1. {{Retraction: Measles-mumps-rubella vaccination timing and autism among young African American boys: a reanalysis of CDC data}}. {Transl Neurodegener};2014;3:22.
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2. Bernard PB, Benke TA. {{Early life seizures: Evidence for chronic deficits linked to autism and intellectual disability across species and models}}. {Exp Neurol};2014 (Oct 2)
Recent work in Exp Neurol by Lugo et al. (2014b) demonstrated chronic alterations in sociability, learning and memory following multiple early life seizures (ELSs) in a mouse model. This work adds to the growing body of evidence supporting the detrimental nature of ELSs on the developing brain to contribute to aspects of an autistic phenotype with intellectual disability. Review of the face validity of behavioral testing and the construct validity of the models used informs the predictive ability and thus the utility of these models to translate underlying molecular and cellular mechanisms into future human studies.
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3. Dillenburger K, Jordan JA, McKerr L, Keenan M. {{The Millennium child with autism: Early childhood trajectories for health, education and economic wellbeing}}. {Dev Neurorehabil};2014 (Oct 7):1-10.
Abstract Objective: Most of what we know about children with autism spectrum disorder (ASD) is based on post-diagnostic, retrospective, self-select studies. Oftentimes, there is no direct comparison between trajectories of children with ASD and children without ASD. Methods: To circumvent both of these problems, the present secondary data analysis utilised a large-scale longitudinal general population survey of children born in the year 2000 (i.e. the Millennium Cohort Study; MCS; n = 18 522). Bi-annual MCS data were available from five data sweeps (children aged 9 months to 11 years of age). Results: Pre-diagnostic data showed early health problems differentiated children later diagnosed with autism from non-diagnosed peers. Prevalence was much higher than previously estimated (3.5% for 11-year olds). Post-diagnosis, trajectories deteriorated significantly for the children with ASD and their families in relation to education, health and economic wellbeing. Conclusion: These findings raise many issues for service delivery and the rights of persons with disabilities and their families.
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4. Dong S, Walker MF, Carriero NJ, DiCola M, Willsey AJ, Ye AY, Waqar Z, Gonzalez LE, Overton JD, Frahm S, Keaney JF, 3rd, Teran NA, Dea J, Mandell JD, Hus Bal V, Sullivan CA, DiLullo NM, Khalil RO, Gockley J, Yuksel Z, Sertel SM, Ercan-Sencicek AG, Gupta AR, Mane SM, Sheldon M, Brooks AI, Roeder K, Devlin B, State MW, Wei L, Sanders SJ. {{De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder}}. {Cell Rep};2014 (Oct 9);9(1):16-23.
Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0-2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 x 10(-9)), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.
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5. Foody C, James JE, Leader G. {{Parenting Stress, Salivary Biomarkers, and Ambulatory Blood Pressure: A Comparison Between Mothers and Fathers of Children with Autism Spectrum Disorders}}. {J Autism Dev Disord};2014 (Oct 7)
Parents of children with autism spectrum disorders (ASD) may experience higher levels of stress and health problems than parents of children with typical development. However, most research has focused on mothers, with emphasis on parent-reported stress and wellbeing. This study compared parenting responsibility, distress, anxiety, depression, cortisol, alpha-amylase, and cardiovascular activity between 19 mother-father dyads of children with ASD. Mothers reported higher parenting responsibility, distress, anxiety, and depression than fathers, while fathers had higher blood pressure and heart rate variability. Mothers and fathers had lower than average morning cortisol levels, suggesting stress effects on the hypothalamic-pituitary-adrenal-axis. Parents of children with ASD may benefit from routine health screening (particularly adrenal and cardiovascular function) and referral for stress reduction interventions or supports.
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6. Frazier TW, Embacher R, Tilot AK, Koenig K, Mester J, Eng C. {{Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism}}. {Mol Psychiatry};2014 (Oct 7)
PTEN is a tumor suppressor associated with an inherited cancer syndrome and an important regulator of ongoing neural connectivity and plasticity. The present study examined molecular and phenotypic characteristics of individuals with germline heterozygous PTEN mutations and autism spectrum disorder (ASD) (PTEN-ASD), with the aim of identifying pathophysiologic markers that specifically associate with PTEN-ASD and that may serve as targets for future treatment trials. PTEN-ASD patients (n=17) were compared with idiopathic (non-PTEN) ASD patients with (macro-ASD, n=16) and without macrocephaly (normo-ASD, n=38) and healthy controls (n=14). Group differences were evaluated for PTEN pathway protein expression levels, global and regional structural brain volumes and cortical thickness measures, neurocognition and adaptive behavior. RNA expression patterns and brain characteristics of a murine model of Pten mislocalization were used to further evaluate abnormalities observed in human PTEN-ASD patients. PTEN-ASD had a high proportion of missense mutations and showed reduced PTEN protein levels. Compared with the other groups, prominent white-matter and cognitive abnormalities were specifically associated with PTEN-ASD patients, with strong reductions in processing speed and working memory. White-matter abnormalities mediated the relationship between PTEN protein reductions and reduced cognitive ability. The Ptenm3m4 murine model had differential expression of genes related to myelination and increased corpus callosum. Processing speed and working memory deficits and white-matter abnormalities may serve as useful features that signal clinicians that PTEN is etiologic and prompting referral to genetic professionals for gene testing, genetic counseling and cancer risk management; and could reveal treatment targets in trials of treatments for PTEN-ASD.Molecular Psychiatry advance online publication, 7 October 2014; doi:10.1038/mp.2014.125.
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7. Grisdale E, Lind SE, Eacott MJ, Williams DM. {{Self-referential memory in autism spectrum disorder and typical development: Exploring the ownership effect}}. {Conscious Cogn};2014 (Oct 3);30C:133-141.
Owned objects occupy a privileged cognitive processing status and are viewed almost as extensions of the self. It has been demonstrated that items over which a sense of ownership is felt will be better remembered than other items (an example of the « self-reference effect »). As autism spectrum disorder (ASD) is characterised by an a typical self-concept, people with ASD may not demonstrate this « ownership effect ». Two experiments were conducted which replicate and extend Cunningham, Turk, MacDonald, and Macrae (2008). In Experiment 1, neurotypical adults completed a card sorting task and cards belonging to the ‘self’ were better remembered than cards belonging to another person. In Experiment 2, adults with ASD recalled self- and other owned items equally well. These results shed light both on the relation between sense of self and the ownership effect, and the nature of the self-concept in ASD.
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8. Helles A, Gillberg CI, Gillberg C, Billstedt E. {{Asperger syndrome in males over two decades: stability and predictors of diagnosis}}. {J Child Psychol Psychiatry};2014 (Oct 4)
OBJECTIVE: To examine the diagnostic stability of a childhood diagnosis of Asperger Syndrome (AS) into adulthood in a prospective longitudinal study, and identify the predictors of stability. METHODS: One hundred males with AS diagnosed in childhood (T0) according to Gillberg’s AS criteria, were followed up prospectively into adulthood over an average of 19 years (range 13-26 years). Fifty males (mean age 30 years) participated in this second follow-up (T2) of the cohort. Seventy-six had participated in a previous follow-up (T1) at mean age 22 years (47 participated in both follow-ups). Diagnosis at T2 was assessed using three sets of diagnostic criteria (Gillberg’s AS criteria, DSM-IV Pervasive Developmental Disorder (PDD) and DSM-5 Autism Spectrum Disorder (ASD) criteria) and compared to previous assessments. Background predictors of diagnostic stability were analyzed. General functioning at T2 was assessed and compared to T1. RESULTS: There was a decline in the stability of AS diagnosis over time, the rate dropping from 82% at T1 to 44% at T2, when using the Gillberg criteria. There was also a significant decrease in the rate of cases fulfilling any PDD diagnosis according to the DSM-IV, from 91% at T1 to 76% at T2 in the 47 cases followed up twice. Severity of autism spectrum symptoms at T1 was the main predictor of diagnostic stability at T2. Twenty percent of those meeting criteria for a PDD diagnosis according to DSM-IV, did not meet DSM-5 ASD criteria although they had marked difficulties in everyday life. CONCLUSION: Asperger Syndrome, when considered as an ASD/PDD diagnosis, was fairly stable into adulthood, but there was a significant increase over time in cases no longer meeting criteria for an ASD diagnosis according to the DSM-IV, or AS according to the Gillberg criteria. Cases with a stable diagnosis showed significantly more core ASD symptoms in adolescence/young adulthood.
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9. James SJ, Shpyleva S, Melnyk S, Pavliv O, Pogribny IP. {{Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum}}. {Transl Psychiatry};2014;4:e460.
Epigenetic mechanisms regulate programmed gene expression during prenatal neurogenesis and serve as a mediator between genetics and environment in postnatal life. The recent discovery of 5-hydroxymethylcytosine (5-hmC), with highest concentration in the brain, has added a new dimension to epigenetic regulation of neurogenesis and the development of complex behavior disorders. Here, we take a candidate gene approach to define the role 5-hmC in Engrailed-2 (EN-2) gene expression in the autism cerebellum. The EN-2 homeobox transcription factor, previously implicated in autism, is essential for normal cerebellar patterning and development. We previously reported EN-2 overexpression associated with promoter DNA hypermethylation in the autism cerebellum but because traditional DNA methylation methodology cannot distinguish 5-methylcytosine (5-mC) from 5-hmC, we now extend our investigation by quantifying global and gene-specific 5-mC and 5-hmC. Globally, 5-hmC was significantly increased in the autism cerebellum and accompanied by increases in the expression of de novo methyltransferases DNMT3A and DNMT3B, ten-eleven translocase genes TET1 and TET3, and in 8-oxo-deoxyguanosine (8-oxo-dG) content, a marker of oxidative DNA damage. Within the EN-2 promoter, there was a significant positive correlation between 5-hmC content and EN-2 gene expression. Based on reports of reduced MeCP2 affinity for 5-hmC, MeCP2 binding studies in the EN-2 promoter revealed a significant decrease in repressive MeCP2 binding that may contribute to the aberrant overexpression of EN-2. Because normal cerebellar development depends on perinatal EN-2 downregulation, the sustained postnatal overexpression suggests that a critical window of cerebellar development may have been missed in some individuals with autism with downstream developmental consequences. Epigenetic regulation of the programmed on-off switches in gene expression that occur at birth and during early brain development warrants further investigation.
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10. Kalkbrenner AE, Windham GC, Serre ML, Akita Y, Wang X, Hoffman K, Thayer BP, Daniels JL. {{Particulate Matter Exposure, Prenatal and Postnatal Windows of Susceptibility, and Autism Spectrum Disorders}}. {Epidemiology};2014 (Oct 3)
BACKGROUND:: Recent studies suggest that exposure to traffic-related air pollutants, including particulate matter (PM), is associated with autism spectrum disorder (autism). METHODS:: Children with autism were identified by records-based surveillance (n = 645 born in North Carolina in 1994, 1996, 1998, or 2000, and n = 334 born in the San Francisco Bay Area in California in 1996). They were compared with randomly sampled children born in the same counties and years identified from birth records (n = 12,434 in North Carolina and n = 2,232 in California). Exposure to PM less than 10 mum (PM10) at the birth address was assigned to each child by a geostatistical interpolation method using daily concentrations from air pollution regulatory monitors. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for a 10 mug/m increase in PM10 within 3-month periods from preconception through the child’s first birthday, adjusting for year, state, maternal education and age, race/ethnicity, and neighborhood-level urbanization and median household income, and including a nonparametric term for week of birth to account for seasonal trends. RESULTS:: Temporal patterns in PM10 were pronounced, leading to an inverse correlation between the first- and third-trimester concentrations (r = -0.7). Adjusted ORs were, for the first trimester, 0.86 (95% CI = 0.74-0.99), second trimester, 0.97 (0.83-1.15), and third trimester, 1.36 (1.13-1.63); and, after simultaneously including first- and third-trimester concentrations to account for the inverse correlation, were: first trimester, 1.01 (0.81-1.27) and third trimester, 1.38 (1.03-1.84). CONCLUSIONS:: Our study adds to previous work in California showing a relation between traffic-related air pollution and autism, and adds similar findings in an eastern US state, with results consistent with increased susceptibility in the third-trimester.
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11. Killian JT, Lane JB, Cutter GR, Skinner SA, Kaufmann WE, Tarquinio DC, Glaze DG, Motil KJ, Neul JL, Percy AK. {{Pubertal Development in Rett Syndrome Deviates From Typical Females}}. {Pediatr Neurol};2014 (Aug 29)
BACKGROUND: Rett syndrome is a unique neurodevelopmental disorder, affecting approximately one in 10,000 live female births, most experiencing reduced growth. We characterized pubertal trajectories in females with Rett syndrome. We hypothesized that pubertal trajectory deviates from the general female population with early pubertal onset and delayed menarche. METHODS: Participants were individuals enrolled in the Rett Syndrome Natural History Study with clinical diagnosis of Rett syndrome or mutations in MECP2. Intervals to thelarche, adrenarche, and menarche were assessed by survival analysis; body mass index, mutation type, clinical severity, and pubertal milestone relationships were assessed by log-likelihood test; pathway synchrony (relationship between thelarche, adrenarche, and menarche) was assessed by chi-squared analysis. RESULTS: Compared with the general female population, more than 25% initiated puberty early, yet entered menarche later (median age 13.0 years). A total of 19% experienced delayed menarche. Median length of puberty, from thelarche to menarche, was 3.9 years. Higher body mass index correlated with earlier thelarche and adrenarche but not menarche; milder mutations correlated with earlier menarche; and milder clinical presentation correlated with earlier thelarche and menarche. Fifty-two percent entered puberty in synchrony, but different from the general population, 15% led with thelarche and 32% with adrenarche. CONCLUSIONS: Pubertal trajectories in Rett syndrome differ from general population, entering puberty early and reaching menarche later. Body mass index affects pubertal timing, but the relationship between specific mutations, clinical presentation, and underlying neuroendocrine pathology is less clear.
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12. Noto A, Fanos V, Barberini L, Grapov D, Fattuoni C, Zaffanello M, Casanova A, Fenu G, De Giacomo A, De Angelis M, Moretti C, Papoff P, Ditonno R, Francavilla R. {{The urinary metabolomics profile of an Italian autistic children population and their unaffected siblings}}. {J Matern Fetal Neonatal Med};2014 (Oct);27 Suppl 2:46-52.
Abstract Objective: A supervised multivariate model to classify the metabolome alterations between autistic spectrum disorders (ASD) patients and controls, siblings of autistic patients, has been realized and used to realize a network model of the ASD patients’ metabolome. METHODS: In our experiment we propose a quantification of urinary metabolites with the Mass Spectroscopy technique couple to Gas Chromatography. A multivariate model has been used to extrapolate the variables of importance for a network model of interaction between metabolites. In this way we are able to propose a network-based approach to ASD description. RESULTS: Children with autistic disease composing our studied population showed elevated concentration of several organic acids and sugars. Interactions among diet, intestinal flora and genes may explain such findings. Among them, the 3-(3-hydroxyphenyl)-3-hydroxypropanoic acid has been previously described as altered in autistic subjects. Other metabolites increased are 3,4-dihydroxybutyric acid, glycolic acid and glycine, cis-aconitic acid; phenylalanine, tyrosine, p-hydroxyphenylacetic acid, and homovanillic acid are all involved in the tyrosine pathway leading to neurotransmitter cathecolamine. CONCLUSION: GC-MS-based metabolomic analysis of the urinary metabolome suggests to have the required sensitivity and specificity to gain insight into ASD phenotypes and aid a personalized network-based medicine approach.
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13. Raz R, Weisskopf MG, Davidovitch M, Pinto O, Levine H. {{Differences in Autism Spectrum Disorders Incidence by Sub-Populations in Israel 1992-2009: A Total Population Study}}. {J Autism Dev Disord};2014 (Oct 7)
We analyzed data from the Israeli National Insurance Institute (NII). Autism Spectrum Disorder (ASD) incidence was calculated for all children born in Israel 1992-2009, and by population groups. Overall, 9,109 ASD cases among 2,431,649 children were identified. ASD cumulative incidence by age 8 years increased 10-fold during 2000-2011, from 0.49 % to 0.49 %, while other child disabilities in NII increased only 1.65-fold. There was a consistent increase in ASD incidence with advancing birth cohorts born 1992-2004, stabilizing among those born 2005-2009. ASD rates among Israeli Arabs were substantially lower, and increased about 10 years later than the general population. The findings suggest a role for ASD awareness, accessing of the government benefit, or the way the concept of ASD is perceived.
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14. Retico A, Tosetti M, Muratori F, Calderoni S. {{Neuroimaging-based methods for autism identification: a possible translational application?}}. {Funct Neurol};2014 (Oct 7):1-9.
Classification methods based on machine learning (ML) techniques are becoming widespread analysis tools in neuroimaging studies. They have the potential to enhance the diagnostic power of brain data, by assigning a predictive index, either of pathology or of treatment response, to the single subject’s acquisition. ML techniques are currently finding numerous applications in psychiatric illness, in addition to the widely studied neurodegenerative diseases. In this review we give a comprehensive account of the use of classification techniques applied to structural magnetic resonance images in autism spectrum disorders (ASDs). Understanding of these highly heterogeneous neurodevelopmental diseases could greatly benefit from additional descriptors of pathology and predictive indices extracted directly from brain data. A perspective is also provided on the future developments necessary to translate ML methods from the field of ASD research into the clinic.
15. Schelinski S, Riedel P, von Kriegstein K. {{Visual abilities are important for auditory-only speech recognition: Evidence from autism spectrum disorder}}. {Neuropsychologia};2014 (Oct 1)
In auditory-only conditions, for example when we listen to someone on the phone, it is essential to fast and accurately recognize what is said (speech recognition). Previous studies have shown that speech recognition performance in auditory-only conditions is better if the speaker is known not only by voice, but also by face. Here, we tested the hypothesis that such an improvement in auditory-only speech recognition depends on the ability to lip-read. To test this we recruited a group of adults with autism spectrum disorder (ASD), a condition associated with difficulties in lip-reading, and typically-developed controls. All participants were trained to identify six speakers by name and voice. Three speakers were learned by a video showing their face and three others were learned in a matched control condition without face. After training, participants performed an auditory-only speech recognition test that consisted of sentences spoken by the trained speakers. As a control condition, the test also included speaker identity recognition on the same auditory material. The results showed that, in the control group, performance in speech recognition was improved for speakers known by face in comparison to speakers learned in the matched control condition without face. The ASD group lacked such a performance benefit. For the ASD group auditory-only speech recognition was even worse for speakers known by face compared to speakers not known by face. In speaker identity recognition, the ASD group performed worse than the control group independent of whether the speakers were learned with or without face. Two additional visual experiments showed that the ASD group performed worse in lip-reading whereas face identity recognition was within the normal range. The findings support the view that auditory-only communication involves specific visual mechanisms. Further, they indicate that in ASD, speaker-specific dynamic visual information is not available to optimize auditory-only speech recognition.
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16. Sugathan A, Biagioli M, Golzio C, Erdin S, Blumenthal I, Manavalan P, Ragavendran A, Brand H, Lucente D, Miles J, Sheridan SD, Stortchevoi A, Kellis M, Haggarty SJ, Katsanis N, Gusella JF, Talkowski ME. {{CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors}}. {Proc Natl Acad Sci U S A};2014 (Oct 7)
Truncating mutations of chromodomain helicase DNA-binding protein 8 (CHD8), and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA sequencing) with genome-wide CHD8 binding (ChIP sequencing). Suppressing CHD8 to levels comparable with the loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8-binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (P < 10-8) and CHD8-bound genes (P = 0.0043), which align with previously identified coexpression modules during fetal development. We also find an intriguing enrichment of cancer-related gene sets among CHD8-bound genes (P < 10-10). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations. These data indicate that heterozygous disruption of CHD8 precipitates a network of gene-expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis.
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17. Zeedyk SM, Rodriguez G, Tipton LA, Baker BL, Blacher J. {{Bullying of youth with autism spectrum disorder, intellectual disability, or typical development: Victim and parent perspectives}}. {Res Autism Spectr Disord};2014 (Sep 1);8(9):1173-1183.
In-depth interviews conducted separately with 13-year-olds with autism spectrum disorder (ASD), intellectual disability (ID), or typical development (TD) and their mothers investigated the experiences of victimization in the form of bullying. Coded constructs from the interviews were utilized to compare groups on the frequency, type, and impact of victimization. Youth with ASD were victimized more frequently than their ID or TD peers, and the groups differed with regard to the type of bullying and the impact it had, with ASD youth faring the worst. Higher internalizing problems and conflict in friendships were found to be significant predictors of victimization, according to both youth- and mother-reports. These predictors were found to be more salient than ASD status alone. Implications for practice are discussed.
