1. Cheslack-Postava K, Rantakokko PV, Hinkka-Yli-Salomaki S, Surcel HM, McKeague IW, Kiviranta HA, Sourander A, Brown AS. {{Maternal Serum Persistent Organic Pollutants in the Finnish Prenatal Study of Autism: A Pilot Study}}. {Neurotoxicol Teratol};2013 (Apr 13)
Recent research emphasizes the contribution of environmental as well as genetic factors to the etiology of autism but studies testing associations between chemical exposures and autism have been limited. Prenatal exposure to persistent organic pollutants (POPs) has previously been associated with decrements in cognitive and developmental performance. We conducted a pilot study in the Finnish Prenatal Study of Autism (FiPS-A). Seventy-five cases with autism and 75 controls matched on sex, birth year, urbanization and maternal age were sampled from first-born children in the Finnish Maternity Cohort, which includes over 1 million births. The study sample included births occurring from 1991 to 2000. Subjects were followed up for autism through 2007. DDT, DDE, PCB-118, PCB-138, PCB-153, PCB-156, PCB-170, PCB-180, hexachlorobenzene, and BDE-47 were measured in archived maternal serum samples taken during pregnancy using gas chromatography-high resolution mass spectrometry. Correlations between pollutant measures were assessed and mechanistically-related weighting schemes for summarizing PCB levels were compared. Case and control differences were assessed using graphical and statistical methods. All analytes, with the exception of DDT and BDE-47, were detected above the limit of quantification in all samples. The correlation between levels of individual PCB congeners and weighted summary measures was high (0.71-1.00). Paired t-tests revealed no significant differences between cases and controls for log-transformed mean values of any analyte; however, in an adjusted model the odds ratio for autism was 1.91 (p=0.29) and 1.79 (p=0.36) respectively, for subjects with total PCBs and DDE above the 90th percentile of control values. Levels of prenatal PCB exposure in FIPS-A were similar to levels previously correlated with poorer neurodevelopmental measures in other populations. Further study in a larger sample will be required to fully determine whether exposure to high POP levels are associated with autism diagnosis in the population.
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2. Jakab A, Emri M, Spisak T, Szeman-Nagy A, Beres M, Kis SA, Molnar P, Berenyi E. {{Autistic traits in neurotypical adults: correlates of graph theoretical functional network topology and white matter anisotropy patterns}}. {PLoS One};2013;8(4):e60982.
Attempts to explicate the neural abnormalities behind autism spectrum disorders frequently revealed impaired brain connectivity, yet our knowledge is limited about the alterations linked with autistic traits in the non-clinical population. In our study, we aimed at exploring the neural correlates of dimensional autistic traits using a dual approach of diffusion tensor imaging (DTI) and graph theoretical analysis of resting state functional MRI data. Subjects were sampled from a public neuroimaging dataset of healthy volunteers. Inclusion criteria were adult age (age: 18-65), availability of DTI and resting state functional acquisitions and psychological evaluation including the Social Responsiveness Scale (SRS) and Autistic Spectrum Screening Questionnaire (ASSQ). The final subject cohort consisted of 127 neurotypicals. Global brain network structure was described by graph theoretical parameters: global and average local efficiency. Regional topology was characterized by degree and efficiency. We provided measurements for diffusion anisotropy. The association between autistic traits and the neuroimaging findings was studied using a general linear model analysis, controlling for the effects of age, gender and IQ profile. Significant negative correlation was found between the degree and efficiency of the right posterior cingulate cortex and autistic traits, measured by the combination of ASSQ and SRS scores. Autistic phenotype was associated with the decrease of whole-brain local efficiency. Reduction of diffusion anisotropy was found bilaterally in the temporal fusiform and parahippocampal gyri. Numerous models describe the autistic brain connectome to be dominated by reduced long-range connections and excessive short-range fibers. Our finding of decreased efficiency supports this hypothesis although the only prominent effect was seen in the posterior limbic lobe, which is known to act as a connector hub. The neural correlates of the autistic trait in neurotypicals showed only limited similarities to the reported findings in clinical populations with low functioning autism.
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3. Kasari C, Smith T. {{Interventions in schools for children with autism spectrum disorder: Methods and recommendations}}. {Autism};2013 (Apr 16)
Although researchers have identified many promising teaching strategies and intervention programs for children with autism spectrum disorder, research on implementation of these interventions in school settings has lagged. Barriers to implementation include incompletely developed interventions, limited evidence of their utility in promoting long-term and meaningful change, and poor fit with school environments. To overcome these barriers, interventions need to be detailed in manuals that identify key components yet allow for flexibility, and studies need to evaluate long-term, real-life outcomes. Innovative research strategies also may be important, particularly carrying out research on new interventions in school settings from the outset, conducting partial effectiveness trials in which study personnel administer interventions in school settings, using community-partnered participatory research approaches, and redesigning interventions in a modular format.
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4. Liu L, Sabo A, Neale BM, Nagaswamy U, Stevens C, Lim E, Bodea CA, Muzny D, Reid JG, Banks E, Coon H, Depristo M, Dinh H, Fennel T, Flannick J, Gabriel S, Garimella K, Gross S, Hawes A, Lewis L, Makarov V, Maguire J, Newsham I, Poplin R, Ripke S, Shakir K, Samocha KE, Wu Y, Boerwinkle E, Buxbaum JD, Cook EH, Jr., Devlin B, Schellenberg GD, Sutcliffe JS, Daly MJ, Gibbs RA, Roeder K. {{Analysis of Rare, Exonic Variation amongst Subjects with Autism Spectrum Disorders and Population Controls}}. {PLoS Genet};2013 (Apr);9(4):e1003443.
We report on results from whole-exome sequencing (WES) of 1,039 subjects diagnosed with autism spectrum disorders (ASD) and 870 controls selected from the NIMH repository to be of similar ancestry to cases. The WES data came from two centers using different methods to produce sequence and to call variants from it. Therefore, an initial goal was to ensure the distribution of rare variation was similar for data from different centers. This proved straightforward by filtering called variants by fraction of missing data, read depth, and balance of alternative to reference reads. Results were evaluated using seven samples sequenced at both centers and by results from the association study. Next we addressed how the data and/or results from the centers should be combined. Gene-based analyses of association was an obvious choice, but should statistics for association be combined across centers (meta-analysis) or should data be combined and then analyzed (mega-analysis)? Because of the nature of many gene-based tests, we showed by theory and simulations that mega-analysis has better power than meta-analysis. Finally, before analyzing the data for association, we explored the impact of population structure on rare variant analysis in these data. Like other recent studies, we found evidence that population structure can confound case-control studies by the clustering of rare variants in ancestry space; yet, unlike some recent studies, for these data we found that principal component-based analyses were sufficient to control for ancestry and produce test statistics with appropriate distributions. After using a variety of gene-based tests and both meta- and mega-analysis, we found no new risk genes for ASD in this sample. Our results suggest that standard gene-based tests will require much larger samples of cases and controls before being effective for gene discovery, even for a disorder like ASD.
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5. Mandell D, Stahmer AC, Shin S, Xie M, Reisinger E, Marcus SC. {{The role of treatment fidelity on outcomes during a randomized field trial of an autism intervention}}. {Autism};2013 (Apr 16)
This randomized field trial comparing Strategies for Teaching based on Autism Research and Structured Teaching enrolled educators in 33 kindergarten-through-second-grade autism support classrooms and 119 students, aged 5-8 years in the School District of Philadelphia. Students were assessed at the beginning and end of the academic year using the Differential Ability Scales. Program fidelity was measured through video coding and use of a checklist. Outcomes were assessed using linear regression with random effects for classroom and student. Average fidelity was 57% in Strategies for Teaching based on Autism Research classrooms and 48% in Structured Teaching classrooms. There was a 9.2-point (standard deviation = 9.6) increase in Differential Ability Scales score over the 8-month study period, but no main effect of program. There was a significant interaction between fidelity and group. In classrooms with either low or high program fidelity, students in Strategies for Teaching based on Autism Research experienced a greater gain in Differential Ability Scales score than students in Structured Teaching (11.2 vs 5.5 points and 11.3 vs 8.9 points, respectively). In classrooms with moderate fidelity, students in Structured Teaching experienced a greater gain than students in Strategies for Teaching based on Autism Research (10.1 vs 4.4 points). The results suggest significant variability in implementation of evidence-based practices, even with supports, and also suggest the need to address challenging issues related to implementation measurement in community settings.
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6. Mucchetti CA. {{Adapted shared reading at school for minimally verbal students with autism}}. {Autism};2013 (Apr 16)
Almost nothing is known about the capacity of minimally verbal students with autism to develop literacy skills. Shared reading is a regular practice in early education settings and is widely thought to encourage language and literacy development. There is some evidence that children with severe disabilities can be engaged in adapted shared reading activities. The current study examines the impact of teacher-led adapted shared reading activities on engagement and story comprehension in minimally verbal 5-6-year-old children with autism using a multiple baseline/alternating treatment design. Four students and three teachers participated. Teachers conducted adapted shared reading activities with modified books (visual supports, three-dimensional objects, simplified text) and used specific strategies for increasing student engagement. Student performance during adapted activities was compared to performance during standard shared reading sessions. Results: All four students showed increased story comprehension and engagement during adapted shared reading. Average percentage of session engaged was 87%-100% during adapted sessions, compared with 41%-52% during baseline. Average number of correct responses to story comprehension questions was 4.2-4.8 out of 6 during adapted sessions compared with 1.2-2 during baseline. Visual supports, tactile objects, and specific teaching strategies offer ways for minimally verbal students to meaningfully participate in literacy activities. Future research should investigate adapted shared reading activities implemented classroomwide as well as joint engagement, language, and literacy outcomes after using such activities over time.
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7. Pequegnat B, Sagermann M, Valliani M, Toh M, Chow H, Allen-Vercoe E, Monteiro MA. {{A vaccine and diagnostic target for Clostridium bolteae, an autism-associated bacterium}}. {Vaccine};2013 (Apr 18)
Constipation and diarrhea are common in autistic patients. Treatment with antibiotics against bacteria appears to partially alleviate autistic-related symptoms. Clostridium bolteae is a bacterium that has been shown to be overabundant in the intestinal tract of autistic children suffering from gastric intestinal ailments, and as such is an organism that could potentially aggravate gastrointestinal symptoms. We set out to investigate the cell-wall polysaccharides of C. bolteae in order to evaluate their structure and immunogenicity. Our explorations revealed that C. bolteae produces a conserved specific capsular polysaccharide comprised of rhamnose and mannose units: [–>3)-alpha-D-Manp-(1–>4)-beta-d-Rhap-(1–>], which is immunogenic in rabbits. These findings are the first description of a C. bolteae immunogen and indicate the prospect of using this polysaccharide as a vaccine to reduce or prevent C. bolteae colonization of the intestinal tract in autistic patients, and as a diagnostic marker for the rapid detection of C. bolteae in a clinical setting.
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8. Shi L, Zhang X, Golhar R, Otieno FG, He M, Hou C, Kim C, Keating B, Lyon GJ, Wang K, Hakonarson H. {{Whole-genome sequencing in an autism multiplex family}}. {Mol Autism};2013 (Apr 18);4(1):8.
BACKGROUND: Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental disorders that affect 1 in 88 children in the US. Previous exome sequencing studies on family trios have implicated a role for rare, de-novo mutations in the pathogenesis of autism. METHODS: To examine the utility of whole-genome sequencing to identify inherited disease candidate variants and genes, we sequenced two probands from a large pedigree, including two parents and eight children. We evaluated multiple analytical strategies to identify a prioritized list of candidate genes. RESULTS: By assuming a recessive model of inheritance, we identified seven candidate genes shared by the two probands. We also evaluated a different analytical strategy that does not require the assumption of disease model, and identified a list of 59 candidate variants that may increase susceptibility to autism. Manual examination of this list identified ANK3 as the most likely candidate gene. Finally, we identified 33 prioritized non-coding variants such as those near SMG6 and COQ5, based on evolutionary constraint and experimental evidence from ENCODE. Although we were unable to confirm rigorously whether any of these genes indeed contribute to the disease, our analysis provides a prioritized shortlist for further validation studies. CONCLUSIONS: Our study represents one of the first whole-genome sequencing studies in autism leveraging a large family-based pedigree. These results provide for a discussion on the relative merits of finding de-novo mutations in sporadic cases versus finding inherited mutations in large pedigrees, in the context of neuropsychiatric and neurodevelopmental diseases.
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9. Wang SM, Li M, Yang YL, Pan H, Liu J, Pan KF, Bu DF. {{[Mutational analysis of the methyl-CpG-binding protein 2 (MECP2)gene in male autism patients]}}. {Beijing Da Xue Xue Bao};2013 (Apr 18);45(2):197-201.
OBJECTIVE: To investigate mutations in the methyl-CpG-binding protein 2 (MECP2) gene in male autism patients by PCR, denaturing high-performance liquid chromatography (DHPLC) and sequencing to explore the role of mutations in MECP2 in autism patients. METHODS: We recruited DNA samples from 44 male autism patients who matched the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DMS-IV) standards. DHPLC was used to screen the mutations in MECP2 gene, and DNA sequencing was performed for the samples with positive DHPLC results. The family members were further investigated in the patients with missense mutations in MECP2 gene. RESULTS: Four cases were found to have mutations in MECP2 gene, including missense mutations of c.590C>T(T197M)in one case and c.602C>T(A201V)in one case, and synonymous mutations of c.1053C>G in one case and c.897C>T in one case. In addition, we found C>T variation in intron 3 at the +74 bp before exon 4, a SNP (rs2071569) usually detected in Chinese population. In the case with c.602C>T(A201V)mutation, his mother and maternal grandfather had the same mutation. His mother had normal phenotype, but his maternal grandfather had depressive disease. CONCLUSION: Mutations in MECP2 are present in male autism patients with relatively higher prevalence, suggesting that these mutations may play roles in the pathogenesis of autism.
