1. Gianakopoulos PJ, Zhang Y, Pencea N, Orlic-Milacic M, Mittal K, Windpassinger C, White SJ, Kroisel PM, Chow EW, Saunders CJ, Minassian BA, Vincent JB. {{Mutations in MECP2 exon 1 in classical rett patients disrupt MECP2_e1 transcription, but not transcription of MECP2_e2}}. {American journal of medical genetics Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics}. 2011 Dec 27.
The overwhelming majority of Rett syndrome cases are caused by mutations in the gene MECP2. MECP2 has two isoforms, termed MECP2_e1 and MECP2_e2, which differ in their N-terminal amino acid sequences. A growing body of evidence has indicated that MECP2_e1 may be the etiologically relevant isoform in Rett Syndrome based on its expression profile in the brain and because, strikingly, no mutations have been discovered that affect MECP2_e2 exclusively. In this study we sought to characterize four classical Rett patients with mutations that putatively affect only the MECP2_e1 isoform. Our hypothesis was that the classical Rett phenotype seen here is the result of disrupted MECP2_e1 expression, but with MECP2_e2 expression unaltered. We used quantitative reverse transcriptase PCR to assay mRNA expression for each isoform independently, and used cytospinning methods to assay total MECP2 in peripheral blood lymphocytes (PBL). In the two Rett patients with identical 11 bp deletions within the coding portion of exon 1, MECP2_e2 levels were unaffected, whilst a significant reduction of MECP2_e1 levels was detected. In two Rett patients harboring mutations in the exon 1 start codon, MECP2_e1 and MECP2_e2 mRNA amounts were unaffected. In summary, we have shown that patients with exon 1 mutations transcribe normal levels of MECP2_e2 mRNA, and most PBL are positive for MeCP2 protein, despite them theoretically being unable to produce the MECP2_e1 isoform, and yet still exhibit the classical RTT phenotype. Altogether, our work further supports our hypothesis that MECP2_e1 is the predominant isoform involved in the neuropathology of Rett syndrome. (c) 2011 Wiley Periodicals, Inc.
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2. Kaya N, Colak D, Albakheet A, Al-Owain M, Abu-Dheim N, Al-Younes B, Al-Zahrani J, Mukaddes NM, Dervent A, Al-Dosari N, Al-Odaib A, Kayaalp IV, Al-Sayed M, Al-Hassnan Z, Nester MJ, Al-Dosari M, Al-Dhalaan H, Chedrawi A, Gunoz H, Karakas B, Sakati N, Alkuraya FS, Gascon GG, Ozand PT. {{A novel X-linked disorder with developmental delay and autistic features}}. {Annals of neurology}. 2011 Nov 25.
OBJECTIVE: Genomic duplications that lead to autism and other human diseases are interesting pathological lesions since the underlying mechanism almost certainly involves dosage sensitive genes. We aim to understand a novel genomic disorder with profound phenotypic consequences, most notably global developmental delay, autism, psychosis, and anorexia nervosa. METHODS: We evaluated the affected individuals, all maternally related, using childhood autism rating scale (CARS) and Vineland Adaptive scales, magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) brain, electroencephalography (EEG), electromyography (EMG), muscle biopsy, high-resolution molecular karyotype arrays, Giemsa banding (G-banding) and fluorescent in situ hybridization (FISH) experiments, mitochondrial DNA (mtDNA) sequencing, X-chromosome inactivation study, global gene expression analysis on Epstein-Barr virus (EBV)-transformed lymphoblasts, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). RESULTS: We have identified a novel Xq12-q13.3 duplication in an extended family. Clinically normal mothers were completely skewed in favor of the normal chromosome X. Global transcriptional profiling of affected individuals and controls revealed significant alterations of genes and pathways in a pattern consistent with previous microarray studies of autism spectrum disorder patients. Moreover, expression analysis revealed copy number-dependent increased messenger RNA (mRNA) levels in affected patients compared to control individuals. A subset of differentially expressed genes was validated using qRT-PCR. INTERPRETATION: Xq12-q13.3 duplication is a novel global developmental delay and autism-predisposing chromosomal aberration; pathogenesis of which may be mediated by increased dosage of genes contained in the duplication, including NLGN3, OPHN1, AR, EFNB1, TAF1, GJB1, and MED12. ANN NEUROL 2011.
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3. Locke J, Rotheram-Fuller E, Kasari C. {{Exploring the Social Impact of Being a Typical Peer Model for Included Children with Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2012 Jan 4.
This study examined the social impact of being a typical peer model as part of a social skills intervention for children with autism spectrum disorder (ASD). Participants were drawn from a randomized-controlled-treatment trial that examined the effects of targeted interventions on the social networks of 60 elementary-aged children with ASD. Results demonstrated that typical peer models had higher social network centrality, received friendships, friendship quality, and less loneliness than non-peer models. Peer models were also more likely to be connected with children with ASD than non-peer models at baseline and exit. These results suggest that typical peers can be socially connected to children with ASD, as well as other classmates, and maintain a strong and positive role within the classroom.
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4. Lundstrom S, Chang Z, Rastam M, Gillberg C, Larsson H, Anckarsater H, Lichtenstein P. {{Autism spectrum disorders and autisticlike traits: similar etiology in the extreme end and the normal variation}}. {Archives of general psychiatry}. 2012 Jan;69(1):46-52.
CONTEXT: Autism spectrum disorders (ASDs) have been suggested to represent the extreme end of a normal distribution of autisticlike traits (ALTs). However, the evidence of this notion is inconclusive. OBJECTIVE: To study whether there are similar genetic and/or environmental etiologies behind ASDs and ALTs. DESIGN: A nationwide twin study. PARTICIPANTS: Consenting parents of all Swedish twins aged 9 and 12 years, born between July 1, 1992, and December 31, 2001 (n = 19 208), were interviewed by telephone to screen for child psychiatric conditions, including ASDs. MAIN OUTCOME MEASURES: Two validated cutoffs for ASDs, 2 cutoffs encompassing the normal variation, and 1 continuous measure of ALTs were used with DeFries-Fulker extreme-end analyses and standard twin study methods. RESULTS: We discerned a strong correlation between the 4 cutoffs and the full variation of ALTs. The correlation was primarily affected by genes. We also found that the heritability for the 4 cutoffs was similar. CONCLUSION: We demonstrate an etiological similarity between ASDs and ALTs in the normal variation and, with results from previous studies, our data suggest that ASDs and ALTs are etiologically linked.
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5. Mandell DS, Xie M, Morales KH, Lawer L, McCarthy M, Marcus SC. {{The interplay of outpatient services and psychiatric hospitalization among medicaid-enrolled children with autism spectrum disorders}}. {Archives of pediatrics & adolescent medicine}. 2012 Jan;166(1):68-73.
OBJECTIVE: To examine whether increased provision of community-based services is associated with decreased psychiatric hospitalizations among children with autism spectrum disorders (ASDs). DESIGN: Retrospective cohort study using discrete-time logistic regression to examine the association of service use in the preceding 60 days with the risk of hospitalization. SETTING: The Medicaid-reimbursed health care system in the continental United States. PARTICIPANTS: Medicaid-enrolled children with an ASD diagnosis in 2004 (N = 28 428). Main Exposures Use of respite care and therapeutic services, based on procedure codes. MAIN OUTCOME MEASURES: Hospitalizations associated with a diagnosis of ASD (International Classification of Diseases, 10th Revision, codes 299.0, 299.8, and 299.9). RESULTS: Each $1000 increase in spending on respite care during the preceding 60 days resulted in an 8% decrease in the odds of hospitalization in adjusted analysis. Use of therapeutic services was not associated with reduced risk of hospitalization. CONCLUSIONS: Respite care is not universally available through Medicaid. It may represent a critical type of service for supporting families in addressing challenging child behaviors. States should increase the availability of respite care for Medicaid-enrolled children with ASDs. The lack of association between therapeutic services and hospitalization raises concerns regarding the effectiveness of these services.
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6. Meehan TF, Carr CJ, Jay JJ, Bult CJ, Chesler EJ, Blake JA. {{Autism candidate genes via mouse phenomics}}. {Journal of biomedical informatics}. 2011 Dec;44 Suppl 1:S5-S11.
Autism spectrum disorders (ASD) represent a group of developmental disabilities with a strong genetic basis. The laboratory mouse is increasingly used as a model organism for ASD, and MGI, the Mouse Genome Informatics resource, is the primary model organism database for the laboratory mouse. MGI uses the Mammalian Phenotype (MP) ontology to describe mouse models of human diseases. Using bioinformatics tools including Phenologs, MouseNET, and the Ontological Discovery Environment, we tested data associated with MP terms to characterize new gene-phenotype associations related to ASD. Our integrative analysis using these tools identified numerous mouse genotypes that are likely to have previously uncharacterized autistic-like phenotypes. The genes implicated in these mouse models had considerable overlap with a set of over 300 genes recently associated with ASD due to small, rare copy number variation (Pinto et al., 2010). Prediction and characterization of autistic mutant mouse alleles assists researchers in studying the complex nature of ASD and provides a generalizable approach to candidate gene prioritization.
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7. Nordahl CW, Scholz R, Yang X, Buonocore MH, Simon T, Rogers S, Amaral DG. {{Increased rate of amygdala growth in children aged 2 to 4 years with autism spectrum disorders: a longitudinal study}}. {Archives of general psychiatry}. 2012 Jan;69(1):53-61.
CONTEXT: Precocious amygdala enlargement is commonly observed in young children with autism. However, the age at which abnormal amygdala enlargement begins and the relative growth trajectories of the amygdala and total brain remain unclear. OBJECTIVE: To determine whether the rate of amygdala growth is abnormal and disproportionate to total brain growth in very young children with autism spectrum disorders (ASDs). DESIGN: Longitudinal structural magnetic resonance imaging study. SETTING: Neuroimaging and diagnostic assessments were performed at an academic medical center. Participants were recruited from the community. PARTICIPANTS: Baseline scans were acquired in 132 boys (85 with ASD and 47 control subjects with typical development [TD]; mean age, 37 months). Longitudinal magnetic resonance images were acquired in 70 participants (45 with ASD and 25 TD controls) 1 year later. Main Outcome Measure Amygdala volumes and total cerebral volumes (TCVs) were evaluated at both time points, and 1-year growth rates were calculated. RESULTS: The amygdala was larger in children with ASD at both time points, but the magnitude of enlargement was greater at time 2. The TCV was also enlarged in the children with ASD by the same magnitude at both time points. When we controlled for TCV, amygdala enlargement remained significant at both time points. The rate of amygdala growth during this 1-year interval was faster in children with ASD than in TD controls. The rate of TCV growth did not differ between groups. Post hoc exploratory analyses revealed 3 patterns of amygdala and TCV growth rates in the ASD group. CONCLUSIONS: Disproportionate amygdala enlargement is present by 37 months of age in ASD. The amygdala continues to grow at an increased rate, but substantial heterogeneity exists in amygdala and TCV growth patterns. Future studies aimed at clinical characterization of different growth patterns could have implications for choice and outcomes of treatment and behavioral therapy.
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8. Patriquin MA, Scarpa A, Friedman BH, Porges SW. {{Respiratory sinus arrhythmia: A marker for positive social functioning and receptive language skills in children with autism spectrum disorders}}. {Developmental psychobiology}. 2011 Dec 27.
The current study builds on the emerging autism spectrum disorder (ASD) literature that associates autonomic nervous system activity with social function, and examines the link between respiratory sinus arrhythmia (RSA) and both social behavior and cognitive function. The RSA response pattern was assessed in 23 4- to 7-year-old children diagnosed with an ASD. Higher baseline RSA amplitudes were associated with better social behavior (i.e., more conventional gestures, more instances of joint attention) and receptive language abilities. Similar to reports of typically developing children, ASD children with higher RSA amplitude at baseline showed greater RSA and HP reactivity during an attention-demanding task. These results highlight the importance of studying RSA as a marker of positive function in children with ASD. (c) 2011 Wiley Periodicals, Inc. Dev Psychobiol.
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9. Reynolds S, Lynch SL, Litman S. {{Training care teams of children with autism spectrum disorders in positive behaviour support: an innovative approach}}. {Healthcare quarterly (Toronto, Ont)}. 2011 Oct;14 Spec No 3:95-9.
As part of a team, the authors developed a workshop to help parents and teams address the behavioural needs of children with autism using a positive behaviour support (PBS) approach. Teams received comprehensive training in PBS and completed weekly homework assignments. Measures of participant satisfaction, parent satisfaction and efficacy and child behaviour suggested this training as an effective intervention for these teams. Participants reported improvements and the effective implementation of strategies after involvement in the workshops. This innovative model suggests potential for teams struggling with communication challenges in addressing problem behaviours in children with autism.
10. Scerif G, Longhi E, Cole V, Karmiloff-Smith A, Cornish K. {{Attention across modalities as a longitudinal predictor of early outcomes: the case of fragile X syndrome}}. {J Child Psychol Psychiatry}. 2011 Dec 29.
Background: Fragile X syndrome (FXS) is an early diagnosed monogenic disorder, associated with a striking pattern of cognitive/attentional difficulties and a high risk of poor behavioural outcomes. FXS therefore represents an ideal model disorder to study prospectively the impact of early attention deficits on behaviour. Methods: Thirty-seven boys with FXS aged 4-10 years and 74 typically developing (TD) boys took part. Study 1 was designed to assess visual and auditory attention at two time-points, 1 year apart. Study 2 investigated attention to multimodal information. Both tested attention markers as longitudinal predictors of risk for poor behaviour in FXS. Results: Children with FXS attended less well than mental-age matched TD boys and experienced greater difficulties with auditory compared to visual stimuli. In addition, unlike TD children, they did not benefit from multimodal information. Attention markers were significant predictors of later behavioural difficulties in boys with FXS. Conclusions: Findings demonstrate, for the first time, greater difficulties with auditory attention and atypical processing of multimodal information, in addition to pervasive global attentional difficulties in boys with FXS. Attention predicted outcomes longitudinally, underscoring the need to dissect what drives differing developmental trajectories for individual children within a seemingly homogeneous group.
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11. Weigelt S, Koldewyn K, Kanwisher N. {{Face identity recognition in autism spectrum disorders: A review of behavioral studies}}. {Neuroscience and biobehavioral reviews}. 2011 Dec 23.
Face recognition – the ability to recognize a person from their facial appearance – is essential for normal social interaction. Face recognition deficits have been implicated in the most common disorder of social interaction: autism. Here we ask: is face identity recognition in fact impaired in people with autism? Reviewing behavioral studies we find no strong evidence for a qualitative difference in how facial identity is processed between those with and without autism: markers of typical face identity recognition, such as the face inversion effect, seem to be present in people with autism. However, quantitatively – i.e., how well facial identity is remembered or discriminated – people with autism perform worse than typical individuals. This impairment is particularly clear in face memory and in face perception tasks in which a delay intervenes between sample and test, and less so in tasks with no memory demand. Although some evidence suggests that this deficit may be specific to faces, further evidence on this question is necessary.
