1. Aoki Y, Yamasue H. {{Reply: Does imitation act as an oxytocin nebulizer in autism spectrum disorder?}}. {Brain};2015 (Mar 11)
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2. Atladottir HO, Schendel DE, Parner ET, Henriksen TB. {{A Descriptive Study on the Neonatal Morbidity Profile of Autism Spectrum Disorders, Including a Comparison with Other Neurodevelopmental Disorders}}. {J Autism Dev Disord};2015 (Mar 11)
The aim of this study was to describe the profile of specific neonatal morbidities in children later diagnosed with autism spectrum disorder (ASD), and to compare this profile with the profile of children with hyperkinetic disorder, cerebral palsy, epilepsy or intellectual disability. This is a Danish population based cohort study, including all children born in Denmark from 1994, through 2010, and surviving the first year of life. Children with ASD as a whole have significantly elevated rates of a range of neurologic, respiratory, inflammatory, and metabolic problems in the neonatal period compared to the general population, but there are few if any indicators of a distinctive neonatal morbidity profile in ASD compared to other neurodevelopmental outcomes.
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3. Cheak-Zamora NC, Teti M, First J. {{‘Transitions are Scary for our Kids, and They’re Scary for us’: Family Member and Youth Perspectives on the Challenges of Transitioning to Adulthood with Autism}}. {J Appl Res Intellect Disabil};2015 (Mar 5)
BACKGROUND: Adolescents with autism spectrum disorder (ASD) face many challenges as they age into adulthood. Because little is known about the perspectives of caregivers and youth during this critical transition, this study explored their social, educational, and vocational needs and experiences. METHOD: Two focus groups were conducted with youth with ASD (n = 13) and two focus groups were conducted with their caregivers (n = 19), where theme analysis strategies derived from Grounded Theory were utilized to identify themes. RESULTS: Both groups experienced fear and anxiety about transitioning, unmet needs were also high, leaving caregivers struggling to fill gaps. Most caregivers and youth reported lacking individualized services. Caregivers faced difficulty in motivating youth and creating opportunities for education and employment. Although youth have future goals, they were unaware of steps needed to accomplish them and hesitant to talk to caregivers. CONCLUSIONS: Findings indicate considerable unmet needs for caregivers and youth with ASD. Perspectives of both groups should be considered when developing programmes and educating providers.
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4. Clarke TK, Lupton MK, Fernandez-Pujals AM, Starr J, Davies G, Cox S, Pattie A, Liewald DC, Hall LS, MacIntyre DJ, Smith BH, Hocking LJ, Padmanabhan S, Thomson PA, Hayward C, Hansell NK, Montgomery GW, Medland SE, Martin NG, Wright MJ, Porteous DJ, Deary IJ, McIntosh AM. {{Common polygenic risk for autism spectrum disorder (ASD) is associated with cognitive ability in the general population}}. {Mol Psychiatry};2015 (Mar 10)
Cognitive impairment is common among individuals diagnosed with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). It has been suggested that some aspects of intelligence are preserved or even superior in people with ASD compared with controls, but consistent evidence is lacking. Few studies have examined the genetic overlap between cognitive ability and ASD/ADHD. The aim of this study was to examine the polygenic overlap between ASD/ADHD and cognitive ability in individuals from the general population. Polygenic risk for ADHD and ASD was calculated from genome-wide association studies of ASD and ADHD conducted by the Psychiatric Genetics Consortium. Risk scores were created in three independent cohorts: Generation Scotland Scottish Family Health Study (GS:SFHS) (n=9863), the Lothian Birth Cohorts 1936 and 1921 (n=1522), and the Brisbane Adolescent Twin Sample (BATS) (n=921). We report that polygenic risk for ASD is positively correlated with general cognitive ability (beta=0.07, P=6 x 10-7, r2=0.003), logical memory and verbal intelligence in GS:SFHS. This was replicated in BATS as a positive association with full-scale intelligent quotient (IQ) (beta=0.07, P=0.03, r2=0.005). We did not find consistent evidence that polygenic risk for ADHD was associated with cognitive function; however, a negative correlation with IQ at age 11 years (beta=-0.08, Z=-3.3, P=0.001) was observed in the Lothian Birth Cohorts. These findings are in individuals from the general population, suggesting that the relationship between genetic risk for ASD and intelligence is partly independent of clinical state. These data suggest that common genetic variation relevant for ASD influences general cognitive ability.Molecular Psychiatry advance online publication, 10 March 2015; doi:10.1038/mp.2015.12.
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5. Cotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ, Niu W, Liu W, Klei L, Lei J, Yin J, Reilly SK, Tebbenkamp AT, Bichsel C, Pletikos M, Sestan N, Roeder K, State MW, Devlin B, Noonan JP. {{The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment}}. {Nat Commun};2015;6:6404.
Recent studies implicate chromatin modifiers in autism spectrum disorder (ASD) through the identification of recurrent de novo loss of function mutations in affected individuals. ASD risk genes are co-expressed in human midfetal cortex, suggesting that ASD risk genes converge in specific regulatory networks during neurodevelopment. To elucidate such networks, we identify genes targeted by CHD8, a chromodomain helicase strongly associated with ASD, in human midfetal brain, human neural stem cells (hNSCs) and embryonic mouse cortex. CHD8 targets are strongly enriched for other ASD risk genes in both human and mouse neurodevelopment, and converge in ASD-associated co-expression networks in human midfetal cortex. CHD8 knockdown in hNSCs results in dysregulation of ASD risk genes directly targeted by CHD8. Integration of CHD8-binding data into ASD risk models improves detection of risk genes. These results suggest loss of CHD8 contributes to ASD by perturbing an ancient gene regulatory network during human brain development.
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6. Cox A, Kohls G, Naples AJ, Mukerji CE, Coffman MC, Rutherford HJ, Mayes LC, McPartland JC. {{Diminished social reward anticipation in the broad autism phenotype as revealed by event-related brain potentials}}. {Soc Cogn Affect Neurosci};2015 (Mar 9)
Diminished responsivity to reward incentives is a key contributor to the social-communication problems seen in autism spectrum disorders (ASD). Social motivation theories suggest that individuals with ASD do not experience social interactions as rewarding, leading to negative consequences for the development of brain circuitry subserving social information. In this study, we examined neural responses to social and non-social reward anticipation in 35 typically developing young adults, examining modulation of reward sensitivity by level of autistic traits. Using an ERP incentive-delay task incorporating novel, more ecologically valid forms of reward, higher expression of autistic traits was associated with an attenuated P3 response to the anticipation of social (simulated real-time video feedback from an observer), but not non-social (candy), rewards. Exploratory analyses revealed that this was unrelated to mentalizing ability. The P3 component reflects motivated attention to reward signals, suggesting attenuated motivation allocation specific to social incentives. The study extends prior findings of atypical reward anticipation in ASD, demonstrating that attenuated social reward responsiveness extends to autistic traits in the range of typical functioning. Results support the development of innovative paradigms for investigating social and non-social reward responsiveness. Insight into vulnerabilities in reward processing is critical for understanding social function in ASD.
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7. Davidson C, O’Hare A, Mactaggart F, Green J, Young D, Gillberg C, Minnis H. {{Social relationship difficulties in autism and reactive attachment disorder: Improving diagnostic validity through structured assessment}}. {Res Dev Disabil};2015 (Mar 6);40C:63-72.
BACKGROUND: Autism Spectrum Disorder (ASD) versus Reactive Attachment Disorder (RAD) is a common diagnostic challenge for clinicians due to overlapping difficulties with social relationships. RAD is associated with neglect or maltreatment whereas ASD is not: accurate differential diagnosis is therefore critical. Very little research has investigated the relationship between the two, and it is unknown if standardised measures are able to discriminate between ASD and RAD. The current study aimed to address these issues. METHODS: Fifty eight children with ASD, and no history of maltreatment, were group matched on age with 67 children with RAD. Group profiles on multi-informant measures of RAD were investigated and group differences explored. Discriminant function analysis determined assessment features that best discriminated between the two groups. RESULTS: Although, according to parent report, children with ASD presented with significantly fewer indiscriminate friendliness behaviours compared to the RAD group (p<0.001), 36 children with ASD appeared to meet core RAD criteria. However, structured observation clearly demonstrated that features were indicative of ASD and not RAD for all but 1 of these 36 children. CONCLUSIONS: Children with RAD and children with ASD may demonstrate similar social relationship difficulties but there appears to be a difference in the social quality of the interactions between the groups. In most cases it was possible to differentiate between children with ASD and children with RAD via structured observation. Nevertheless, for a small proportion of children with ASD, particularly those whose difficulties may be more subtle, our current standardised measures, including structured observation, may not be effective in differentiating RAD from ASD.
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8. Davis JM, Searles Quick VB, Sikela JM. {{Replicated linear association between DUF1220 copy number and severity of social impairment in autism}}. {Hum Genet};2015 (Mar 11)
Sequences encoding DUF1220 protein domains exhibit an exceptional human-specific increase in copy number and have been associated with several phenotypes related to brain size. Autism is a highly heritable and heterogeneous condition characterized behaviorally by social and communicative impairments, and increased repetitive and stereotyped behavior. Given the accelerated brain growth pattern observed in many individuals with autism, and the association between DUF1220 subtype CON1 copy number and brain size, we previously investigated associations between CON1 copy number and autism-related symptoms. We determined that CON1 copy number increase is associated with increasing severity of all three behavioral features of autism. The present study sought to replicate these findings in an independent population (N = 166). Our results demonstrate a replication of the linear relationship between CON1 copy number and the severity of social impairment in individuals with autism as measured by Autism Diagnostic Interview-Revised Social Diagnostic Score, such that with each additional copy of CON1 Social Diagnostic Score increased 0.24 points (SE = 0.11, p = 0.036). We also identified an analogous trend between CON1 copy number and Communicative Diagnostic Score, but did not replicate the relationship between CON1 copy number and Repetitive Behavior Diagnostic Score. Interestingly, these associations appear to be most pronounced in multiplex children. These results, representing the first replication of a gene dosage relationship with the severity of a primary symptom of autism, lend further support to the possibility that the same protein domain family implicated in the evolutionary expansion of the human brain may also be involved in autism severity.
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9. Ellegood J, Nakai N, Nakatani J, Henkelman M, Takumi T, Lerch J. {{Neuroanatomical Phenotypes Are Consistent With Autism-Like Behavioral Phenotypes in the 15q11-13 Duplication Mouse Model}}. {Autism Res};2015 (Mar 7)
Paternally and maternally inherited deletions and duplications of human chromosome 15q11-13 are relatively common in the human population. Furthermore, duplications in the 15q region are often associated with autism. Both maternal and paternal interstitial 15q11-13 duplication mouse models have been previously created, where several behavioral differences were found in the paternal duplication (patDp/+) mouse but not in the maternal duplication (matDp/+). These included decreased sociability, behavioral inflexibility, abnormal ultrasonic vocalizations, decreased spontaneous activity, and increased anxiety. Similarly, in the current study, we found several anatomical differences in the patDp/+ mice that were not seen in the matDp/+ mice. Regional differences that are evident only in the paternal duplication are a smaller dentate gyrus and smaller medial striatum. These differences may be responsible for the behavioral inflexibility. Furthermore, a smaller dorsal raphe nucleus could be responsible for the reported serotonin defects. This study highlights consistency that can be found between behavioral and anatomical phenotyping. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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10. Ellis Weismer S, Kover ST. {{Preschool language variation, growth, and predictors in children on the autism spectrum}}. {J Child Psychol Psychiatry};2015 (Mar 10)
BACKGROUND: There is wide variation in language abilities among young children with autism spectrum disorders (ASD), with some toddlers developing age-appropriate language while others remain minimally verbal after age 5. Conflicting findings exist regarding predictors of language outcomes in ASD and various methodological issues limit the conclusions that can be drawn about factors associated with positive language growth that could provide insights into more effective intervention approaches for increasing communication skills. METHODS: Language development was investigated in 129 children with ASD participating in four assessments from mean age 2(1/2) years (Visit 1) through 5(1/2) years (Visit 4). Language ability was measured by a clinician-administered test of comprehension and production. Hierarchical linear modeling was used to identify predictors of language ability. Stability of language status was examined in subgroups of Preverbal versus Verbal children identified at Visit 1. Discriminant function analysis was used to classify another subset of cases according to Low Language (minimally verbal) versus High Language outcome at Visit 4. RESULTS: ASD severity was a significant predictor of growth in both language comprehension and production during the preschool period, while cognition predicted growth in production. For the highest and lowest language performers at Visit 4, cognition, maternal education, and response to joint attention correctly classified over 80% of total cases. The vast majority of children who were preverbal at 2(1/2) years attained some level of verbal skills by 5(1/2) years. CONCLUSIONS: Findings indicate that it is possible, by 2(1/2) years, to predict language growth for children with ASD across the preschool years and identify factors that discriminate between children who remain minimally verbal at 5(1/2) years from those with high language proficiency. Results suggest that early intervention focused on reducing core ASD symptoms may also be important for facilitating language development in young children with ASD.
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11. Flanagan T, Brodeur DA, Burack JA. {{A Point of Departure in the Comparison of Social and Nonsocial Visual Orienting Among Persons With Autism Spectrum Disorders}}. {Autism Res};2015 (Mar 7)
Endogenous visual orienting among children with autism spectrum disorders (ASDs) and among typically developing (TD) children was examined using a Posner-type task that was modified to include social and nonsocial cues and targets to test hypotheses regarding information (social or nonsocial) and cue processing (long or short stimulus onset asynchronies (SOAs)). The findings suggest intact endogenous orienting to face and mixed face targets using hand and arrow cues among children with ASDs who were matched to typically developing children (TDC) on the basis of nonverbal mental age (MA) at approximately 8.5 years. The findings from this study challenge the notions of a social orienting impairment and of mechanical social orienting as the children with ASDs in this study demonstrated strong orienting effects in all conditions and social sensitivity in the long stimulus onset asynchrony (SOA) condition. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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12. Gabel HW, Kinde B, Stroud H, Gilbert CS, Harmin DA, Kastan NR, Hemberg M, Ebert DH, Greenberg ME. {{Disruption of DNA-methylation-dependent long gene repression in Rett syndrome}}. {Nature};2015 (Mar 11)
Disruption of the MECP2 gene leads to Rett syndrome (RTT), a severe neurological disorder with features of autism. MECP2 encodes a methyl-DNA-binding protein that has been proposed to function as a transcriptional repressor, but despite numerous mouse studies examining neuronal gene expression in Mecp2 mutants, no clear model has emerged for how MeCP2 protein regulates transcription. Here we identify a genome-wide length-dependent increase in gene expression in MeCP2 mutant mouse models and human RTT brains. We present evidence that MeCP2 represses gene expression by binding to methylated CA sites within long genes, and that in neurons lacking MeCP2, decreasing the expression of long genes attenuates RTT-associated cellular deficits. In addition, we find that long genes as a population are enriched for neuronal functions and selectively expressed in the brain. These findings suggest that mutations in MeCP2 may cause neurological dysfunction by specifically disrupting long gene expression in the brain.
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13. Grinker RR, Kang-Yi CD, Ahmann C, Beidas RS, Lagman A, Mandell DS. {{Cultural Adaptation and Translation of Outreach Materials on Autism Spectrum Disorder}}. {J Autism Dev Disord};2015 (Mar 11)
In order to connect with families and influence treatment trajectories, outreach materials should address cultural perceptions of the condition, its causes, and post-diagnostic care. This paper describes the cultural adaptation and translation of the Autism Speaks First 100 Days Kit into Korean for the purpose of improving autism spectrum disorder (ASD) diagnosis, assessment, and interventions. The goal of this study is to describe a methodology for future cross-cultural adaptations and translations of outreach materials on ASD, using the Autism Speaks First 100 Days Kit as an exemplar. The research involved two stages of qualitative interviews: unstructured individual and group interviews with 19 Korean child health and education professionals in Queens, NY, followed by structured cultural consensus modeling interviews with 23 Korean mothers, with and without children with ASD, in Queens, NY and the greater Washington, DC area. We conclude that a systematic approach to cultural translation of outreach materials is feasible. Cultural consensus modeling yielded information about numerous barriers to care, had a demonstrable effect on the translation of the kit, and was efficient when employed with coherent segments of a relatively homogeneous population and focused on a single condition.
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14. Marr C, Leonard H, Torode I, Downs J. {{Spinal fusion in girls with Rett syndrome: post-operative recovery and family experiences}}. {Child Care Health Dev};2015 (Mar 9)
BACKGROUND: Rett syndrome is a severe neurodevelopmental disorder mainly affecting females and scoliosis is a common co-morbidity. Spinal fusion may be recommended if the scoliosis is progressive. This qualitative study investigated recovery of girls with Rett syndrome during the first 12 post-operative months and explored family perspectives and coping around the time of surgery. METHOD: Parents registered with the population-based Australian Rett Syndrome Database were recruited to this study if their daughter had a confirmed pathogenic MECP2 mutation and spinal fusion between 2006 and 2012. Twenty-five interviews were conducted to determine their daughter’s recovery and parental stresses and coping. Themes in the interview data were identified with content analysis, and the regaining of gross motor skills over the first 12 post-operative months was described with time-to-event (survival) analysis. RESULTS: Pain and energy levels, appetite, mood and coinciding health issues influenced their daughter’s post-operative recovery. The majority of girls recovered preoperative sitting (88%), standing (81%) and walking (80%) by 12 months. The decision to proceed with surgery was associated with feelings of fear, obligation, relief and guilt for families. Development of complications, poor support and feelings of isolation increased their emotional burden whereas adequate information and discharge preparation, confidence in self and staff, and balancing personal needs with their daughter’s care relieved this burden. INTERPRETATION: Our study identified clinical practice issues in relation to families whose daughter with Rett syndrome undergoes spinal fusion, issues that are also relevant to other severe disabilities. Return of wellness and gross motor skills following spinal fusion in girls with Rett syndrome occurred within the first 12 post-operative months in most cases. Parents require information and practical support to alleviate their emotional burden.
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15. Mostafa GA, Al-Ayadhi LY. {{Reduced levels of plasma polyunsaturated fatty acids and serum carnitine in autistic children: relation to gastrointestinal manifestations}}. {Behav Brain Funct};2015;11(1):4.
BACKGROUND: Gastrointestinal (GI) manifestations are common in autistic children. Polyunsaturated fatty acids (PUFAs) and carnitine are anti-inflammatory molecules and their deficiency may result in GI inflammation. The relationship between the increased frequency of GI manifestations and reduced levels of PUFAs and carnitine was not previously investigated in autistic patients. This study was the first to investigate plasma levels of PUFAs and serum carnitine in relation to GI manifestations in autistic children. METHODS: Plasma levels of PUFAs (including linoleic, alphalinolenic, arachidonic « AA » and docosahexaenoic « DHA » acids) and serum carnitine were measured in 100 autistic children and 100 healthy-matched children. RESULTS: Reduced levels of serum carnitine and plasma DHA, AA, linolenic and linoleic acids were found in 66%, 62%, 60%, 43% and 38%, respectively of autistic children. On the other hand, 54% of autistic patients had elevated omega6/omega3 ratio. Autistic patients with GI manifestations (48%) had significantly decreased levels of serum carnitine and plasma DHA than patients without such manifestations. In addition, autistic patients with GI manifestations had significantly increased percentage of reduced serum carnitine (91.7%) and plasma DHA levels (87.5%) than patients without such manifestations (42.3% and 38.5%, respectively), (P < 0.001 and P < 0.001%, respectively). CONCLUSIONS: Reduced levels of plasma DHA and serum carnitine levels may be associated with the GI problems in some autistic patients. However, this is an initial report, studies are recommended to invesigate whether reduced levels of carnitine and DHA are a mere association or have a pathogenic role in GI problems in autistic patients.
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16. Orinstein AJ, Suh J, Porter K, De Yoe KA, Tyson KE, Troyb E, Barton ML, Eigsti IM, Stevens MC, Fein DA. {{Social Function and Communication in Optimal Outcome Children and Adolescents with an Autism History on Structured Test Measures}}. {J Autism Dev Disord};2015 (Mar 11)
Youth who lose their ASD diagnosis may have subtle social and communication difficulties. We examined social and communication functioning in 44 high-functioning autism (HFA), 34 optimal outcome (OO) and 34 typically developing (TD) youth. Results indicated that OO participants had no autism communication symptoms, no pragmatic language deficits, and were judged as likable as TD peers. Some group differences were found: OO youth had less insight into social relationships and poorer friendship descriptions than TD youth. OO participants had attention, self-control, and immaturity difficulties that may impact social abilities. However, OO participants were most engaged, friendliest, warmest, and most approachable. Overall, OO participants had no social and communicative impairments, although some exhibited mild social difficulties that often accompany attentional problems.
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17. Ratcliffe B, Wong M, Dossetor D, Hayes S. {{The Association Between Social Skills and Mental Health in School-Aged Children with Autism Spectrum Disorder, With and Without Intellectual Disability}}. {J Autism Dev Disord};2015 (Mar 11)
Autism Spectrum Disorder (ASD) is associated with social skills deficits and co-occurring mental health difficulties. ASD frequently co-occurs with Intellectual Disability (ID). There is scant literature exploring the association between social skills and mental health in children with ASD, with or without ID. Participants were 292 children aged six to 13 with ASD (217 without ID; 76 with Mild ID). Parents and teachers rated social skills and mental health using standardised questionnaires. Greater mental health difficulties were associated with greater social responsiveness difficulties and poorer social skills across the sample. Effect sizes were large. Social skills explained a significant proportion of the variance in mental health scores across the sample. The study has important implications for treatment and future research.
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18. Rose S, Frye RE, Slattery J, Wynne R, Tippett M, Melnyk S, James SJ. {{Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines}}. {Transl Psychiatry};2015;5:e526.
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19. Silverman JL, Pride MC, Hayes JE, Puhger KR, Butler-Struben H, Baker S, Crawley JN. {{GABA Receptor Agonist R-Baclofen Reverses Social Deficits and Reduces Repetitive Behavior in Two Mouse Models of Autism}}. {Neuropsychopharmacology};2015 (Mar 10)
Autism spectrum disorder (ASD) is diagnosed by two core behavioral criteria, unusual reciprocal social interactions and communication, and stereotyped, repetitive behaviors with restricted interests. Excitatory/inhibitory imbalance is a prominent hypothesis for the etiology of autism. The selective GABAB receptor agonist R-baclofen reversed social deficits and reduced repetitive behaviors in a mouse model of Fragile X syndrome, and Arbaclofen improved some clinical symptoms in some Fragile X and ASD patients. To evaluate R-baclofen in a broader range of mouse models of ASD, we tested both the R-baclofen enantiomer and the less potent S-baclofen enantiomer in two inbred strains of mice that display low sociability and/or high repetitive or stereotyped behaviors. R-baclofen treatment reversed social approach deficits in BTBR T+ Itpr3tf/J (BTBR), reduced repetitive self-grooming and high marble burying scores in BTBR, and reduced stereotyped jumping in C58/J (C58), at non-sedating doses. S-baclofen produced minimal effects at the same doses. These findings encourage investigations of R-baclofen in other preclinical model systems. Additional clinical studies may be warranted, to further evaluate the hypothesis that the GABAB receptor represents a promising pharmacological target for treating appropriately stratified subsets of individuals with ASD.Neuropsychopharmacology accepted article preview online, 10 March 2015. doi:10.1038/npp.2015.66.
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20. Tilot AK, Bebek G, Niazi F, Altemus JB, Romigh T, Frazier TW, Eng C. {{Neural transcriptome of constitutional Pten dysfunction in mice and its relevance to human idiopathic autism spectrum disorder}}. {Mol Psychiatry};2015 (Mar 10)
Autism spectrum disorder (ASD) is a neurodevelopmental condition with a clear, but heterogeneous, genetic component. Germline mutations in the tumor suppressor Pten are a well-established risk factor for ASD with macrocephaly, and conditional Pten mouse models have impaired social behavior and brain development. Some mutations observed in patients disrupt the normally balanced nuclear-cytoplasmic localization of the Pten protein, and we developed the Ptenm3m4 model to study the effects of a cytoplasm-predominant Pten. In this model, germline mislocalization of Pten causes inappropriate social behavior with intact learning and memory, a profile reminiscent of high-functioning ASD. These animals also exhibit histological evidence of neuroinflammation and expansion of glial populations by 6 weeks of age. We hypothesized that the neural transcriptome of this model would be altered in a manner that could inform human idiopathic ASD, a constitutional condition. Using total RNA sequencing, we found progressive disruption of neural gene expression in Ptenm3m4 mice from 2-6 weeks of age, involving both immune and synaptic pathways. These alterations include downregulation of many highly coexpressed human ASD-susceptibility genes. Comparison with a human cortical development coexpression network revealed that genes disrupted in Ptenm3m4 mice were enriched in the same areas as those of human ASD. Although Pten-related ASD is relatively uncommon, our observations suggest that the Ptenm3m4 model recapitulates multiple molecular features of human ASD, and that Pten operates far upstream of common pathways within ASD pathogenesis.Molecular Psychiatry advance online publication, 10 March 2015; doi:10.1038/mp.2015.17.
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21. Tordjman S, Davlantis KS, Georgieff N, Geoffray MM, Speranza M, Anderson GM, Xavier J, Botbol M, Oriol C, Bellissant E, Vernay-Leconte J, Fougerou C, Hespel A, Tavenard A, Cohen D, Kermarrec S, Coulon N, Bonnot O, Dawson G. {{Autism as a disorder of biological and behavioral rhythms: toward new therapeutic perspectives}}. {Front Pediatr};2015;3:1.
There is a growing interest in the role of biological and behavioral rhythms in typical and atypical development. Recent studies in cognitive and developmental psychology have highlighted the importance of rhythmicity and synchrony of motor, emotional, and interpersonal rhythms in early development of social communication. The synchronization of rhythms allows tuning and adaptation to the external environment. The role of melatonin in the ontogenetic establishment of circadian rhythms and the synchronization of the circadian clocks network suggests that this hormone might be also involved in the synchrony of motor, emotional, and interpersonal rhythms. Autism provides a challenging model of physiological and behavioral rhythm disturbances and their possible effects on the development of social communication impairments and repetitive behaviors and interests. This article situates autism as a disorder of biological and behavioral rhythms and reviews the recent literature on the role of rhythmicity and synchrony of rhythms in child development. Finally, the hypothesis is developed that an integrated approach focusing on biological, motor, emotional, and interpersonal rhythms may open interesting therapeutic perspectives for children with autism. More specifically, promising avenues are discussed for potential therapeutic benefits in autism spectrum disorder of melatonin combined with developmental behavioral interventions that emphasize synchrony, such as the Early Start Denver Model.
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22. Tozer R, Atkin K. {{‘Recognized, Valued and Supported’? The Experiences of Adult Siblings of People with Autism Plus Learning Disability}}. {J Appl Res Intellect Disabil};2015 (Mar 5)
BACKGROUND: The potential of adult siblings to offer long-term support to a brother or sister with autism is rarely realized. To understand this, our study explores the expectations of social care among adult siblings. METHOD: Using qualitative interviews, we spoke to 21 adult siblings about their family relationships and engagement with service delivery, met with 12 of their siblings with autism and talked to 12 social care staff. RESULTS: Siblings, although reflecting on the difficulties of growing up with someone who had autism, expressed a commitment towards their brother or sister. Most wanted involvement in their care. While some siblings described positive relationships with services, many felt marginalized. Practitioners largely confirmed their perceptions, while offering a justification for why they struggled to engage with adult siblings. CONCLUSION: By understanding the way relationships between siblings change over time, adult siblings’ contribution to the lives of their disabled brother or sister can be better supported.
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23. Utami KH. {{The implications of de novo coding mutations in simplex autism families}}. {Clin Genet};2015 (Mar 9)
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24. Wohr M, Orduz D, Gregory P, Moreno H, Khan U, Vorckel KJ, Wolfer DP, Welzl H, Gall D, Schiffmann SN, Schwaller B. {{Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities}}. {Transl Psychiatry};2015;5:e525.
Gene mutations and gene copy number variants are associated with autism spectrum disorders (ASDs). Affected gene products are often part of signaling networks implicated in synapse formation and/or function leading to alterations in the excitation/inhibition (E/I) balance. Although the network of parvalbumin (PV)-expressing interneurons has gained particular attention in ASD, little is known on PV’s putative role with respect to ASD. Genetic mouse models represent powerful translational tools for studying the role of genetic and neurobiological factors underlying ASD. Here, we report that PV knockout mice (PV(-/-)) display behavioral phenotypes with relevance to all three core symptoms present in human ASD patients: abnormal reciprocal social interactions, impairments in communication and repetitive and stereotyped patterns of behavior. PV-depleted mice also showed several signs of ASD-associated comorbidities, such as reduced pain sensitivity and startle responses yet increased seizure susceptibility, whereas no evidence for behavioral phenotypes with relevance to anxiety, depression and schizophrenia was obtained. Reduced social interactions and communication were also observed in heterozygous (PV(+/-)) mice characterized by lower PV expression levels, indicating that merely a decrease in PV levels might be sufficient to elicit core ASD-like deficits. Structural magnetic resonance imaging measurements in PV(-/-) and PV(+/-) mice further revealed ASD-associated developmental neuroanatomical changes, including transient cortical hypertrophy and cerebellar hypoplasia. Electrophysiological experiments finally demonstrated that the E/I balance in these mice is altered by modification of both inhibitory and excitatory synaptic transmission. On the basis of the reported changes in PV expression patterns in several, mostly genetic rodent models of ASD, we propose that in these models downregulation of PV might represent one of the points of convergence, thus providing a common link between apparently unrelated ASD-associated synapse structure/function phenotypes.
