1. Boersma M, Kemner C, De Reus M, Collin G, Snijders T, Hofman D, Buitelaar J, Stam C, van den Heuvel M. {{Disrupted functional brain networks in autistic toddlers}}. {Brain connectivity}. 2012 Dec 23.
Communication and integration of information between brain regions plays a key role in healthy brain function. Conversely, disruption in brain communication may lead to cognitive and behavioral problems. Autism is a neurodevelopmental disorder that is characterized by impaired social interactions and aberrant basic information processing. Aberrant brain connectivity patterns have indeed been hypothesized to be a key neural underpinning of autism. In this study, graph analytical tools are used to explore the possible deviant functional brain network organization in autism at a very early stage of brain development. Electroencephalography (EEG) recordings in 12 toddlers with autism (mean age 3.5 years) and 19 control subjects were used to assess interregional functional brain connectivity, with functional brain networks constructed at the level of temporal synchronization between brain regions underlying the EEG electrodes. Children with autism showed significantly increased normalized path length and reduced normalized clustering, suggesting a reduced global communication capacity already during early brain development. In addition, whole brain connectivity was found to be significantly reduced in these young patients suggesting an overall under-connectivity of functional brain networks in autism. Our findings support the hypothesis of abnormal neural communication in autism, with deviating effects already present at the early stages of brain development.
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2. Buxbaum JD, Daly MJ, Devlin B, Lehner T, Roeder K, State MW, The Autism Sequencing C. {{The Autism Sequencing Consortium: Large-Scale, High-Throughput Sequencing in Autism Spectrum Disorders}}. {Neuron}. 2012 Dec 20;76(6):1052-6.
Research during the past decade has seen significant progress in the understanding of the genetic architecture of autism spectrum disorders (ASDs), with gene discovery accelerating as the characterization of genomic variation has become increasingly comprehensive. At the same time, this research has highlighted ongoing challenges. Here we address the enormous impact of high-throughput sequencing (HTS) on ASD gene discovery, outline a consensus view for leveraging this technology, and describe a large multisite collaboration developed to accomplish these goals. Similar approaches could prove effective for severe neurodevelopmental disorders more broadly.
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3. Das DK, Raha S, Sanghavi D, Maitra A, Udani V. {{Spectrum of MECP2 Gene Mutations in a Cohort of Indian Patients with Rett Syndrome: Report of Two Novel Mutations}}. {Gene}. 2012 Dec 19.
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder, primarily affecting females and characterized by developmental regression, epilepsy, stereotypical hand movements, and motor abnormalities. Its prevalence is about 1 in 10,000 female births. Rett Syndrome is caused by mutations within methyl CpG-binding protein 2 (MECP2) gene, Over 270 individual nucleotide changes which cause pathogenic mutations have been reported. However, eight most commonly occurring missense and nonsense mutations account for almost 70% of all patients. We screened 90 individuals with Rett syndrome phenotype. A total of 19 different MECP2 mutations and polymorphisms were identified in 27 patients. Of the 19 mutations, we identified 7 (37%) frameshift, 6 (31%) nonsense, 14 (74%) missense mutations and one duplication (5%). The most frequent pathogenic changes were: p.T158M (11%), p.R133C (7.4%), p.R306C (7.4%) missense and p.R168X (11%), p.R255X (7.4%) nonsense mutations. We have identified two novel mutations namely p.385-388delPLPP present in an atypical patients and p.Glu290AlafsX38 present in a classical patient of Rett syndrome. Sequence homology for p.385-388delPLPP mutation revealed that these 4 amino acids were conserved across mammalian species. This indicated the importance of these 4 amino acids in structure and function of the protein. A novel variant p.T479T was also identified in a patient with atypical Rett syndrome. A total of 62 (69%) patients remained without molecular genetic diagnosis that necessitates further search for mutations in other genes like CDKL5 and FOXG1 known to cause Rett phenotype. The majority of mutations are detected in exon 4 and only one mutation was present in exon 3. Therefore, our study suggests the need for screening exon 4 of MECP2 as first line of diagnosis in these patients.
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4. Holt JM, Christensen KM. {{Utahns’ understanding of autism spectrum disorder}}. {Disability and health journal}. 2013 Jan;6(1):52-62.
BACKGROUND: The general public has numerous misconceptions and a lack of awareness and understanding regarding some of the prevalence, characteristics, and treatments of autism. As a result, education and awareness activities to increase the general public’s understanding and awareness of autism are important. This study was conducted throughout Utah to inform public education and awareness efforts being planned as part of Utah’s State Plan for Improving Outcomes for Individuals with Autism Spectrum Disorders and Development Disorders. OBJECTIVE: The purpose of this study was to identify public awareness and knowledge of ASD in Utah, such as the public’s understanding of the prevalence, characteristics, and treatments of autism, as well as the sources of this information. METHODS: To identify public perceptions and attitudes of autism spectrum disorder, 1001 Utah residents 18 years of age or older were surveyed using a 32-question statewide random-digit dialed telephone survey. RESULTS: The percentages of responses for 15 of the 20 autism-related questions are presented by ethnicity (Hispanic or Latino), education level, and income level. CONCLUSIONS: The study indicates that autism education efforts need to address the least understood aspects of autism; the causes of autism, how autism is diagnosed, and how autism is treated. Radio or TV outlets are more effective, particularly so with Hispanic or Latinos and populations with less education. Medical professionals are also an important resource for families with direct autism-related needs.
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5. Kaartinen M, Puura K, Helminen M, Salmelin R, Pelkonen E, Juujarvi P. {{Reactive aggression among children with and without autism spectrum disorder}}. {J Autism Dev Disord}. 2012 Dec 21.
Twenty-seven boys and eight girls with ASD and thirty-five controls matched for gender, age and total score intelligence were studied to ascertain whether boys and girls with ASD display stronger reactive aggression than boys and girls without ASD. Participants performed a computerized version of the Pulkkinen aggression machine that examines the intensity of reactive aggression against attackers of varying gender and age. Relative to the control group boys, the boys with ASD reacted with more serious forms of aggression when subjected to mild aggressive attacks and did not consider a child attacker’s opposite sex an inhibitory factor. The girls with ASD, on the other hand, reacted less aggressively than the girls without ASD. According to the results boys with ASD may not follow the typical development in cognitive regulation of reactive aggression.
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6. Maenner MJ, Smith LE, Hong J, Makuch R, Greenberg JS, Mailick MR. {{Evaluation of an activities of daily living scale for adolescents and adults with developmental disabilities}}. {Disability and health journal}. 2013 Jan;6(1):8-17.
BACKGROUND: Activity limitations are an important and useful dimension of disability, but there are few validated measures of activity limitations for adolescents and adults with developmental disabilities. OBJECTIVE/HYPOTHESIS: To describe the development of the Waisman Activities of Daily Living (W-ADL) Scale for adolescents and adults with developmental disabilities, and systematically evaluate its measurement properties according to an established set of criteria. METHODS: The W-ADL was administered among four longitudinally studied groups of adolescents and adults with developmental disabilities: 406 with autism; 147 with fragile-X syndrome; 169 with Down syndrome; and 292 with intellectual disability of other or unknown origin. The W-ADL contains 17 activities and each is rated on a 3-point scale (0 = « does not do at all », 1 = « does with help », 2 = « independent »), and a standard set of criteria were used to evaluate its measurement properties. RESULTS: Across the disability groups, Cronbach’s alphas ranged from 0.88 to 0.94, and a single-factor structure was most parsimonious. The W-ADL was reliable over time, with weighted kappas between 0.92 and 0.93. Criterion and construct validity were supported through substantial associations with the Vineland Screener, need for respite services, caregiving burden, and competitive employment. No floor or ceiling effects were present. There were significant group differences in W-ADL scores by maternally reported level of intellectual disability (mild, moderate, severe, profound). CONCLUSIONS: The W-ADL exceeded the recommended threshold for each quality criterion the authors evaluated. This freely available tool is an efficient measure of activities of daily living for surveys and epidemiological research concerning adolescents and adults with developmental disabilities.
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7. Michaelson JJ, Shi Y, Gujral M, Zheng H, Malhotra D, Jin X, Jian M, Liu G, Greer D, Bhandari A, Wu W, Corominas R, Peoples A, Koren A, Gore A, Kang S, Lin GN, Estabillo J, Gadomski T, Singh B, Zhang K, Akshoomoff N, Corsello C, McCarroll S, Iakoucheva LM, Li Y, Wang J, Sebat J. {{Whole-genome sequencing in autism identifies hot spots for de novo germline mutation}}. {Cell}. 2012 Dec 21;151(7):1431-42.
De novo mutation plays an important role in autism spectrum disorders (ASDs). Notably, pathogenic copy number variants (CNVs) are characterized by high mutation rates. We hypothesize that hypermutability is a property of ASD genes and may also include nucleotide-substitution hot spots. We investigated global patterns of germline mutation by whole-genome sequencing of monozygotic twins concordant for ASD and their parents. Mutation rates varied widely throughout the genome (by 100-fold) and could be explained by intrinsic characteristics of DNA sequence and chromatin structure. Dense clusters of mutations within individual genomes were attributable to compound mutation or gene conversion. Hypermutability was a characteristic of genes involved in ASD and other diseases. In addition, genes impacted by mutations in this study were associated with ASD in independent exome-sequencing data sets. Our findings suggest that regional hypermutation is a significant factor shaping patterns of genetic variation and disease risk in humans. PAPERFLICK:
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8. Santini E, Huynh TN, Macaskill AF, Carter AG, Pierre P, Ruggero D, Kaphzan H, Klann E. {{Exaggerated translation causes synaptic and behavioural aberrations associated with autism}}. {Nature}. 2012 Dec 23.
Autism spectrum disorders (ASDs) are an early onset, heterogeneous group of heritable neuropsychiatric disorders with symptoms that include deficits in social interaction skills, impaired communication abilities, and ritualistic-like repetitive behaviours. One of the hypotheses for a common molecular mechanism underlying ASDs is altered translational control resulting in exaggerated protein synthesis. Genetic variants in chromosome 4q, which contains the EIF4E locus, have been described in patients with autism. Importantly, a rare single nucleotide polymorphism has been identified in autism that is associated with increased promoter activity in the EIF4E gene. Here we show that genetically increasing the levels of eukaryotic translation initiation factor 4E (eIF4E) in mice results in exaggerated cap-dependent translation and aberrant behaviours reminiscent of autism, including repetitive and perseverative behaviours and social interaction deficits. Moreover, these autistic-like behaviours are accompanied by synaptic pathophysiology in the medial prefrontal cortex, striatum and hippocampus. The autistic-like behaviours displayed by the eIF4E-transgenic mice are corrected by intracerebroventricular infusions of the cap-dependent translation inhibitor 4EGI-1. Our findings demonstrate a causal relationship between exaggerated cap-dependent translation, synaptic dysfunction and aberrant behaviours associated with autism.
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9. Sato JR, Hoexter MQ, Oliveira PP, Jr., Brammer MJ, Consortium MA, Murphy D, Ecker C. {{Inter-regional cortical thickness correlations are associated with autistic symptoms: A machine-learning approach}}. {Journal of psychiatric research}. 2012 Dec 19.
The investigation of neural substrates of autism spectrum disorder using neuroimaging has been the focus of recent literature. In addition, machine-learning approaches have also been used to extract relevant information from neuroimaging data. There are only few studies directly exploring the inter-regional structural relationships to identify and characterize neuropsychiatric disorders. In this study, we concentrate on addressing two issues: (i) a novel approach to extract individual subject features from inter-regional thickness correlations based on structural magnetic resonance imaging (MRI); (ii) using these features in a machine-learning framework to obtain individual subject prediction of a severity scores based on neurobiological criteria rather than behavioral information. In a sample of 82 autistic patients, we have shown that structural covariances among several brain regions are associated with the presence of the autistic symptoms. In addition, we also demonstrated that structural relationships from the left hemisphere are more relevant than the ones from the right. Finally, we identified several brain areas containing relevant information, such as frontal and temporal regions. This study provides evidence for the usefulness of this new tool to characterize neuropsychiatric disorders.
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10. Scattoni ML, Martire A, Cartocci G, Ferrante A, Ricceri L. {{Reduced social interaction, behavioural flexibility and BDNF signalling in the BTBR T+tf/J strain, a mouse model of autism}}. {Behavioural brain research}. 2012 Dec 25.
Autism is a neurodevelopmental disorder characterized by social and communication impairments and repetitive behaviours. The inbred BTBR T+tf/J (BTBR) strain, a putative mouse model of autism, exhibits lower social interactions, higher repetitive self-grooming levels and unusual pattern of vocalizations as compared to C57BL/6J strain. First aim of the present study was to evaluate at adolescence (postnatal days 30-35) male BTBR and C57BL/6J performances in two different tasks involving either investigation of social cues (same strain partners) or non social ones (inanimate objects). In the social interaction test, BTBR mice showed a reduction of investigation of the social partner, due to a selective reduction of head sniffing, associated with a decrease in ultrasonic vocalizations. By contrast, no strain differences were detected in object investigations. Second aim of the study was to evaluate adult male BTBR and C57BL/6J performances in a fear conditioning task. Strain differences were evident during contextual retest: these strain differences primarily suggested a lack of behavioural flexibility in BTBR mice (i.e. realizing the occurrence of changes in the experimental paradigm). Subsequent electrophysiological analysis in hippocampal slices from adult BTBR and C57BL/6J mice revealed a significant reduction of Brain Derived Neurotrophic Factor (BDNF)-induced potentiation of synaptic transmission in BTBR mice. BDNF and tyrosine kinase B (TrkB) protein levels measured in the hippocampal region were also lower in BTBR as compared to C57BL/6J mice. These data confirm the presence of low levels of direct interaction with social stimuli in BTBR mice at adolescence, in the absence of any strain difference as for investigation of physical objects. At adulthood in BTBR mice clear signs of behavioural inflexibility were evident whereas both biochemical and electrophysiological data point to decreased BDNF signalling (likely due to a reduction in TrkB levels) in the hippocampus of this mouse strain.
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11. Tsai NP, Wilkerson JR, Guo W, Maksimova MA, Demartino GN, Cowan CW, Huber KM. {{Multiple Autism-Linked Genes Mediate Synapse Elimination via Proteasomal Degradation of a Synaptic Scaffold PSD-95}}. {Cell}. 2012 Dec 21;151(7):1581-94.
The activity-dependent transcription factor myocyte enhancer factor 2 (MEF2) induces excitatory synapse elimination in mouse neurons, which requires fragile X mental retardation protein (FMRP), an RNA-binding protein implicated in human cognitive dysfunction and autism. We report here that protocadherin 10 (Pcdh10), an autism-spectrum disorders gene, is necessary for this process. MEF2 and FMRP cooperatively regulate the expression of Pcdh10. Upon MEF2 activation, PSD-95 is ubiquitinated by the ubiquitin E3 ligase murine double minute 2 (Mdm2) and then binds to Pcdh10, which links it to the proteasome for degradation. Blockade of the Pcdh10-proteasome interaction inhibits MEF2-induced PSD-95 degradation and synapse elimination. In FMRP-lacking neurons, elevated protein levels of eukaryotic translation elongation factor 1 alpha (EF1alpha), an Mdm2-interacting protein and FMRP target mRNA, sequester Mdm2 and prevent MEF2-induced PSD-95 ubiquitination and synapse elimination. Together, our findings reveal roles for multiple autism-linked genes in activity-dependent synapse elimination.
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12. Wiggins LD, Piazza V, Robins DL. {{Comparison of a broad-based screen versus disorder-specific screen in detecting young children with an autism spectrum disorder}}. {Autism}. 2012 Dec 21.
The goals of our study were to (a) compare agreement between autism spectrum disorder diagnosis and outcome of the Modified Checklist for Autism in Toddlers and Parents Evaluation of Developmental Status in a sample of toddlers and (b) examine specific concerns noted for toddlers who screened negative on the Modified Checklist for Autism in Toddlers or Parents Evaluation of Developmental Status but were later diagnosed with autism spectrum disorder. Participants were administered the Modified Checklist for Autism in Toddlers and Parents Evaluation of Developmental Status during well-child visits. Families were invited for a clinical evaluation if autism spectrum disorder symptoms were noted on the Modified Checklist for Autism in Toddlers and Modified Checklist for Autism in Toddlers Follow-Up Interview or if autism spectrum disorder concerns were noted by the pediatrician. Fifty-two children completed the Modified Checklist for Autism in Toddlers, Parents Evaluation of Developmental Status, and a clinical evaluation, and 30 of these children were diagnosed with an autism spectrum disorder. Modified Checklist for Autism in Toddlers results showed higher agreement with autism spectrum disorder diagnosis than any individual Parents Evaluation of Developmental Status screen result, although the latter detected many children with other developmental concerns. Children who screened negative on the Modified Checklist for Autism in Toddlers or Parents Evaluation of Developmental Status but were diagnosed with autism spectrum disorder had concerns noted in sensory response and proto-declarative pointing that can be considered in the context of screen results. In sum, our findings support universal autism spectrum disorder-specific screening in addition to general developmental screening and offer considerations to encourage early identification of toddlers with autism spectrum disorder.
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13. Zablotsky B, Anderson C, Law P. {{The Association Between Child Autism Symptomatology, Maternal Quality of Life, and Risk for Depression}}. {J Autism Dev Disord}. 2012 Dec 21.
Parents raising children with autism spectrum disorders (ASDs) have been shown to experience high levels of stress and report a lower quality of life. The current study examined the association between child autism symptomatology, mother’s quality of life, and mother’s risk for depression in a sample of 1,110 mothers recruited from a web-based registry of families with children with an ASD. Higher autism symptomatology and a greater number of co-occurring psychiatric disorders in the child were associated with an increased risk for current treatment of maternal depression and a lower maternal quality of life. The results highlight the importance of screening for depression, particularly in mothers of children with ASD and mental health and behavioral challenges.
