CNVs may by themselves not be sufficient to cause ASD, but still may contribute to the phenotype by additive or epistatic interactions with inherited (transmitted) mutations or non-genetic factors. Our study extends the scope of genome-wide CNV profiling beyond de novo CNVs in sporadic patients and may aid in uncovering missing heritability in genome-wide screening studies of complex psychiatric disorders.
