1. Alrayes N, Mohamoud HS, Ahmed S, Almramhi MM, Shuaib TM, Wang J, Al-Aama JY, Everett K, Nasir J, Jelani M. {{The alkylglycerol monooxygenase (AGMO) gene previously involved in autism also causes a novel syndromic form of primary microcephaly in a consanguineous Saudi family}}. {J Neurol Sci}. 2016; 363: 240-4.
Autosomal recessive primary microcephaly (MCPH) refers to a genetically heterogeneous group of neurodevelopmental disorders in which patients exhibit a marked decrease in occipitofrontal head circumference at birth and a variable degree of intellectual disability. To date, 18 genes have been reported for MCPH worldwide. We enrolled a consanguineous family from Saudi Arabia presenting with primary microcephaly, developmental delay, short stature and intellectual disability. Whole exome sequencing (WES) with 100x coverage was performed on two affected siblings after defining common regions of homozygosity through genome-wide single nucleotide polymorphism (SNP) microarray genotyping. WES data analysis, confirmed by subsequent Sanger sequence validation, identified a novel homozygous deletion mutation (c.967delA; p.Glu324Lysfs12*) in exon 10 of the alkylglycerol monooxygenase (AGMO) gene on chromosome 7p21.2. Population screening of 178 ethnically matched control chromosomes and consultation of the Exome Aggregation Consortium database, containing 60,706 individuals’ exomes worldwide, confirmed that this mutation was not present outside the family. To the best of our knowledge, this is the first evidence of an AGMO mutation underlying primary microcephaly and intellectual disability in humans. Our findings further expand the genetic heterogeneity of MCPH in familial cases.
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2. Bolkan S, Gordon JA. {{Neuroscience: Untangling autism}}. {Nature}. 2016.
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3. Chen MH, Lan WH, Hsu JW, Huang KL, Su TP, Li CT, Lin WC, Tsai CF, Tsai SJ, Lee YC, Chen YS, Pan TL, Chang WH, Chen TJ, Bai YM. {{Risk of Developing Type 2 Diabetes in Adolescents and Young Adults With Autism Spectrum Disorder: A Nationwide Longitudinal Study}}. {Diabetes Care}. 2016.
OBJECTIVE: Studies have suggested the association between autism spectrum disorder (ASD) and type 2 diabetes mellitus (DM)-related risk factors, such as obesity and dyslipidemia. However, the association between ASD and type 2 DM remains unknown. RESEARCH DESIGN AND METHODS: We used the Taiwan National Health Insurance Research Database for enrolling 6,122 adolescents and young adults with ASD and 24,488 age- and sex-matched control subjects between 2002 and 2009 and monitored them until the end of 2011. Participants who developed type 2 DM during the follow-up period were identified. RESULTS: Adolescents (hazard ratio [HR] 2.71 [95% CI 1.64-4.48]) and young adults (HR 5.31 [95% CI 2.85-9.90]) with ASD had a higher risk of developing type 2 DM than those without ASD, after adjustment for demographic data, atypical antipsychotics use, and medical comorbidities. Sensitivity analyses after excluding first year (HR 3.03 [95% CI 2.03-4.51]) and first 3-year (HR 2.62 [95% CI 1.62-4.23]) observation periods were consistent. Short-term (HR 1.97 [95% CI 1.20-3.23]) and long-term (HR 1.64 [95% CI 1.02-2.63]) use of atypical antipsychotics were associated with a higher likelihood of subsequent type 2 DM. CONCLUSIONS: Adolescents and young adults with ASD were more likely to develop type 2 DM during the follow-up. In addition, those with ASD using atypical antipsychotics exhibited a high risk. Therefore, further research is necessary to investigate the common pathophysiology of ASD and type 2 DM.
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4. Coenraads M. {{A Mother’s Story: Fighting Rett Syndrome Head On}}. {Hum Gene Ther}. 2016; 27(3): 214-8.
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5. Furukawa TA. {{Diagnosing autism spectrum disorder (ASD) among adults}}. {Evid Based Ment Health}. 2016.
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6. Garcia-Lopez C, Sarria E, Pozo P. {{Parental Self-Efficacy and Positive Contributions Regarding Autism Spectrum Condition: An Actor-Partner Interdependence Model}}. {J Autism Dev Disord}. 2016.
Couples affect each other cognitively, emotionally and behaviorally. The goal of this study is to test the benefits and potential use of the actor-partner interdependence model in examining how parental self-efficacy and positive contributions of fathers and mothers of children with Autism Spectrum Condition influence each other’s psychological adaptation. The sample includes 76 Spanish couples who completed validated questionnaires measuring predictors, i.e., self-efficacy and positive contributions, and adaptation outcomes i.e., stress, anxiety, depression and psychological well-being. Multilevel analysis revealed many actor and some partner effects of parental self-efficacy and positive contributions to be important determinants of adaptation above and beyond child and sociodemographic factors, and as such, these effects should be targeted in clinical intervention programs.
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7. Harker CM, Ibanez LV, Nguyen TP, Messinger DS, Stone WL. {{The Effect of Parenting Style on Social Smiling in Infants at High and Low Risk for ASD}}. {J Autism Dev Disord}. 2016.
This study examined how parenting style at 9 months predicts growth in infant social engagement (i.e., social smiling) between 9 and 18 months during a free-play interaction in infants at high (HR-infants) and low (LR-infants) familial risk for autism spectrum disorder (ASD). Results indicated that across all infants, higher levels of maternal responsiveness were concurrently associated with higher levels of social smiling, while higher levels of maternal directiveness predicted slower growth in social smiling. When accounting for maternal directiveness, which was higher in mothers of HR-infants, HR-infants exhibited greater growth in social smiling than LR-infants. Overall, each parenting style appears to make a unique contribution to the development of social engagement in infants at high- and low-risk for ASD.
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8. Ipser A, Ring M, Murphy J, Gaigg SB, Cook R. {{Similar exemplar pooling processes underlie the learning of facial identity and handwriting style: Evidence from typical observers and individuals with Autism}}. {Neuropsychologia}. 2016.
Considerable research has addressed whether the cognitive and neural representations recruited by faces are similar to those engaged by other types of visual stimuli. For example, research has examined the extent to which objects of expertise recruit holistic representation and engage the fusiform face area. Little is known, however, about the domain-specificity of the exemplar pooling processes thought to underlie the acquisition of familiarity with particular facial identities. In the present study we sought to compare observers’ ability to learn facial identities and handwriting styles from exposure to multiple exemplars. Crucially, while handwritten words and faces differ considerably in their topographic form, both learning tasks share a common exemplar pooling component. In our first experiment, we find that typical observers’ ability to learn facial identities and handwriting styles from exposure to multiple exemplars correlates closely. In our second experiment, we show that observers with autism spectrum disorder (ASD) are impaired at both learning tasks. Our findings suggest that similar exemplar pooling processes are recruited when learning facial identities and handwriting styles. Models of exemplar pooling originally developed to explain face learning, may therefore offer valuable insights into exemplar pooling across a range of domains, extending beyond faces. Aberrant exemplar pooling, possibly resulting from structural differences in the inferior longitudinal fasciculus, may underlie difficulties recognising familiar faces often experienced by individuals with ASD, and leave observers overly reliant on local details present in particular exemplars.
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9. Jumah F, Ghannam M, Adeeb N, Tubbs RS. {{Neuroanatomical variation in autism spectrum disorder: A comprehensive review}}. {Clin Anat}. 2016.
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impairments in socialization, communication, and behavior. Many investigators have described the anatomical abnormalities in autistic brains, in an attempt to correlate them with the manifestations of ASD. Herein, we reviewed all the available literature about the neuroanatomical findings in ASD available via « PubMed » and « Google Scholar. » References found in review articles were also searched manually. There was substantial discrepancy throughout the literature regarding the reported presence and significance of neuroanatomical findings in ASD, and this is thoroughly discussed in the present review. This article is protected by copyright. All rights reserved.
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10. Kenkel WM, Yee JR, Moore K, Madularu D, Kulkarni P, Gamber K, Nedelman M, Ferris CF. {{Functional magnetic resonance imaging in awake transgenic fragile X rats: evidence of dysregulation in reward processing in the mesolimbic/habenular neural circuit}}. {Transl Psychiatry}. 2016; 6: e763.
Anxiety and social deficits, often involving communication impairment, are fundamental clinical features of fragile X syndrome. There is growing evidence that dysregulation in reward processing is a contributing factor to the social deficits observed in many psychiatric disorders. Hence, we hypothesized that transgenic fragile X mental retardation 1 gene (fmr1) KO (FX) rats would display alterations in reward processing. To this end, awake control and FX rats were imaged for changes in blood oxygen level dependent (BOLD) signal intensity in response to the odor of almond, a stimulus to elicit the innate reward response. Subjects were ‘odor naive’ to this evolutionarily conserved stimulus. The resulting changes in brain activity were registered to a three-dimensional segmented, annotated rat atlas delineating 171 brain regions. Both wild-type (WT) and FX rats showed robust brain activation to a rewarding almond odor, though FX rats showed an altered temporal pattern and tended to have a higher number of voxels with negative BOLD signal change from baseline. This pattern of greater negative BOLD was especially apparent in the Papez circuit, critical to emotional processing and the mesolimbic/habenular reward circuit. WT rats showed greater positive BOLD response in the supramammillary area, whereas FX rats showed greater positive BOLD response in the dorsal lateral striatum, and greater negative BOLD response in the retrosplenial cortices, the core of the accumbens and the lateral preoptic area. When tested in a freely behaving odor-investigation paradigm, FX rats failed to show the preference for almond odor which typifies WT rats. However, FX rats showed investigation profiles similar to WT when presented with social odors. These data speak to an altered processing of this highly salient novel odor in the FX phenotype and lend further support to the notion that altered reward systems in the brain may contribute to fragile X syndrome symptomology.
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11. Pedapati EV, Gilbert DL, Erickson CA, Horn PS, Shaffer RC, Wink LK, Laue CS, Wu SW. {{Abnormal Cortical Plasticity in Youth with Autism Spectrum Disorder: A Transcranial Magnetic Stimulation Case-Control Pilot Study}}. {J Child Adolesc Psychopharmacol}. 2016.
OBJECTIVE: This case-control study investigated the use of a low-intensity repetitive transcranial magnetic stimulation (rTMS) protocol to measure motor cortex (M1) plasticity in youth with autism spectrum disorder (ASD) compared with typically developing children (TDC). We hypothesized that impairments in long-term potentiation-like properties represent a neurophysiological biomarker of abnormal cortical function in ASD. METHODS: We studied youth with ASD aged 11-18 years and matched controls (TDC). Intermittent theta burst stimulation (iTBS) was delivered to the dominant M1 at an intensity of 70% of resting motor threshold. Suprathreshold single-pulse TMS was performed to compare amplitudes of motor-evoked potentials (MEP) measured from surface electromyography electrodes on a target muscle before (20 pulses) and after (10 pulses/time point) iTBS at predefined timepoints (up to 30 minutes) to measure any potentiation effects. A linear mixed model was used to examine group differences in MEP amplitudes over time following iTBS. RESULTS: Nine youth with ASD (mean age 15.6; 7 males; 6 right-hand dominant) and 9 TDC (mean age 14.5; 5 males; 9 right-hand dominant) participated. All subjects tolerated the procedure well. Both groups had a mean increase in excitability after iTBS for 30 minutes; however, the time course of excitability changes differed (F9,144 = 2.05; p = 0.038). Post-hoc testing identified a significant decrease in amplitude of the ASD group at 20 minutes following iTBS compared with the TDC after correcting for multiple comparisons. CONCLUSION: In this study, we demonstrate early evidence for a potential physiological biomarker of cortical plasticity in youth with ASD using a rapid low-intensity rTMS protocol with a discriminate measure at 20 minutes following stimulation. The procedure was well tolerated by all 18 participants. Future work will include modification of the protocol to improve the ability to distinguish subtypes of ASD based on behavioral and cognitive testing.
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12. Sam AM, Reszka SS, Boyd BA, Pan Y, Hume K, Odom SL. {{The Association between Adult Participation and the Engagement of Preschoolers with ASD}}. {Autism Res Treat}. 2016; 2016: 6029837.
The ability for a child to engage in the classroom is associated with better academic outcomes. Yet, there is limited information on how child characteristics of autism and adult behavior impact engagement. This study examined (1) the pattern of adult participation and child engagement in preschool classrooms that serve children with ASD, (2) the associations between child engagement and adult participation, and (3) how characteristics of ASD (autism severity, language ability, and challenging behavior) moderate the relationship between adult participation and child engagement. Overall, children were less likely to be engaged when adults were actively or passively participating with them. Moderators impacted this relationship. Children with higher levels of autism severity were more likely to be engaged when adults were actively or passively participating with them. Similarly, children with lower language abilities were more likely to be engaged when adults were actively or passively participating with them. Finally, children with higher levels of challenging behaviors were less likely to be engaged when adults were actively or passively participating with them. These findings have important implications for how adults can best support the engagement of children with ASD.
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13. Santosh P, Tarver J, Gibbons F, Vitoratou S, Simonoff E. {{Protocol for the development and validation of a questionnaire to assess concerning behaviours and mental health in individuals with autism spectrum disorders: the Assessment of Concerning Behaviour (ACB) scale}}. {BMJ Open}. 2016; 6(3): e010693.
INTRODUCTION: Co-occurring psychiatric conditions and concerning behaviours are prevalent in individuals with autism spectrum disorders (ASD), and are likely to be detrimental to functioning and long-term outcomes. The cognitive rigidity and deficits in emotional literacy and verbal behaviour that commonly occur in ASD can adversely affect clinicians’ confidence to identify concerning behaviours and mental health problems. There is a need to develop a measure that is tailored towards individuals with ASD, and differentiates between symptoms of psychopathology and core ASD symptoms. Furthermore, it should be modified to capture internalising symptoms that individuals with ASD may find difficult or be unable to verbalise. This protocol describes the intended development and validation of the Assessment of Concerning Behaviour (ACB) scale. The ACB will aim to be a multidimensional measure of concerning behaviours in ASD incorporating self-report, parent/carer, teacher/employer and clinician report versions that can be used across the lifespan and spectrum of intellectual ability. METHODS AND ANALYSIS: This study will be guided by the methods described in the US Food and Drug Administration Guidance for Industry Patient-reported Outcome Measures. A literature review, cognitive interviews and focus groups with individuals who have experience of working or living with ASDs will be used for item generation. A sample of children and adults with ASD will complete the ACB, in addition to other gold standard measures of concerning behaviour in order to establish the initial psychometric properties of the scale. ETHICS AND DISSEMINATION: This study has received ethical approval from the NHS Research Ethics Committee: London-Camden and King’s Cross (ref: 15/LO/0085). Study findings will be disseminated to healthcare professionals and scientists in the field through publication in peer-reviewed journals and conference presentations.
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14. Skewes JC, Gebauer L. {{Brief Report: Suboptimal Auditory Localization in Autism Spectrum Disorder: Support for the Bayesian Account of Sensory Symptoms}}. {J Autism Dev Disord}. 2016.
Convergent research suggests that people with ASD have difficulties localizing sounds in space. These difficulties have implications for communication, the development of social behavior, and quality of life. Recently, a theory has emerged which treats perceptual symptoms in ASD as the product of impairments in implicit Bayesian inference; as suboptimalities in the integration of sensory evidence with prior perceptual knowledge. We present the results of an experiment that applies this new theory to understanding difficulties in auditory localization, and we find that adults with ASD integrate prior information less optimally when making perceptual judgments about the spatial sources of sounds. We discuss these results in terms of their implications for formal models of symptoms in ASD.
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15. Tabolacci E, Mancano G, Lanni S, Palumbo F, Goracci M, Ferre F, Helmer-Citterich M, Neri G. {{Genome-wide methylation analysis demonstrates that 5-aza-2-deoxycytidine treatment does not cause random DNA demethylation in fragile X syndrome cells}}. {Epigenetics Chromatin}. 2016; 9: 12.
BACKGROUND: Fragile X syndrome (FXS) is caused by CGG expansion over 200 repeats at the 5′ UTR of the FMR1 gene and subsequent DNA methylation of both the expanded sequence and the CpGs of the promoter region. This epigenetic change causes transcriptional silencing of the gene. We have previously demonstrated that 5-aza-2-deoxycytidine (5-azadC) treatment of FXS lymphoblastoid cell lines reactivates the FMR1 gene, concomitant with CpG sites demethylation, increased acetylation of histones H3 and H4 and methylation of lysine 4 on histone 3. RESULTS: In order to check the specificity of the 5-azadC-induced DNA demethylation, now we performed bisulphite sequencing of the entire methylation boundary upstream the FMR1 promoter region, which is preserved in control wild-type cells. We did not observe any modification of the methylation boundary after treatment. Furthermore, methylation analysis by MS-MLPA of PWS/AS and BWS/SRS loci demonstrated that 5-azadC treatment has no demethylating effect on these regions. Genome-wide methylation analysis through Infinium 450K (Illumina) showed no significant enrichment of specific GO terms in differentially methylated regions after 5-azadC treatment. We also observed that reactivation of FMR1 transcription lasts up to a month after a 7-day treatment and that maximum levels of transcription are reached at 10-15 days after last administration of 5-azadC. CONCLUSIONS: Taken together, these data demonstrate that the demethylating effect of 5-azadC on genomic DNA is not random, but rather restricted to specific regions, if not exclusively to the FMR1 promoter. Moreover, we showed that 5-azadC has a long-lasting reactivating effect on the mutant FMR1 gene.
