Pubmed du 15/08/19

jeudi 15 août 2019

1. Amoruso L, Narzisi A, Pinzino M, Finisguerra A, Billeci L, Calderoni S, Fabbro F, Muratori F, Volzone A, Urgesi C. Contextual priors do not modulate action prediction in children with autism. Proc Biol Sci ;2019 (Aug 14) ;286(1908):20191319.

Bayesian accounts of autism suggest that this disorder may be rooted in an impaired ability to estimate the probability of future events, possibly owing to reduced priors. Here, we tested this hypothesis within the action domain in children with and without autism using a behavioural paradigm comprising a familiarization and a testing phase. During familiarization, children observed videos depicting a child model performing actions in diverse contexts. Crucially, within this phase, we implicitly biased action-context associations in terms of their probability of co-occurrence. During testing, children observed the same videos but drastically shortened (i.e. reduced amount of kinematics information) and were asked to infer action unfolding. Since during the testing phase movement kinematics became ambiguous, we expected children’s responses to be biased to contextual priors, thus compensating for perceptual uncertainty. While this probabilistic effect was present in controls, no such modulation was observed in autistic children, overall suggesting an impairment in using contextual priors when predicting other peoples’ actions in uncertain environments.

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2. Bilder DA, Esplin MS, Coon H, Burghardt P, Clark EAS, Fraser A, Smith KR, Worsham W, Chappelle K, Rayner T, Bakian AV. Early Second Trimester Maternal Serum Steroid-Related Biomarkers Associated with Autism Spectrum Disorder. J Autism Dev Disord ;2019 (Aug 13)

Epidemiologic studies link increased autism spectrum disorder (ASD) risk to obstetrical conditions associated with inflammation and steroid dysregulation, referred to as prenatal metabolic syndrome (PNMS). This pilot study measured steroid-related biomarkers in early second trimester maternal serum collected during the first and second trimester evaluation of risk study. ASD case and PNMS exposure status of index offspring were determined through linkage with autism registries and birth certificate records. ASD case (N = 53) and control (N = 19) groups were enriched for PNMS exposure. Higher estradiol and lower sex hormone binding globulin (SHBG) were significantly associated with increased ASD risk. Study findings provide preliminary evidence to link greater placental estradiol activity with ASD and support future investigations of the prenatal steroid environment in ASD.

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3. Chabbert D, Caubit X, Roubertoux PL, Carlier M, Habermann B, Jacq B, Salin P, Metwaly M, Frahm C, Fatmi A, Garratt AN, Severac D, Dubois E, Kerkerian-Le Goff L, Fasano L, Gubellini P. Postnatal Tshz3 Deletion Drives Altered Corticostriatal Function and Autism Spectrum Disorder-like Behavior. Biol Psychiatry ;2019 (Aug 15) ;86(4):274-285.

BACKGROUND : Heterozygous deletion of the TSHZ3 gene, encoding for the teashirt zinc-finger homeobox family member 3 (TSHZ3) transcription factor that is highly expressed in cortical projection neurons (CPNs), has been linked to an autism spectrum disorder (ASD) syndrome. Similarly, mice with Tshz3 haploinsufficiency show ASD-like behavior, paralleled by molecular changes in CPNs and corticostriatal synaptic dysfunctions. Here, we aimed at gaining more insight into "when" and "where" TSHZ3 is required for the proper development of the brain, and its deficiency crucial for developing this ASD syndrome. METHODS : We generated and characterized a novel mouse model of conditional Tshz3 deletion, obtained by crossing Tshz3(flox/flox) with CaMKIIalpha-Cre mice, in which Tshz3 is deleted in CPNs from postnatal day 2 to 3 onward. We characterized these mice by a multilevel approach combining genetics, cell biology, electrophysiology, behavioral testing, and bioinformatics. RESULTS : These conditional Tshz3 knockout mice exhibit altered cortical expression of more than 1000 genes, approximately 50% of which have their human orthologue involved in ASD, in particular genes encoding for glutamatergic synapse components. Consistently, we detected electrophysiological and synaptic changes in CPNs and impaired corticostriatal transmission and plasticity. Furthermore, these mice showed strong ASD-like behavioral deficits. CONCLUSIONS : Our study reveals a crucial postnatal role of TSHZ3 in the development and functioning of the corticostriatal circuitry and provides evidence that dysfunction in these circuits might be determinant for ASD pathogenesis. Our conditional Tshz3 knockout mouse constitutes a novel ASD model, opening the possibility for an early postnatal therapeutic window for the syndrome linked to TSHZ3 haploinsufficiency.

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4. Cheng Y, Jin P. Dysfunction of Habituation Learning : A Novel Pathogenic Paradigm of Intellectual Disability and Autism Spectrum Disorder. Biol Psychiatry ;2019 (Aug 15) ;86(4):253-254.

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5. Connolly S, Anney R, Gallagher L, Heron EA. Evidence of Assortative Mating in Autism Spectrum Disorder. Biol Psychiatry ;2019 (Aug 15) ;86(4):286-293.

BACKGROUND : Assortative mating is a nonrandom mating system in which individuals with similar genotypes and/or phenotypes mate with one another more frequently than would be expected in a random mating system. Assortative mating has been hypothesized to play a role in autism spectrum disorder (ASD) in an attempt to explain some of the increase in the prevalence of ASD that has recently been observed. ASD is considered to be a heritable neurodevelopmental disorder, but there is limited understanding of its causes. Assortative mating can be explored through both phenotypic and genotypic data, but up until now it has never been investigated through genotypic measures in ASD. METHODS : We investigated genotypically similar mating pairs using genome-wide single nucleotide polymorphism data on trio families (Autism Genome Project data [1590 parents] and Simons Simplex Collection data [1962 parents]). To determine whether or not an excess in genetic similarity was present, we employed kinship coefficients and examined spousal correlation between the principal components in both the Autism Genome Project and Simons Simplex Collection datasets. We also examined assortative mating using phenotype data on the parents to detect any correlation between ASD traits. RESULTS : We found significant evidence of genetic similarity between the parents of ASD offspring using both methods in the Autism Genome Project dataset. In the Simons Simplex Collection, there was also significant evidence of genetic similarity between the parents when explored through spousal correlation. CONCLUSIONS : This study gives further support to the hypothesis that positive assortative mating plays a role in ASD.

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6. Fenckova M, Blok LER, Asztalos L, Goodman DP, Cizek P, Singgih EL, Glennon JC, IntHout J, Zweier C, Eichler EE, von Reyn CR, Bernier RA, Asztalos Z, Schenck A. Habituation Learning Is a Widely Affected Mechanism in Drosophila Models of Intellectual Disability and Autism Spectrum Disorders. Biol Psychiatry ;2019 (Aug 15) ;86(4):294-305.

BACKGROUND : Although habituation is one of the most ancient and fundamental forms of learning, its regulators and its relevance for human disease are poorly understood. METHODS : We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and we tested these models in light-off jump habituation. We dissected neuronal substrates underlying the identified habituation deficits and integrated genotype-phenotype annotations, gene ontologies, and interaction networks to determine the clinical features and molecular processes that are associated with habituation deficits. RESULTS : We identified >100 genes required for habituation learning. For 93 of these genes, a role in habituation learning was previously unknown. These genes characterize ID disorders with macrocephaly and/or overgrowth and comorbid ASD. Moreover, individuals with ASD from the Simons Simplex Collection carrying damaging de novo mutations in these genes exhibit increased aberrant behaviors associated with inappropriate, stereotypic speech. At the molecular level, ID genes required for normal habituation are enriched in synaptic function and converge on Ras/mitogen-activated protein kinase (Ras/MAPK) signaling. Both increased Ras/MAPK signaling in gamma-aminobutyric acidergic (GABAergic) neurons and decreased Ras/MAPK signaling in cholinergic neurons specifically inhibit the adaptive habituation response. CONCLUSIONS : Our work supports the relevance of habituation learning to ASD, identifies an unprecedented number of novel habituation players, supports an emerging role for inhibitory neurons in habituation, and reveals an opposing, circuit-level-based mechanism for Ras/MAPK signaling. These findings establish habituation as a possible, widely applicable functional readout and target for pharmacologic intervention in ID/ASD.

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7. Graciarena M. Cytokines and Chemokines in Novel Roles : Exploring Their Potential as Predictors of Autism Spectrum Disorder. Biol Psychiatry ;2019 (Aug 15) ;86(4):e11-e12.

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8. Heuer LS, Croen LA, Jones KL, Yoshida CK, Hansen RL, Yolken R, Zerbo O, DeLorenze G, Kharrazi M, Ashwood P, Van de Water J. An Exploratory Examination of Neonatal Cytokines and Chemokines as Predictors of Autism Risk : The Early Markers for Autism Study. Biol Psychiatry ;2019 (Aug 15) ;86(4):255-264.

BACKGROUND : The identification of an early biomarker for autism spectrum disorder (ASD) would improve the determination of risk, leading to earlier diagnosis and, potentially, earlier intervention and improved outcomes. METHODS : Data were generated from the Early Markers for Autism study, a population-based case-control study of prenatal and neonatal biomarkers of ASD. Newborn bloodspots of children with ASD (n = 370), children with developmental delay (n = 140), and general population (GP) controls (n = 378) were analyzed for 42 different immune markers using a Luminex multiplex platform. Comparisons of immune marker concentrations between groups were examined using logistic regression and partial least squares discriminant analysis. RESULTS : Children with ASD had significantly increased neonatal levels of interleukin-6 (IL-6) and IL-8 compared with GP controls. An increase in IL-8 was especially significant in the ASD group with early onset compared with the GP group, with an adjusted odds ratio of 1.97 (95% confidence interval, 1.39-2.83 ; p = .00014). In addition, children with ASD had significantly elevated levels of eotaxin-1, interferon-gamma, and IL-12p70 relative to children with developmental delay. We observed no significant differences in levels of immune markers between the developmental delay and GP groups. CONCLUSIONS : Elevated levels of some inflammatory markers in newborn bloodspots indicated a higher degree of immune activation at birth in children who were subsequently diagnosed with ASD. The data from this exploratory study suggest that with further expansion, the development of neonatal bloodspot testing for cytokine/chemokine levels might lead to the identification of biomarkers that provide an accurate assessment of ASD risk at birth.

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9. Lake EMR, Finn ES, Noble SM, Vanderwal T, Shen X, Rosenberg MD, Spann MN, Chun MM, Scheinost D, Constable RT. The Functional Brain Organization of an Individual Allows Prediction of Measures of Social Abilities Transdiagnostically in Autism and Attention-Deficit/Hyperactivity Disorder. Biol Psychiatry ;2019 (Aug 15) ;86(4):315-326.

BACKGROUND : Autism spectrum disorder and attention-deficit/hyperactivity disorder (ADHD) are associated with complex changes as revealed by functional magnetic resonance imaging. To date, neuroimaging-based models are not able to characterize individuals with sufficient sensitivity and specificity. Further, although evidence shows that ADHD traits occur in individuals with autism spectrum disorder, and autism spectrum disorder traits in individuals with ADHD, the neurofunctional basis of the overlap is undefined. METHODS : Using individuals from the Autism Brain Imaging Data Exchange and ADHD-200, we apply a data-driven, subject-level approach, connectome-based predictive modeling, to resting-state functional magnetic resonance imaging data to identify brain-behavior associations that are predictive of symptom severity. We examine cross-diagnostic commonalities and differences. RESULTS : Using leave-one-subject-out and split-half analyses, we define networks that predict Social Responsiveness Scale, Autism Diagnostic Observation Schedule, and ADHD Rating Scale scores and confirm that these networks generalize to novel subjects. Networks share minimal overlap of edges (<2%) but some common regions of high hubness (Brodmann areas 10, 11, and 21, cerebellum, and thalamus). Further, predicted Social Responsiveness Scale scores for individuals with ADHD are linked to ADHD symptoms, supporting the hypothesis that brain organization relevant to autism spectrum disorder severity shares a component associated with attention in ADHD. Predictive connections and high-hubness regions are found within a wide range of brain areas and across conventional networks. CONCLUSIONS : An individual’s functional connectivity profile contains information that supports dimensional, nonbinary classification in autism spectrum disorder and ADHD. Furthermore, we can determine disorder-specific and shared neurofunctional pathology using our method.

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10. Li M, Li X, Xie L, Liu J, Wang F, Wang Z. Assisted therapeutic system based on reinforcement learning for children with autism. Comput Assist Surg (Abingdon) ;2019 (Aug 14):1-11.

Assisted therapy is increasingly used in autism spectrum disorders (ASD) for improving social interaction and communication skills in recent years. A lot of studies have proven that the form of interactive games for therapy has a good effect on children with autism. Thus, our study provided an assisted therapeutic system based on Reinforcement Learning (RL) for children with ASD, which has five interactive subgames. As is well known, it is necessary to establish and maintain compelling interactions in therapeutic process. Therefore, we aim to adjust the interactive content according to the emotions of children with autism. However, due to the atypical and unusually differences in children with autism, most systems are based on off-line training of small samples of individuals and online recognition, so the existing assisted systems are limited in their ability to automatically update system parameters of new mappings. The integration of RL and Convolutional Neural Network (CNN)-Support Vector Regression (SVR) was used to deal with the updating online of prediction model’s weights. The normalized emotion labels were evaluated by the therapists. Eleven children with autism as subjects were invited in this experiment and captured facial video images. The experiment lasted for five weeks of intermittent assisted therapy, and the results were evaluated for the system and the therapy effect. Finally, we achieved a general reduction in the root mean square error of the model prediction results and labels. Although there is no significant difference in Social Responsiveness Scale (SRS) scores before and after assisted therapy (p value = 0.60), in individual subjects (Sub. 1, Sub. 2 and Sub.3), the SRS total score is significantly reduced (Average drop of 19 points). These results demonstrate the effectiveness of prediction model based on RL and show the feasibility of assisted therapeutic system in children with autism.

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11. Mouga S, Correia BR, Cafe C, Duque F, Oliveira G. Language Predictors in Autism Spectrum Disorder : Insights from Neurodevelopmental Profile in a Longitudinal Perspective. J Abnorm Child Psychol ;2019 (Aug 13)

Language outcome in individuals with autism spectrum disorder (ASD) is predicted by early developmental milestones and cognitive abilities. The development and acquisition of expressive language (particularly the onset of first phrases) is a relevant clinical milestone by school age, since its early presentation is associated to better long-term life outcomes and to lower core clinical severity of ASD. Focusing on predictors of language in ASD children, a number of outstanding questions remain to be answered, namely, whether there are differences in the early key neurodevelopmental abilities and whether those differences in a specific period of time might predict verbal development and acquisition of expressive language. We aim to understand how the neurodevelopmental profile of ASD children evolves from the preschool to the school age and if and which subarea can better predict acquisition of expressive language. Children with ASD (N = 205) were evaluated with a structured assessment of neurodevelopment in two different age periods : 1) preschool period (mean age four years) and 2) reassessment in the school period (mean age seven years). Our findings demonstrate that in nonverbal preschool children with ASD normal or near normal Performance Developmental Quotient (superior to 73.5) evaluated at preschool age is a good predictor of later language development in ASD, which has important implications for intervention programs targeting this population and family information.

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12. Pain O, Pocklington AJ, Holmans PA, Bray NJ, O’Brien HE, Hall LS, Pardinas AF, O’Donovan MC, Owen MJ, Anney R. Novel Insight Into the Etiology of Autism Spectrum Disorder Gained by Integrating Expression Data With Genome-wide Association Statistics. Biol Psychiatry ;2019 (Aug 15) ;86(4):265-273.

BACKGROUND : A recent genome-wide association study (GWAS) of autism spectrum disorder (ASD) (ncases = 18,381, ncontrols = 27,969) has provided novel opportunities for investigating the etiology of ASD. Here, we integrate the ASD GWAS summary statistics with summary-level gene expression data to infer differential gene expression in ASD, an approach called transcriptome-wide association study (TWAS). METHODS : Using FUSION software, ASD GWAS summary statistics were integrated with predictors of gene expression from 16 human datasets, including adult and fetal brains. A novel adaptation of established statistical methods was then used to test for enrichment within candidate pathways and specific tissues and at different stages of brain development. The proportion of ASD heritability explained by predicted expression of genes in the TWAS was estimated using stratified linkage disequilibrium score regression. RESULTS : This study identified 14 genes as significantly differentially expressed in ASD, 13 of which were outside of known genome-wide significant loci (+/-500 kb). XRN2, a gene proximal to an ASD GWAS locus, was inferred to be significantly upregulated in ASD, providing insight into the functional consequence of this associated locus. One novel transcriptome-wide significant association from this study is the downregulation of PDIA6, which showed minimal evidence of association in the GWAS, and in gene-based analysis using MAGMA. Predicted gene expression in this study accounted for 13.0% of the total ASD single nucleotide polymorphism heritability. CONCLUSIONS : This study has implicated several genes as significantly up/downregulated in ASD, providing novel and useful information for subsequent functional studies. This study also explores the utility of TWAS-based enrichment analysis and compares TWAS results with a functionally agnostic approach.

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13. Seymour RA, Rippon G, Gooding-Williams G, Schoffelen JM, Kessler K. Dysregulated oscillatory connectivity in the visual system in autism spectrum disorder. Brain ;2019 (Aug 13)

Autism spectrum disorder is increasingly associated with atypical perceptual and sensory symptoms. Here we explore the hypothesis that aberrant sensory processing in autism spectrum disorder could be linked to atypical intra- (local) and interregional (global) brain connectivity. To elucidate oscillatory dynamics and connectivity in the visual domain we used magnetoencephalography and a simple visual grating paradigm with a group of 18 adolescent autistic participants and 18 typically developing control subjects. Both groups showed similar increases in gamma (40-80 Hz) and decreases in alpha (8-13 Hz) frequency power in occipital cortex. However, systematic group differences emerged when analysing intra- and interregional connectivity in detail. First, directed connectivity was estimated using non-parametric Granger causality between visual areas V1 and V4. Feedforward V1-to-V4 connectivity, mediated by gamma oscillations, was equivalent between autism spectrum disorder and control groups, but importantly, feedback V4-to-V1 connectivity, mediated by alpha (8-13 Hz) oscillations, was significantly reduced in the autism spectrum disorder group. This reduction was positively correlated with autistic quotient scores, consistent with an atypical visual hierarchy in autism, characterized by reduced top-down modulation of visual input via alpha-band oscillations. Second, at the local level in V1, coupling of alpha-phase to gamma amplitude (alpha-gamma phase amplitude coupling) was reduced in the autism spectrum disorder group. This implies dysregulated local visual processing, with gamma oscillations decoupled from patterns of wider alpha-band phase synchrony (i.e. reduced phase amplitude coupling), possibly due to an excitation-inhibition imbalance. More generally, these results are in agreement with predictive coding accounts of neurotypical perception and indicate that visual processes in autism are less modulated by contextual feedback information.

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14. So R, Makino K, Hirota T, Fujiwara M, Ocho K, Ikeda S, Tsubouchi S, Inagakip M. The 2-Year Course of Internet Addiction Among a Japanese Adolescent Psychiatric Clinic Sample with Autism Spectrum Disorder and/or Attention-Deficit Hyperactivity Disorder. J Autism Dev Disord ;2019 (Aug 13)

Internet addiction (IA) has been reported as prevalent in adolescents with autism spectrum disorders (ASD) and attention-deficit hyperactivity disorder (ADHD). However, the course of IA in this population has not been elucidated. The authors performed a 2-year follow-up study including 89 out of 132 adolescents with ASD and/or ADHD in a psychiatric clinical setting who participated in the original cross-sectional study assessing IA prevalence. Within this sample of participants from both the original and the follow-up study, results showed a 2-year IA remission and incidence rate of 60% and 5%, respectively. Our findings imply that the course of IA in psychiatric populations with ASD and/or ADHD might be similar to reports from previous studies with general adolescent populations.

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15. Vidal S, Xiol C, Pascual-Alonso A, O’Callaghan M, Pineda M, Armstrong J. Genetic Landscape of Rett Syndrome Spectrum : Improvements and Challenges. Int J Mol Sci ;2019 (Aug 12) ;20(16)

Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that primarily affects females, resulting in severe cognitive and physical disabilities, and is one of the most prevalent causes of intellectual disability in females. More than fifty years after the first publication on Rett syndrome, and almost two decades since the first report linking RTT to the MECP2 gene, the research community’s effort is focused on obtaining a better understanding of the genetics and the complex biology of RTT and Rett-like phenotypes without MECP2 mutations. Herein, we review the current molecular genetic studies, which investigate the genetic causes of RTT or Rett-like phenotypes which overlap with other genetic disorders and document the swift evolution of the techniques and methodologies employed. This review also underlines the clinical and genetic heterogeneity of the Rett syndrome spectrum and provides an overview of the RTT-related genes described to date, many of which are involved in epigenetic gene regulation, neurotransmitter action or RNA transcription/translation. Finally, it discusses the importance of including both phenotypic and genetic diagnosis to provide proper genetic counselling from a patient’s perspective and the appropriate treatment.

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16. Wakimizu R, Yamaguchi K, Fujioka H. Family empowerment and quality of life of parents raising children with Developmental Disabilities in 78 Japanese families. Int J Nurs Sci ;2017 (Jan 10) ;4(1):38-45.

Objectives : The families of these children experience distress both at the time of diagnosis and afterward. A top priority is to understand family empowerment, family function, and family members’ quality of life (QoL) and to effectively support these families in Japan. The objective of this study was to assess the actual conditions of families living with children having DDs and to explore the factors associated with family empowerment and parents’ QoL. Methods : We surveyed ninety-three parents (78 mothers, 15 fathers) from 78 families which lived with children with DDs in the capital region of Japan. We assessed two main outcomes using the Japanese versions of the following instruments : Family Empowerment Scale (FES), World Health Organization Quality of Life 26 (WHOQOL26), and other six outcomes. Correlation and multiple regression analyses were conducted. Results : No medication, cooperation with child rearing, assistance from a developmental support center, solved problems related to child rearing, and higher scores in Problem Solving contributed to higher FES scores. Higher WHOQOL26 scores were related to being a full-time housewife, higher self-esteem, no developmental support, a broad emotional support network, higher scores in Problem Solving and Role Function, and lower scores in Affective Reaction and General Function. Conclusions : We revealed that family empowerment and QoL of parents rearing children with DDs in Japan were affected by various subscales of family function and other family attributes. Effective interventions for improving family empowerment and QoL should be researched in the future.

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17. Wester Oxelgren U, Westerlund J, Myrelid A, Anneren G, Johansson L, Aberg M, Gustafsson J, Fernell E. An intervention targeting social, communication and daily activity skills in children and adolescents with Down syndrome and autism : a pilot study. Neuropsychiatr Dis Treat ;2019 ;15:2049-2056.

Purpose : To evaluate whether an intervention, targeting deficits in social communication, interaction and restricted activities in children and adolescents with Down syndrome and autism could lead to enhanced participation in family and school activities. Methods : The intervention included education for parents and school staff about autism, and workshops to identify social-communication and daily living activities that would be meaningful for the child to practice at home and at school. Thereafter, a three-month period of training for the child followed. Outcome measures comprised evaluation of goal achievement for each child, the "Family Strain Index" questionnaire and a visual scale pertaining to the parents’ general opinion about the intervention. Results : On average, more than 90% of the goals were (to some extent or completely) achieved at home and at school. The mean scores of the "Family Strain Index" were almost identical at the follow-up to those before intervention. The evaluation supported that the use of strategies, intended to facilitate activities and communication, remained largely 18 months after start of the intervention. Conclusion : Despite the group involved in this study being composed of older children and adolescents, most of whom had severe and profound intellectual disability, the goal achievements and parents’ views on the intervention were encouraging.

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18. Wray NR, Yengo L. Assortative Mating in Autism Spectrum Disorder : Toward an Evidence Base From DNA Data, but Not There Yet. Biol Psychiatry ;2019 (Aug 15) ;86(4):250-252.

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19. Zhu Y, Mordaunt CE, Yasui DH, Marathe R, Coulson RL, Dunaway KW, Jianu JM, Walker CK, Ozonoff S, Hertz-Picciotto I, Schmidt RJ, LaSalle JM. Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study. Hum Mol Genet ;2019 (Aug 15) ;28(16):2659-2674.

DNA methylation acts at the interface of genetic and environmental factors relevant for autism spectrum disorder (ASD). Placenta, normally discarded at birth, is a potentially rich source of DNA methylation patterns predictive of ASD in the child. Here, we performed whole methylome analyses of placentas from a prospective study MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) of high-risk pregnancies. A total of 400 differentially methylated regions (DMRs) discriminated placentas stored from children later diagnosed with ASD compared to typically developing controls. These ASD DMRs were significantly enriched at promoters, mapped to 596 genes functionally enriched in neuronal development, and overlapped genetic ASD risk. ASD DMRs at CYP2E1 and IRS2 reached genome-wide significance, replicated by pyrosequencing and correlated with expression differences in brain. Methylation at CYP2E1 associated with both ASD diagnosis and genotype within the DMR. In contrast, methylation at IRS2 was unaffected by within DMR genotype but modified by preconceptional maternal prenatal vitamin use. This study therefore identified two potentially useful early epigenetic markers for ASD in placenta.

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20. Zhuang Y, Xu HC, Shinde PV, Warfsmann J, Vasilevska J, Sundaram B, Behnke K, Huang J, Hoell JI, Borkhardt A, Pfeffer K, Taha MS, Herebian D, Mayatepek E, Brenner D, Ahmadian MR, Keitel V, Wieczorek D, Haussinger D, Pandyra AA, Lang KS, Lang PA. Fragile X mental retardation protein protects against tumour necrosis factor-mediated cell death and liver injury. Gut ;2019 (Aug 13)

OBJECTIVE : The Fragile X mental retardation (FMR) syndrome is a frequently inherited intellectual disability caused by decreased or absent expression of the FMR protein (FMRP). Lack of FMRP is associated with neuronal degradation and cognitive dysfunction but its role outside the central nervous system is insufficiently studied. Here, we identify a role of FMRP in liver disease. DESIGN : Mice lacking Fmr1 gene expression were used to study the role of FMRP during tumour necrosis factor (TNF)-induced liver damage in disease model systems. Liver damage and mechanistic studies were performed using real-time PCR, Western Blot, staining of tissue sections and clinical chemistry. RESULTS : Fmr1(null) mice exhibited increased liver damage during virus-mediated hepatitis following infection with the lymphocytic choriomeningitis virus. Exposure to TNF resulted in severe liver damage due to increased hepatocyte cell death. Consistently, we found increased caspase-8 and caspase-3 activation following TNF stimulation. Furthermore, we demonstrate FMRP to be critically important for regulating key molecules in TNF receptor 1 (TNFR1)-dependent apoptosis and necroptosis including CYLD, c-FLIPS and JNK, which contribute to prolonged RIPK1 expression. Accordingly, the RIPK1 inhibitor Necrostatin-1s could reduce liver cell death and alleviate liver damage in Fmr1(null) mice following TNF exposure. Consistently, FMRP-deficient mice developed increased pathology during acute cholestasis following bile duct ligation, which coincided with increased hepatic expression of RIPK1, RIPK3 and phosphorylation of MLKL. CONCLUSIONS : We show that FMRP plays a central role in the inhibition of TNF-mediated cell death during infection and liver disease.

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