1. Bolte S, Girdler S, Marschik PB. {{The contribution of environmental exposure to the etiology of autism spectrum disorder}}. {Cell Mol Life Sci};2018 (Dec 20)
Autism spectrum disorder (ASD) is a neurodevelopmental condition of heterogeneous etiology. While it is widely recognized that genetic and environmental factors and their interactions contribute to autism phenotypes, their precise causal mechanisms remain poorly understood. This article reviews our current understanding of environmental risk factors of ASD and their presumed adverse physiological mechanisms. It comprehensively maps the significance of parental age, teratogenic compounds, perinatal risks, medication, smoking and alcohol use, nutrition, vaccination, toxic exposures, as well as the role of extreme psychosocial factors. Further, we consider the role of potential protective factors such as folate and fatty acid intake. Evidence indicates an increased offspring vulnerability to ASD through advanced maternal and paternal age, valproate intake, toxic chemical exposure, maternal diabetes, enhanced steroidogenic activity, immune activation, and possibly altered zinc-copper cycles and treatment with selective serotonin reuptake inhibitors. Epidemiological studies demonstrate no evidence for vaccination posing an autism risk. It is concluded that future research needs to consider categorical autism, broader autism phenotypes, as well as autistic traits, and examine more homogenous autism variants by subgroup stratification. Our understanding of autism etiology could be advanced by research aimed at disentangling the causal and non-causal environmental effects, both founding and moderating, and gene-environment interplay using twin studies, longitudinal and experimental designs. The specificity of many environmental risks for ASD remains unknown and control of multiple confounders has been limited. Further understanding of the critical windows of neurodevelopmental vulnerability and investigating the fit of multiple hit and cumulative risk models are likely promising approaches in enhancing the understanding of role of environmental factors in the etiology of ASD.
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2. Cauvet E, Van’t Westeinde A, Toro R, Kuja-Halkola R, Neufeld J, Mevel K, Bolte S. {{Sex Differences Along the Autism Continuum: A Twin Study of Brain Structure}}. {Cereb Cortex};2018 (Dec 19)
Females might possess protective mechanisms regarding autism spectrum disorder (ASD) and require a higher detrimental load, including structural brain alterations, before developing clinically relevant levels of autistic traits. This study examines sex differences in structural brain morphology in autism and autistic traits using a within-twin pair approach. Twin design inherently controls for shared confounders and enables the study of gene-independent neuroanatomical variation. N = 148 twins (62 females) from 49 monozygotic and 25 dizygotic same-sex pairs were included. Participants were distributed along the whole continuum of autism including twin pairs discordant and concordant for clinical ASD. Regional brain volume, surface area, and cortical thickness were computed. Within-twin pair increases in autistic traits were related to decreases in cortical volume and surface area of temporal and frontal regions specifically in female twin pairs, in particular regions involved in social communication, while only two regions were associated with autistic traits in males. The same pattern was detected in the monozygotic twin pairs only. Thus, non-shared environmental factors seem to impact female more than male cerebral architecture associated with autistic traits. Our results are in line with the hypothesis of a female protective effect in autism and highlights the need to study ASD in females separately from males.
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3. Cid-Samper F, Gelabert-Baldrich M, Lang B, Lorenzo-Gotor N, Ponti RD, Severijnen L, Bolognesi B, Gelpi E, Hukema RK, Botta-Orfila T, Tartaglia GG. {{An Integrative Study of Protein-RNA Condensates Identifies Scaffolding RNAs and Reveals Players in Fragile X-Associated Tremor/Ataxia Syndrome}}. {Cell Rep};2018 (Dec 18);25(12):3422-3434.e3427.
Recent evidence indicates that specific RNAs promote the formation of ribonucleoprotein condensates by acting as scaffolds for RNA-binding proteins (RBPs). We systematically investigated RNA-RBP interaction networks to understand ribonucleoprotein assembly. We found that highly contacted RNAs are structured, have long UTRs, and contain nucleotide repeat expansions. Among the RNAs with such properties, we identified the FMR1 3′ UTR that harbors CGG expansions implicated in fragile X-associated tremor/ataxia syndrome (FXTAS). We studied FMR1 binding partners in silico and in vitro and prioritized the splicing regulator TRA2A for further characterization. In a FXTAS cellular model, we validated the TRA2A-FMR1 interaction and investigated implications of its sequestration at both transcriptomic and post-transcriptomic levels. We found that TRA2A co-aggregates with FMR1 in a FXTAS mouse model and in post-mortem human samples. Our integrative study identifies key components of ribonucleoprotein aggregates, providing links to neurodegenerative disease and allowing the discovery of therapeutic targets.
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4. Dempsey EE, Smith IM, Flanagan HE, Duku E, Lawrence MA, Szatmari P, Zwaigenbaum L, Vaillancourt T, Volden J, Mirenda P, Wadell C, Georgiades S, Elsabbagh M, Ungar WJ, Bennett T. {{Psychometric Properties of the Merrill-Palmer-Revised Scales of Development in Preschool Children With Autism Spectrum Disorder}}. {Assessment};2018 (Dec 20):1073191118818754.
Psychometrically sound tests of intellectual ability are indispensable for research and assessment of children with autism spectrum disorder (ASD), yet few tests have been validated for use with this population. The Merrill-Palmer-Revised Scales of Development (M-P-R) is a standardized test of intellectual ability that was validated for use with typically developing preschoolers. The current study’s aim was to investigate the criterion validity of the M-P-R for assessing cognitive skills in preschoolers with ASD ( N = 180). Good concurrent validity was demonstrated, with a large positive correlation between the M-P-R Receptive Language domain and the PLS-4 Auditory Comprehension subscale. The Cognitive domain of the M-P-R showed a medium positive correlation with later WISC-4 scores, showing acceptable predictive validity. Cognitive strengths and weaknesses assessed using the M-P-R mirrored those described for other measures, with most children obtaining higher standard scores on the Cognitive than the Receptive Language domain. An exploratory factor analysis suggested that one factor accounted for the majority of variability in M-P-R domains.
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5. Di Salvo E, Casciaro M, Quartuccio S, Genovese L, Gangemi S. {{Do Alarmins Have a Potential Role in Autism Spectrum Disorders Pathogenesis and Progression?}}. {Biomolecules};2018 (Dec 20);9(1)
Autism spectrum disorders (ASDs) represent a disabling condition in early childhood. A number of risk factors were proposed in order to explain their pathogenesis. A multifactorial model was proposed, and data supported the implication of genetic and environmental factors. One of the most accepted speculations is the existence of an imbalance of the immune system. Altered levels of cytokines, chemokines and immunoglobulins were demonstrated in patients with ASDs; in particular, proinflammatory mediators were significantly increased. Alarmins are a multifunctional heterogeneous group of proteins, structurally belonging to specific cells or incorporated by them. They are released in the surrounding tissues as a consequence of cell damage or inflammation. Their functions are multiple as they could activate innate immunity or recruit and activate antigen-presenting cells stimulating an adaptive response. Alarmins are interesting both for understanding the inflammatory process and for diagnostic purposes as biomarkers. Moreover, recent studies, separately, showed that alarmins like interleukin (IL)-33, high-mobility group box 1 (HMGB1), heat-shock protein (HSP) and S100 protein (S100) could play a relevant role in the pathogenesis of ASDs. According to the literature, some of these alarmins could be suitable as biomarkers of inflammation in ASD. Other alarmins, by interfering with the immune system blocking pro-inflammatory mediators, could be the key for ameliorating symptoms and behaviours in autistic disorders.
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6. Guo H, Wang T, Wu H, Long M, Coe BP, Li H, Xun G, Ou J, Chen B, Duan G, Bai T, Zhao N, Shen Y, Li Y, Wang Y, Zhang Y, Baker C, Liu Y, Pang N, Huang L, Han L, Jia X, Liu C, Ni H, Yang X, Xia L, Chen J, Shen L, Li Y, Zhao R, Zhao W, Peng J, Pan Q, Long Z, Su W, Tan J, Du X, Ke X, Yao M, Hu Z, Zou X, Zhao J, Bernier RA, Eichler EE, Xia K. {{Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model}}. {Mol Autism};2018;9:64.
Background: We previously performed targeted sequencing of autism risk genes in probands from the Autism Clinical and Genetic Resources in China (ACGC) (phase I). Here, we expand this analysis to a larger cohort of patients (ACGC phase II) to better understand the prevalence, inheritance, and genotype-phenotype correlations of likely gene-disrupting (LGD) mutations for autism candidate genes originally identified in cohorts of European descent. Methods: We sequenced 187 autism candidate genes in an additional 784 probands and 85 genes in 599 probands using single-molecule molecular inversion probes. We tested the inheritance of potentially pathogenic mutations, performed a meta-analysis of phase I and phase II data and combined our results with existing exome sequence data to investigate the phenotypes of carrier parents and patients with multiple hits in different autism risk genes. Results: We validated recurrent, LGD, de novo mutations (DNMs) in 13 genes. We identified a potential novel risk gene (ZNF292), one novel gene with recurrent LGD DNMs (RALGAPB), as well as genes associated with macrocephaly (GIGYF2 and WDFY3). We identified the transmission of private LGD mutations in genes predominantly associated with DNMs and showed that parental carriers tended to share milder autism-related phenotypes. Patients that carried DNMs in two or more candidate genes show more severe phenotypes. Conclusions: We identify new risk genes and transmission of deleterious mutations in genes primarily associated with DNMs. The fact that parental carriers show milder phenotypes and patients with multiple hits are more severe supports a multifactorial model of risk.
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7. Guo M, Li L, Zhang Q, Chen L, Dai Y, Liu L, Feng J, Cai X, Cheng Q, Chen J, Wei H, Li T. {{Vitamin and mineral status of children with autism spectrum disorder in Hainan Province of China: associations with symptoms}}. {Nutr Neurosci};2018 (Dec 20):1-8.
OBJECTIVE: This study was designed to compare the vitamin and mineral levels of children with autism spectrum disorders (ASDs) with those of age-matched typically developing (TD) children and to investigate their effects on the symptoms of autistic children. METHODS: The Autism Behavior Checklist (ABC), Social Responsiveness Scale (SRS) and Gesell Developmental Scale (GDS) were completed for 274 children diagnosed with ASD. Vitamins and minerals were compared for all ASD children and 97 age-matched TD children. Serum levels of vitamin A (VA) were detected with high-performance liquid chromatography (HPLC); those of vitamin D (VD), folate, vitamin B12 (VB12), and ferritin were measured with immunoassay methods; and those of minerals were detected using atomic absorption spectrophotometry in two groups. RESULTS: The VD and folate levels of children with ASD were significantly lower than those of TD children. The levels of calcium (Ca), magnesium (Mg), iron (Fe), and zinc (Zn) in children with ASD were significantly lower than those in TD children, and no significant difference was found in copper (Cu) levels. Correlation analysis showed that VA and Ca levels were negatively correlated with ASD symptoms. Folate, Ca, Fe and Zn were positively correlated with the GDS scores of autistic children. There were no significant interactions among VD, VB12 and ferritin and symptoms. CONCLUSION: We found that children with autism had more vitamin and mineral insufficiencies than TD children, and their levels were related to ASD symptoms. Therefore, it is essential to formulate a detailed nutritional evaluation for ASD children and provide timely and intensive interventions.
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8. Hanabusa K, Oi M, Tsukidate N, Yoshimura Y. {{Association between maternal Autism Spectrum Quotient scores and the tendency to see pragmatic impairments as a problem}}. {PLoS One};2018;13(12):e0209412.
The aim of the present study was to test the hypothesis that individuals with higher Autism Spectrum Quotient (AQ) scores would be more permissive of pragmatic impairments than those with lower AQ scores. We investigated the presence of a correlation between the AQ scores of mothers with children in grades 1 to 6 and their evaluation of assumed pragmatic impairments in children using the Maternal Evaluation of Pragmatic Impairments in Children (MEPC) measure. Mothers were asked to rate how they would feel if their child showed the communication behaviors listed in scales D (coherence), E (inappropriate initiation), F (stereotyped language), G (use of context), and H (nonverbal communication) of the Children’s Communication Checklist-2, which measures pragmatic impairments. All responses were given on a five-point Likert scale. The results indicated that the higher the maternal AQ score, the less the mother tended to evaluate pragmatic impairments as a problem. We also examined whether the age and gender of assumed children influenced the correlation between AQ and MEPC scores, but found no significant correlation. The partial correlation coefficients were calculated for each subscale, none of which was significant. A negative correlation was found between AQ and MEPC scores as a whole.
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9. Hong SJ, Hyung B, Paquola C, Bernhardt BC. {{The Superficial White Matter in Autism and Its Role in Connectivity Anomalies and Symptom Severity}}. {Cereb Cortex};2018 (Dec 19)
In autism spectrum disorders (ASDs), the majority of neuroimaging studies have focused on the analysis of cortical morphology. White matter changes remain less understood, particularly their association to cortical structure and function. Here, we focused on region that has gained only little attention in ASD neuroimaging: the superficial white matter (SWM) immediately beneath the cortical interface, a compartment playing a prominent role in corticogenesis that incorporates long- and short-range fibers implicated in corticocortical connectivity. Studying a multicentric dataset of ASD and neurotypical controls, we harnessed surface-based techniques to aggregate microstructural SWM diffusion features. Multivariate analysis revealed SWM anomalies in ASD compared with controls in medial parietal and temporoparietal regions. Effects were similar in children and adolescents/adults and consistent across sites. Although SWM anomalies were more confined when correcting for cortical thickness and surface area, findings were overall robust. Diffusion anomalies modulated functional connectivity reductions in ASD and related to symptom severity. Furthermore, mediation models indicated a link between SWM changes, functional connectivity, and symptom load. Analyses targeting the SWM offer a novel perspective on the interplay between structural and functional network perturbations in ASD, highlighting a potentially important neurobiological substrate contributing to its diverse behavioral phenotype.
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10. Kratz HE, Stahmer A, Xie M, Marcus SC, Pellecchia M, Locke J, Beidas R, Mandell DS. {{The effect of implementation climate on program fidelity and student outcomes in autism support classrooms}}. {J Consult Clin Psychol};2018 (Dec 20)
OBJECTIVE: An organization’s implementation climate, or the extent to which use of an intervention is expected, supported, and rewarded by colleagues and supervisors, has been identified as critical to successful intervention implementation and outcomes. The effect of implementation climate has not been well studied in special education settings. The present study examines the association between teachers’ perceptions of implementation climate, teacher fidelity to a school-based program for students with autism, and student outcomes (measured as changes in IQ) over time. METHOD: Participants included 158 students from 45 classrooms and their teachers. Teachers provided a measure of implementation climate at the beginning of the academic year; program fidelity was measured monthly throughout the year. The main and interaction effects of perceived implementation climate and fidelity on student outcomes were examined using longitudinal nested linear models with random effects for classroom and student, controlling for important covariates. RESULTS: On average, IQ scores improved 2.2 points (SD = 8.7). There were no main effects of perceived implementation climate or fidelity on student outcomes; however, the interaction between perceived implementation climate and fidelity was associated with student outcomes (p < .05, d = 0.54). Among classrooms with a strong perceived implementation climate, higher fidelity was associated with better student outcomes. CONCLUSIONS: While preliminary and requiring replication, these findings suggest that perceived implementation climate and program fidelity each may be important but not sufficient for optimizing outcomes for students with autism. (PsycINFO Database Record (c) 2018 APA, all rights reserved). Lien vers le texte intégral (Open Access ou abonnement)
11. Lee AW, Ventola P, Budimirovic D, Berry-Kravis E, Visootsak J. {{Clinical Development of Targeted Fragile X Syndrome Treatments: An Industry Perspective}}. {Brain Sci};2018 (Dec 5);8(12)
Fragile X syndrome (FXS) is the leading known cause of inherited intellectual disability and autism spectrum disorder. It is caused by a mutation of the fragile X mental retardation 1 (FMR1) gene, resulting in a deficit of fragile X mental retardation protein (FMRP). The clinical presentation of FXS is variable, and is typically associated with developmental delays, intellectual disability, a wide range of behavioral issues, and certain identifying physical features. Over the past 25 years, researchers have worked to understand the complex relationship between FMRP deficiency and the symptoms of FXS and, in the process, have identified several potential targeted therapeutics, some of which have been tested in clinical trials. Whereas most of the basic research to date has been led by experts at academic institutions, the pharmaceutical industry is becoming increasingly involved with not only the scientific community, but also with patient advocacy organizations, as more promising pharmacological agents are moving into the clinical stages of development. The objective of this review is to provide an industry perspective on the ongoing development of mechanism-based treatments for FXS, including identification of challenges and recommendations for future clinical trials.
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12. Orellana LM, Cantero-Fuentealba C, Schmidlin-Espinoza L, Luengo L. {{Psychoeducational intervention to improve oral assessment in people with autism spectrum disorder, BIO-BIO region, Chile}}. {Med Oral Patol Oral Cir Bucal};2018 (Dec 20)
BACKGROUND: Lichen planus (LP) is a chronic autoimmune disease that affects the oral mucosa as well as the skin, genital mucosa and other sites. OBJECTIVE: to evaluate the correlation between oral, genital and cutaneous lichen planus, in a sample of LP patients. MATERIAL AND METHODS: This descriptive study reviewed 274 clinical histories of patients, who all presented histological confirmation of lichen planus verified by a pathologist, attending research centers in Barcelona. RESULTS: A total of 40 LP patients (14.59%) presented genital lesions. Of 131 patients with cutaneous LP (47.8%), the most commonly affected zones were the body’s flexor surfaces, representing 60.1% of cases. 24% of patients (n=55) related the start of the lesions with previous stress events. Of the 131 subjects with cutaneous lesions, 19% (n=25) also presented oral lichen planus (OLP). Of the total sample, 53.6% (n=147) of patients presented oral lesions. The systemic diseases most commonly associated with this patient sample were psychological problems such as stress, anxiety and depression (48%), hypertension (27%), gastric problems (12%), and diabetes (9.7%). A family history of lichen planus was found in only 2 cases (0,72%) out of the total of 274. CONCLUSIONS: Any patient with OLP should undergo a thorough history and examination to investigate potential extraoral manifestations. The fact that 37 patients with OLP in this series were identified with simultaneous involvement at more than one site highlights the need for exhaustive evaluation and multidisciplinary approaches to this disease.
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13. Ramaiah M, Tan K, Plank TM, Song HW, Dumdie JN, Jones S, Shum EY, Sheridan SD, Peterson KJ, Gromoll J, Haggarty SJ, Cook-Andersen H, Wilkinson MF. {{A microRNA cluster in the Fragile-X region expressed during spermatogenesis targets FMR1}}. {EMBO Rep};2018 (Dec 20)
Testis-expressed X-linked genes typically evolve rapidly. Here, we report on a testis-expressed X-linked microRNA (miRNA) cluster that despite rapid alterations in sequence has retained its position in the Fragile-X region of the X chromosome in placental mammals. Surprisingly, the miRNAs encoded by this cluster (Fx-mir) have a predilection for targeting the immediately adjacent gene, Fmr1, an unexpected finding given that miRNAs usually act in trans, not in cis Robust repression of Fmr1 is conferred by combinations of Fx-mir miRNAs induced in Sertoli cells (SCs) during postnatal development when they terminate proliferation. Physiological significance is suggested by the finding that FMRP, the protein product of Fmr1, is downregulated when Fx-mir miRNAs are induced, and that FMRP loss causes SC hyperproliferation and spermatogenic defects. Fx-mir miRNAs not only regulate the expression of FMRP, but also regulate the expression of eIF4E and CYFIP1, which together with FMRP form a translational regulatory complex. Our results support a model in which Fx-mir family members act cooperatively to regulate the translation of batteries of mRNAs in a developmentally regulated manner in SCs.
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14. Sayad A, Omrani MD, Fallah H, Taheri M, Ghafouri-Fard S. {{Aberrant Expression of Long Non-coding RNAs in Peripheral Blood of Autistic Patients}}. {J Mol Neurosci};2018 (Dec 18)
Long non-coding RNAs (lncRNAs) constitute a large proportion of human transcriptome and are involved in fundamental aspects of neurodevelopment. In the present study, we evaluated expression levels of three lncRNAs, namely, Nuclear Paraspeckle Assembly Transcript 1 (NEAT1), p21-associated ncRNA DNA damage-activated (PANDA), and taurine-upregulated gene 1 (TUG1), in peripheral blood of autism spectrum disorder (ASD) patients compared with those in healthy subjects. We found a significant upregulation of NEAT1 and TUG1 in ASD patients. In addition, relative expressions of the pairs of lncRNAs were significantly correlated in both patients and healthy subjects. However, expressions of these lncRNAs were not correlated with age of study participants. The present study provides further evidences for dysregulation of lncRNAs in ASD patients.
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15. Sutherland R, Trembath D, Hodge MA, Rose V, Roberts J. {{Telehealth and autism: Are telehealth language assessments reliable and feasible for children with autism?}}. {Int J Lang Commun Disord};2018 (Nov 22)
BACKGROUND: Access to timely and appropriate speech-language pathology (SLP) services is a significant challenge for many families. Telehealth has been used successfully to treat a range of communication disorders in children and adults. Research examining the use of telehealth for children with autism has focused largely on diagnosis, parent-implemented interventions, and behavioural interventions involving interactions between clinicians and parents. There is, however, very limited research into the use of telehealth directly to assess or intervene with children with autism. This paper reports the outcomes of a study of telehealth language assessments with primary school-aged children with autism. AIMS: To evaluate the reliability and feasibility of telehealth language assessments for school-aged children with autism. METHODS & PROCEDURES: The language skills of 13 children with autism aged 9-12 who attended mainstream schools or support classes were assessed using the Clinical Evaluation of Language Fundamentals-4th Edition. An SLP delivered and scored four subtests of the assessment via telehealth from a remote location. A second SLP at the same location as the child co-scored the online subtests to provide a measure of reliability and delivered the remaining subtests. The local SLP completed checklists in both conditions to provide observations regarding behaviour. Parent feedback was elicited via survey. OUTCOMES & RESULTS: There was strong interrater reliability between the telehealth and face-to-face conditions (correlation coefficients ranged from r = 0.919 to 0.990 across the subtests and Core Language Score) and good agreement between clinicians on all measures. Analysis using the Wilcoxon Signed Rank test indicated no significant differences in children’s behaviour between the telehealth and face-to-face conditions, although variation between individuals was observed. Parents provided generally positive feedback about the use of telehealth for the assessments. CONCLUSIONS & IMPLICATIONS: The findings of this study provide preliminary support the use of telehealth assessments of school-aged children with autism. Comparison of telehealth and face-to-face assessment scores showed high agreement and correlation, and while the children showed individual differences in their behaviour during the telehealth sessions, there was no clear difference between the conditions at the group level. The findings suggest that telehealth may present a reliable and feasible approach to the assessment of language for children with autism in some circumstances as a primary or adjunct service model, while acknowledging that individual differences among these children may be important to consider when planning both assessment and intervention via telehealth.
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16. Wichnick-Gillis AM, Vener SM, Poulson CL. {{Script fading for children with autism: generalization of social initiation skills from school to home}}. {J Appl Behav Anal};2018 (Dec 19)
We used a script-fading package to teach children with autism to initiate social interactions across various activities in the school setting, and we programmed for generalization in the untrained home setting with a sibling. The three participants, ages 8 to 10 years, demonstrated deficits in social initiations with their peers. During baseline, the participants emitted initiations to one another, although this behavior was variable and did not endure over time. With the introduction of the script-fading package, however, social initiations systematically increased. Moreover, the effects of the script-fading package generalized to the untrained home setting with a sibling. This study expands upon previous research by demonstrating the generalization of social initiations from school with peers to the home setting with siblings.
