1. Ardhanareeswaran K, Coppola G, Vaccarino F. {{The Use of Stem Cells to Study Autism Spectrum Disorder}}. {Yale J Biol Med};2015 (Mar);88(1):5-16.
Autism spectrum disorder (ASD) affects as many as 1 in 68 children and is said to be the fastest-growing serious developmental disability in the United States. There is currently no medical cure or diagnostic test for ASD. Furthermore, the U.S. Food and Drug Administration has yet to approve a single drug for the treatment of autism’s core symptoms. Despite numerous genome studies and the identification of hundreds of genes that may cause or predispose children to ASD, the pathways underlying the pathogenesis of idiopathic ASD still remain elusive. Post-mortem brain samples, apart from being difficult to obtain, offer little insight into a disorder that arises through the course of development. Furthermore, ASD is a disorder of highly complex, human-specific behaviors, making it difficult to model in animals. Stem cell models of ASD can be generated by performing skin biopsies of ASD patients and then dedifferentiating these fibroblasts into human-induced pluripotent stem cells (hiPSCs). iPSCs closely resemble embryonic stem cells and retain the unique genetic signature of the ASD patient from whom they were originally derived. Differentiation of these iPSCs into neurons essentially recapitulates the ASD patient’s neuronal development in a dish, allowing for a patient-specific model of ASD. Here we review our current understanding of the underlying neurobiology of ASD and how the use of stem cells can advance this understanding, possibly leading to new therapeutic avenues.
2. Cianfaglione R, Clarke A, Kerr M, Hastings RP, Oliver C, Moss J, Heald M, Felce D. {{A national survey of Rett syndrome: behavioural characteristics}}. {J Neurodev Disord};2015;7(1):11.
BACKGROUND: The aim was to gain a UK national sample of people with Rett syndrome (RTT) across the age range and compare their characteristics using a variety of relevant behavioural measures with a well-chosen contrast group. METHODS: The achieved sample was 91 girls and women, aged from 4 to 47 years, of whom 71 were known to be MECP2 positive. The contrast group (n = 66), matched for age, gender, language and self-help skills, comprised individuals with six other syndromes associated with intellectual disability. Parental questionnaire measures of RTT specific characteristics, impulsivity, overactivity, mood, interest and pleasure, repetitive behaviour and self-injury were administered. RESULTS: Hand stereotypies, breathing irregularities, night-time unrest and anxiety or inappropriate fear were commonly reported among the RTT sample. Problems of low mood were also reported as common. However, mood and interest and pleasure were no lower than found in the contrast group. In addition, self-injury was lower than in the contrast group and was associated with factors found to predict self-injury in other groups of people with severe intellectual disabilities. CONCLUSIONS: There is variability in the manifestation of problem behaviours potentially associated with the syndrome across individuals, with some more severely affected in most areas than others. Some of this variability appears to be underpinned by genetic mutation.
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3. 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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4. 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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5. Crowley B, Howe YJ, McDougle CJ. {{Topiramate for Weight Loss in Two Young Adult Women with Autism Spectrum Disorder}}. {J Child Adolesc Psychopharmacol};2015 (Mar 6)
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6. Di Napoli A, Warrier V, Baron-Cohen S, Chakrabarti B. {{Genetic variant rs17225178 in the ARNT2 gene is associated with Asperger Syndrome}}. {Mol Autism};2015;6:9.
BACKGROUND: Autism Spectrum Conditions (ASC) are neurodevelopmental conditions characterized by difficulties in communication and social interaction, alongside unusually repetitive behaviours and narrow interests. Asperger Syndrome (AS) is one subgroup of ASC and differs from classic autism in that in AS there is no language or general cognitive delay. Genetic, epigenetic and environmental factors are implicated in ASC and genes involved in neural connectivity and neurodevelopment are good candidates for studying the susceptibility to ASC. The aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) gene encodes a transcription factor involved in neurodevelopmental processes, neuronal connectivity and cellular responses to hypoxia. A mutation in this gene has been identified in individuals with ASC and single nucleotide polymorphisms (SNPs) have been nominally associated with AS and autistic traits in previous studies. METHODS: In this study, we tested 34 SNPs in ARNT2 for association with AS in 118 cases and 412 controls of Caucasian origin. P values were adjusted for multiple comparisons, and linkage disequilibrium (LD) among the SNPs analysed was calculated in our sample. Finally, SNP annotation allowed functional and structural analyses of the genetic variants in ARNT2. We tested the replicability of our result using the genome-wide association studies (GWAS) database of the Psychiatric Genomics Consortium (PGC). RESULTS: We report statistically significant association of rs17225178 with AS. This SNP modifies transcription factor binding sites and regions that regulate the chromatin state in neural cell lines. It is also included in a LD block in our sample, alongside other genetic variants that alter chromatin regulatory regions in neural cells. CONCLUSIONS: These findings demonstrate that rs17225178 in the ARNT2 gene is associated with AS and support previous studies that pointed out an involvement of this gene in the predisposition to ASC.
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7. 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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8. Gelbar NW, Shefyck A, Reichow B. {{A comprehensive survey of current and former college students with autism spectrum disorders}}. {Yale J Biol Med};2015 (Mar);88(1):45-68.
BACKGROUND: There is a paucity of research concerning individuals with autism spectrum disorders (ASD) pursuing higher education. METHOD: This study sought to augment this gap in the literature by surveying individuals with ASD who are currently college students or who have previously attended college. RESULTS: Thirty-five individuals completed an online survey. These individuals reported receiving extensive academic supports that enabled their academic success. Their reported difficulties in the social and emotional domains received less support. In addition, not all areas of campus life were supportive, as study abroad and career service offices were reported to not understand individuals with ASD. CONCLUSIONS: Overall, the results of this survey indicate the importance of self-advocacy and the need for institutions of higher education to provide comprehensive supports for individuals with ASD in the academic, social, and emotional domains in order to effectively integrate this group into the campus environment.
9. Grapel JN, Cicchetti DV, Volkmar FR. {{Sensory features as diagnostic criteria for autism: sensory features in autism}}. {Yale J Biol Med};2015 (Mar);88(1):69-71.
In this study, we examined the frequency of sensory-related issues as reported by parents in a large sample of school-age adolescents and adults with autism/autism spectrum disorder (ASD) [1] as compared to a group of individuals receiving similar clinical evaluations for developmental/behavioral difficulties but whose final diagnoses were not on the autism spectrum. In no comparison were the features examined predictive of autism or autism spectrum in comparison to the non-ASD sample. Only failure to respond to noises had sensitivity above .75 in the comparison of the broader autism spectrum group, but specificity was poor. While sensory issues are relatively common in autism/ASD, they are also frequent in other disorders. These results question the rationale for including sensory items as a diagnostic criterion for autism.
10. Keil A, Breunig C, Fleischfresser S, Oftedahl E. {{Promoting routine use of developmental and autism-specific screening tools by pediatric primary care clinicians}}. {WMJ};2014 (Dec);113(6):227-231.
INTRODUCTION: In 2006, the American Academy of Pediatrics published a policy statement recommending routine developmental screening for all children. Most clinicians at that time were using informal methods to monitor child development. METHODS: Outreach to Wisconsin primary care clinicians designed to promote use of validated developmental screening tools began in 2006. A survey of 157 Wisconsin primary care clinicians was conducted in late 2012 to assess routine use of developmental and autism-specific tools. RESULTS: As compared with a similar survey conducted in 2007, where only 25% of clinicians reported use of a validated developmental screening tool, over 55% of clinicians in this survey reported routine use of validated developmental and autism-specific screening tools within well-child care. CONCLUSION: Outreach to clinicians and their care teams, in conjunction with policy statements from national professional organizations and supporting evidence, can contribute to quality improvement in well-child care delivery.
11. Kellaher DC. {{Sexual behavior and autism spectrum disorders: an update and discussion}}. {Curr Psychiatry Rep};2015 (Apr);17(4):562.
In the last few years, we have gained a deeper understanding about sexuality among individuals with autism spectrum disorder (ASD). Greater interest in this subject and improvements in the empirical study of ASD populations are driving this enlightenment. The data is dispelling antiquated notions that ASD individuals are asexual, sexually unknowledgeable and inexperienced, and/or disinterested in relationships. We still have a ways to go in examining paraphilic or deviant arousal sexual behaviors among ASD individuals. This manuscript provides an update on sexuality research in ASD in the last few years. This is accompanied by a discussion of the paraphilic type sexual behaviors observed among some ASD individuals.
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12. Klin A, Wetherby AM, Woods J, Saulnier C, Stapel-Wax J, Klaiman C, Jones W, Rubin E, Scahill L, Call N, Bearss K, Gunter C, Courtemanche CJ, Lemieux A, Cox JC, Mandell DS, Van Decar JP, Miller RA, Shireman CL. {{Toward Innovative, Cost-Effective, and Systemic Solutions to Improve Outcomes and Well-Being of Military Families Affected by Autism Spectrum Disorder}}. {Yale J Biol Med};2015 (Mar);88(1):73-79.
The burdens faced by military families who have a child with autism are unique. The usual challenges of securing diagnostic, treatment, and educational services are compounded by life circumstances that include the anxieties of war, frequent relocation and separation, and a demand structure that emphasizes mission readiness and service. Recently established military autism-specific health care benefits set the stage for community-viable and cost-effective solutions that can achieve better outcomes for children and greater well-being for families. Here we argue for implementation of evidence-based solutions focused on reducing age of diagnosis and improving access to early intervention, as well as establishment of a tiered menu of services, individualized to the child and family, that fit with the military ethos and system of health care. Absence of this new model of care could compromise the utility and sustainability of the autism-specific benefit.
13. Martin HG, Lassalle O, Brown JT, Manzoni OJ. {{Age-Dependent Long-Term Potentiation Deficits in the Prefrontal Cortex of the Fmr1 Knockout Mouse Model of Fragile X Syndrome}}. {Cereb Cortex};2015 (Mar 5)
The most common inherited monogenetic cause of intellectual disability is Fragile X syndrome (FXS). The clinical symptoms of FXS evolve with age during adulthood; however, neurophysiological data exploring this phenomenon are limited. The Fmr1 knockout (Fmr1 KO) mouse models FXS, but studies in these mice of prefrontal cortex (PFC) function are underrepresented, and aging linked data are absent. We studied synaptic physiology and activity-dependent synaptic plasticity in the medial PFC of Fmr1 KO mice from 2 to 12 months. In young adult Fmr1 KO mice, NMDA receptor (NMDAR)-mediated long-term potentiation (LTP) is intact; however, in 12-month-old mice this LTP is impaired. In parallel, there was an increase in the AMPAR/NMDAR ratio and a concomitant decrease of synaptic NMDAR currents in 12-month-old Fmr1 KO mice. We found that acute pharmacological blockade of mGlu5 receptor in 12-month-old Fmr1 KO mice restored a normal AMPAR/NMDAR ratio and LTP. Taken together, the data reveal an age-dependent deficit in LTP in Fmr1 KO mice, which may correlate to some of the complex age-related deficits in FXS.
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14. Nystrom P, Gredeback G, Bolte S, Falck-Ytter T. {{Hypersensitive pupillary light reflex in infants at risk for autism}}. {Mol Autism};2015;6:10.
BACKGROUND: Post mortem brain tissue data and animal modeling work indicate cholinergic disruptions in autism. Moreover, the cholinergic system plays a key role in the early neurodevelopmental processes believed to be derailed early in life in individuals with the disorder. Yet, there is no data from human infants supporting a developmentally important role of this neurotransmitter system. Because the pupillary light reflex depends largely on cholinergic synaptic transmission, we assessed this reflex in a sample of infants at risk for autism as well as infants at low (average) risk. METHODS: Ten-month-old infants with an older sibling with autism (n = 29, 16 females), and thus a genetic predisposition to developing the disorder themselves, were presented with white flashes on a computer monitor, and pupillary responses were captured using eye tracking. A control group matched on age and developmental level (n = 15, seven females) was also tested. RESULTS: The siblings of children with autism had a faster and stronger pupillary light reflex compared to control infants. Baseline pupil diameter was equal in the two groups, ruling out tonic autonomic imbalance as an explanation for these differences. CONCLUSIONS: This study establishes that infant siblings of children with autism have hypersensitive pupillary light reflexes, a result which supports the view that altered sensory processing in infancy is associated with elevated autism risk. Moreover, the study indicates that individual differences in autism susceptibility are linked to differences in the cholinergic system during an early developmental period.
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15. Port RG, Anwar AR, Ku M, Carlson GC, Siegel SJ, Roberts TP. {{Prospective MEG Biomarkers in ASD: Pre-Clinical Evidence and Clinical Promise of Electrophysiological Signatures}}. {Yale J Biol Med};2015 (Mar);88(1):25-36.
Autism spectrum disorders (ASD) are characterized by social impairments and restricted/stereotyped behaviors and currently affect an estimated 1 in 68 children aged 8 years old. While there has been substantial recent focus on ASD in research, both the biological pathology and, perhaps consequently, a fully effective treatment have yet to be realized. What has remained throughout is the hypothesis that ASD has neurobiological underpinnings and the observation that both the phenotypic expression and likely the underlying etiology is highly heterogeneous. Given the neurodevelopmental basis of ASD, a biologically based marker (biomarker) could prove useful not only for diagnostic and prognostic purposes, but also for stratification and response indices for pharmaceutical development. In this review, we examine the current state of the field for MEG-related biomarkers in ASD. We describe several potential biomarkers (middle latency delays [M50/M100], mismatch negativity latency, gamma-band oscillatory activity), and investigate their relation to symptomology, core domains of dysfunction (e.g., language impairment), and putative biological underpinnings.
16. Rolison MJ, Naples AJ, McPartland JC. {{Interactive Social Neuroscience to Study Autism Spectrum Disorder}}. {Yale J Biol Med};2015 (Mar);88(1):17-24.
Individuals with autism spectrum disorder (ASD) demonstrate difficulty with social interactions and relationships, but the neural mechanisms underlying these difficulties remain largely unknown. While social difficulties in ASD are most apparent in the context of interactions with other people, most neuroscience research investigating ASD have provided limited insight into the complex dynamics of these interactions. The development of novel, innovative « interactive social neuroscience » methods to study the brain in contexts with two interacting humans is a necessary advance for ASD research. Studies applying an interactive neuroscience approach to study two brains engaging with one another have revealed significant differences in neural processes during interaction compared to observation in brain regions that are implicated in the neuropathology of ASD. Interactive social neuroscience methods are crucial in clarifying the mechanisms underlying the social and communication deficits that characterize ASD.
17. 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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18. Roy M, Prox-Vagedes V, Ohlmeier MD, Dillo W. {{Beyond childhood: Psychiatric comorbidities and social background of adults with Asperger syndrome}}. {Psychiatr Danub};2015 (Mar);27(1):50-59.
BACKGROUND: Over the past few years, our knowledge about Asperger syndrome (AS) has increased enormously. Although it used to be a syndrome mainly encountered in childhood and adolescent psychiatry, it is now increasingly recognized in adult psychiatry. Nevertheless, little is known about psychiatric comorbidities and life course of adults with AS. The current study aimed to gain an insight into comorbidities and the development of the social situation of adults with AS. SUBJECTS AND METHODS: We investigated psychiatric comorbidities, psychiatric history, professional background, partnerships, and children in 50 adults with AS (34 men and 16 women) over a broad age range (20-62 years). RESULTS: Seventy percent of adults with AS had at least one psychiatric comorbiditiy. Most frequent comorbidities were depression and anxiety disorders. Obsessive-compulsive disorder and alcohol abuse/dependence were also observed. Many adults had previously been treated with psychopharmacological or psychotherapeutic interventions. Although most adults had a high-level school leaving certificate and had gone on to complete training/university studies, less than half were currently in employment. Fourteen adults were living in a partnership and 10 had children. CONCLUSIONS: Adults with AS often have psychiatric comorbidities, indicating lower levels of mental health. Additionally, they seem to have severe limitations concerning professional success, despite having a good school education. Their family situation is also impaired with regard to starting a family. These considerable limitations in the life of adults with AS may help to understand their specific problems, and emphasize the importance of developing specific treatments for improving their mental health and social integration.
19. Sanders EJ, Irvin DW, Belardi K, McCune L, Boyd BA, Odom SL. {{The questions verbal children with autism spectrum disorder encounter in the inclusive preschool classroom}}. {Autism};2015 (Mar 6)
This study investigated questions adults asked to children with autism spectrum disorder in inclusive pre-kindergarten classrooms, and whether child (e.g. autism severity) and setting (i.e. adult-to-child ratio) characteristics were related to questions asked during center-time. Videos of verbal children with autism spectrum disorder (n = 42) were coded based on the following question categories adapted from the work of Massey et al.: management, low cognitive challenging, or cognitively challenging. Results indicated that management questions (mean = 19.97, standard deviation = 12.71) were asked more than less cognitively challenging questions (mean = 14.22, standard deviation = 8.98) and less cognitively challenging questions were asked more than cognitively challenging questions (mean = 10.00, standard deviation = 6.9). Children with higher language levels had a greater likelihood of receiving cognitively challenging questions (odds ratio = 1.025; p = 0.007). Cognitively challenging questions had a greater likelihood of being asked in classrooms with more adults relative to children (odds ratio = 1.176; p = 0.037). The findings present a first step in identifying the questions directed at preschoolers with autism spectrum disorder in inclusive classrooms.
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20. 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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21. Sun X, Allison C, Auyeung B, Zhang Z, Matthews FE, Baron-Cohen S, Brayne C. {{Validation of existing diagnosis of autism in mainland China using standardised diagnostic instruments}}. {Autism};2015 (Mar 10)
Research to date in mainland China has mainly focused on children with autistic disorder rather than Autism Spectrum Conditions and the diagnosis largely depended on clinical judgment without the use of diagnostic instruments. Whether children who have been diagnosed in China before meet the diagnostic criteria of Autism Spectrum Conditions is not known nor how many such children would meet these criteria. The aim of this study was to evaluate children with a known diagnosis of autism in mainland China using the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised to verify that children who were given a diagnosis of autism made by Chinese clinicians in China were mostly children with severe autism. Of 50 children with an existing diagnosis of autism made by Chinese clinicians, 47 children met the diagnosis of autism on the Autism Diagnostic Observation Schedule algorithm and 44 children met the diagnosis of autism on the Autism Diagnostic Interview-Revised algorithm. Using the Gwet’s alternative chance-corrected statistic, the agreement between the Chinese diagnosis and the Autism Diagnostic Observation Schedule diagnosis was very good (AC1 = 0.94, p < 0.005, 95% confidence interval (0.86, 1.00)), so was the agreement between the Chinese diagnosis and the Autism Diagnostic Interview-Revised (AC1 = 0.91, p < 0.005, 95% confidence interval (0.81, 1.00)). The agreement between the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised was lower but still very good (AC1 = 0.83, p < 0.005).
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22. 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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23. Trontel HG, Duffield TC, Bigler ED, Abildskov TJ, Froehlich A, Prigge MB, Travers BG, Anderson JS, Zielinski BA, Alexander AL, Lange N, Lainhart JE. {{Mesial temporal lobe and memory function in autism spectrum disorder: An exploration of volumetric findings}}. {J Clin Exp Neuropsychol};2015;37(2):178-192.
Studies have shown that individuals with autism spectrum disorder (ASD) tend to perform significantly below typical developing individuals on standardized measures of memory, even when not significantly different on measures of IQ. The current study sought to examine within ASD whether anatomical correlates of memory performance differed between those with average-to-above-average IQ (AIQ group) and those with low-average to borderline ability (LIQ group) as well as in relations to typically developing comparisons (TDC). Using automated volumetric analyses, we examined regional volume of classic memory areas including the hippocampus, parahippocampal gyrus, entorhinal cortex, and amygdala in an all-male sample AIQ (n = 38) and LIQ (n = 18) individuals with ASD along with 30 typically developing comparisons (TDC). Memory performance was assessed using the Test of Memory and Learning (TOMAL) compared among the groups and then correlated with regional brain volumes. Analyses revealed group differences on almost all facets of memory and learning as assessed by the various subtests of the TOMAL. The three groups did not differ on any region of interest (ROI) memory-related brain volumes. However, significant size-memory function interactions were observed. Negative correlations were found between the volume of the amygdala and composite, verbal, and delayed memory indices for the LIQ ASD group, indicating larger volume related to poorer performance. Implications for general memory functioning and dysfunctional neural connectivity in ASD are discussed.
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24. van Schalkwyk GI, Klingensmith K, Volkmar FR. {{Gender Identity and Autism Spectrum Disorders}}. {Yale J Biol Med};2015 (Mar);88(1):81-83.
In this review, we briefly summarize much of the existing literature on gender-related concerns and autism spectrum disorders (ASD), drawing attention to critical shortcomings in our current understanding and potential clinical implications. Some authors have concluded that gender identity disorder (GID), or gender dysphoria (GD), is more common in individuals with ASD, providing a range of potential explanations. However, existing literature is quantitatively limited, and our capacity to draw conclusions is further complicated by conceptual challenges regarding how gender identity is best understood. Discourses that emphasize gender as a component of identity formation are gaining prominence and seem particularly salient when applied to ASD. Individuals with ASD should enjoy equal rights with regard to treatment for gender dysphoria. Clinicians may be able to assist individuals in understanding this aspect of their identity by broadening the social frame and facilitating an exploration of gender roles.
25. 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.
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26. Yildirim Sari H, Girli A, Ozturk Ozgonenel S, Rowley H. {{Determination of Injury Risks and Safety Measures Taken by Mothers of Children With an Intellectual Disability and Autism Spectrum Disorder}}. {Int J Nurs Knowl};2015 (Mar 10)
PURPOSE: The purpose of the study is to determine the injury risk behaviors and home safety measures in children with an intellectual disability or autism spectrum disorder. METHOD: The study sample included mothers of 100 children between the ages of 2 and 12 years. FINDINGS: There was a significant difference between the home safety measures and the children’s ages, the birth order of the children, and the mother’s and father’s ages. There was not a significant relationship between the children’s ages, diagnosis, and Injury Behavior Checklist (IBC). There is a positive correlation between the total score of the Home Safety Measures Control List and IBC.
