Pubmed du 23/11/17

jeudi 23 novembre 2017

1. Bearss K, Burrell TL, Challa SA, Postorino V, Gillespie SE, Crooks C, Scahill L. Feasibility of Parent Training via Telehealth for Children with Autism Spectrum Disorder and Disruptive Behavior : A Demonstration Pilot. J Autism Dev Disord. 2017.

Telehealth is a potential solution to limited access to specialized services for children with autism spectrum disorder (ASD) in rural areas. We conducted a feasibility trial of parent training with children ages 3-8 with ASD and disruptive behavior from rural communities. Fourteen children (mean age 5.8 +/- 1.7) from four telehealth sites enrolled. Thirteen families (92.9%) completed treatment, with 91.6% of core sessions attended. Therapists attained 98% fidelity to the manual and 93% of expected outcome measures were collected at week 24. Eleven of 14 (78.6%) participants were rated as much/very much improved. Parent training via telehealth was acceptable to parents and treatment could be delivered reliably by therapists. Preliminary efficacy findings suggests further study is justified.

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2. Beker S, Foxe JJ, Molholm S. Ripe for solution : Delayed development of multisensory processing in autism and its remediation. Neurosci Biobehav Rev. 2017.

Difficulty integrating inputs from different sensory sources is commonly reported in individuals with Autism Spectrum Disorder (ASD). Accumulating evidence consistently points to altered patterns of behavioral reactions and neural activity when individuals with ASD observe or act upon information arriving through multiple sensory systems. For example, impairments in the integration of seen and heard speech appear to be particularly acute, with obvious implications for interpersonal communication. Here, we explore the literature on multisensory processing in autism with a focus on developmental trajectories. While much remains to be understood, some consistent observations emerge. Broadly, sensory integration deficits are found in children with an ASD whereas these appear to be much ameliorated, or even fully recovered, in older teenagers and adults on the spectrum. This protracted delay in the development of multisensory processing raises the possibility of applying early intervention strategies focused on multisensory integration, to accelerate resolution of these functions. We also consider how dysfunctional cross-sensory oscillatory neural communication may be one key pathway to impaired multisensory processing in ASD.

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3. Castagnola S, Bardoni B, Maurin T. The Search for an Effective Therapy to Treat Fragile X Syndrome : Dream or Reality ?. Front Synaptic Neurosci. 2017 ; 9 : 15.

Fragile X Syndrome (FXS) is the most common form of intellectual disability and a primary cause of autism. It originates from the lack of the Fragile X Mental Retardation Protein (FMRP), which is an RNA-binding protein encoded by the Fragile X Mental Retardation Gene 1 (FMR1) gene. Multiple roles have been attributed to this protein, ranging from RNA transport (from the nucleus to the cytoplasm, but also along neurites) to translational control of mRNAs. Over the last 20 years many studies have found a large number of FMRP mRNA targets, but it is still not clear which are those playing a critical role in the etiology of FXS. So far, no therapy for FXS has been found, making the quest for novel targets of considerable importance. Several pharmacological approaches have been attempted, but, despite some promising preclinical results, no strategy gave successful outcomes, due either to the induction of major side effects or to the lack of improvement of the phenotypes. However, these studies suggested that, in order to measure the effectiveness of a specific treatment, trials should be redesigned and new endpoints defined in FXS patients. Nevertheless, the search for new therapeutic targets for FXS is very active. In this context, the advances in animal modeling, coupled with better understanding of neurobiology and physiopathology of FXS, are of crucial importance in developing new selected treatments. Here, we discuss the pathways that were recently linked to the physiopathology of FXS (mGluR, GABAR, insulin, Insulin-like Growth Factor 1 (IGF-1), MPP-9, serotonin, oxytocin and endocannabinoid signaling) and that suggest new approaches to find an effective therapy for this disorder. Our goal with this review article is to summarize some recent relevant findings on FXS treatment strategies in order to have a clearer view of the different pathways analyzed to date emphasizing those shared with other synaptic disorders.

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4. Chang YC, Shih W, Landa R, Kaiser A, Kasari C. Symbolic Play in School-Aged Minimally Verbal Children with Autism Spectrum Disorder. J Autism Dev Disord. 2017.

Few interventions exist for school-aged minimally verbal children with autism spectrum disorder (ASD). Even though play skills are associated with children’s production of language, few studies have focused on play for minimally verbal children. Fifty-eight minimally verbal children with ASD received a naturalistic developmental behavioral intervention. Children were randomized to receive a speech generating device in the context of the intervention or not. Children in both conditions improved in play skills at exit. Children demonstrated an increase in play skills in proximal (sessions) and distal (during blind assessment) contexts. Minimally verbal children with ASD can improve their play skills within a targeted intervention. Increases in symbolic play were associated with increases in expressive language skills.

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5. Cuppini C, Ursino M, Magosso E, Ross LA, Foxe JJ, Molholm S. A Computational Analysis of Neural Mechanisms Underlying the Maturation of Multisensory Speech Integration in Neurotypical Children and Those on the Autism Spectrum. Front Hum Neurosci. 2017 ; 11 : 518.

Failure to appropriately develop multisensory integration (MSI) of audiovisual speech may affect a child’s ability to attain optimal communication. Studies have shown protracted development of MSI into late-childhood and identified deficits in MSI in children with an autism spectrum disorder (ASD). Currently, the neural basis of acquisition of this ability is not well understood. Here, we developed a computational model informed by neurophysiology to analyze possible mechanisms underlying MSI maturation, and its delayed development in ASD. The model posits that strengthening of feedforward and cross-sensory connections, responsible for the alignment of auditory and visual speech sound representations in posterior superior temporal gyrus/sulcus, can explain behavioral data on the acquisition of MSI. This was simulated by a training phase during which the network was exposed to unisensory and multisensory stimuli, and projections were crafted by Hebbian rules of potentiation and depression. In its mature architecture, the network also reproduced the well-known multisensory McGurk speech effect. Deficits in audiovisual speech perception in ASD were well accounted for by fewer multisensory exposures, compatible with a lack of attention, but not by reduced synaptic connectivity or synaptic plasticity.

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6. Dickson KS, Suhrheinrich J, Rieth SR, Stahmer AC. Parent and Teacher Concordance of Child Outcomes for Youth with Autism Spectrum Disorder. J Autism Dev Disord. 2017.

Cross-informant ratings of are considered gold standard for child behavioral assessment. To date, little work has examined informant ratings of adaptive functioning for youth with autism spectrum disorder (ASD). In a large, diverse sample of youth with ASD, this study evaluated parent-teacher concordance of ratings of adaptive functioning and ASD-specific symptomatology across time. The impact of child clinical characteristics on concordance was also examined. Participants included 246 children, their caregivers and teachers. Parent-teacher concordance was variable but generally consistent across time. Concordance was significantly impacted by autism severity and child cognitive abilities. Findings inform the broader concordance literature and support the need to consider child clinical factors when assessing child functioning in samples of children with ASD.

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7. Esnafoglu E, Cirrik S. Increased serum Midkine levels in Autism Spectrum Disorder patients. Int J Neurosci. 2017 : 1-14.

BACKGROUND : Midkine (MK) is a heparin binding growth factor and is involved in neurogenesis, neural development and neuroprotection. Additionally MK may contribute to cancer development and pathogenesis of neurodegenerative disorders and schizophrenia. Considering these effects of midkine, this study researched whether MK is involved in Autism spectrum disorders (ASD) pathogenesis. METHODS : We evaluated serum MK levels of 38 patients with ASD and 32 healthy control group. MK levels were measured with ELISA, while ASD severity was assessed with Childhood Autism Rating Scale. RESULTS : Our data showed that the serum MK concentration in ASD patients (mean+/-SD, 11.51 +/- 8.53 pg/ml) is significantly higher than healthy controls (mean+/-SD, 6.19 +/- 3.94 pg/ml) (p = 0.007). CONCLUSIONS : According to these results, midkine may play a role in ASD pathogenesis.

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8. Estes ML, McAllister AK. Brain, Immunity, Gut : "BIG" Links between Pregnancy and Autism. Immunity. 2017 ; 47(5) : 816-9.

Although dysregulation of brain, immune, and gut physiology during pregnancy have each been implicated in neuropsychiatric disorders, whether and how these presumably distinct systems are linked to cause disease is unclear. Kim et al. (2017) and Shin Yim et al. (2017) identify a pathway to explain how these aspects of our physiology are deeply and inextricably connected.

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9. Factor RS, Swain DM, Scarpa A. Child Autism Spectrum Disorder Traits and Parenting Stress : The Utility of Using a Physiological Measure of Parental Stress. J Autism Dev Disord. 2017.

Caregivers of children with autism spectrum disorder (ASD) report greater stress due to unique parenting demands (e.g. ; Estes et al. in Brain Dev 35(2):133-138, 2013). Stress is often studied through self-report and has not been extensively studied using physiological measures. This study compared parenting stress in mothers of children with and without ASD traits. Twenty-seven mother-child dyads participated in an interaction task while measuring mother’s heart rate variability (HRV) and mothers self-reported stress levels. Results demonstrated that while self-report and physiological stress measures were not correlated, ASD symptomology did account for HRV change score (i.e., more severe ASD symptoms were positively related to HRV change). This may reflect an atypical coping response. Implications for using physiological indicators for studying parenting stress are explored.

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10. Finnegan E, Accardo AL. Written Expression in Individuals with Autism Spectrum Disorder : A Meta-Analysis. J Autism Dev Disord. 2017.

Although studies exist measuring the effectiveness of writing interventions for students with autism spectrum disorder (ASD), research assessing the writing skills for this group is sparse. The present study identified differences in the written expression of individuals with ASD compared to typically developing (TD) peers, using variables selected from 13 different studies. Using Pearson Product Moment-correlation the relationship between the quality of research studies and the magnitude of the effect sizes was examined. Findings indicate significant differences in the following components of written expression ; length, legibility, handwriting size, speed, spelling, and overall structure, highlighting the need for future research to determine if the characteristics of written expression in individuals with ASD are similar to other struggling writers.

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11. Gilchrist KH, Hegarty-Craver M, Christian RB, Grego S, Kies AC, Wheeler AC. Automated Detection of Repetitive Motor Behaviors as an Outcome Measurement in Intellectual and Developmental Disabilities. J Autism Dev Disord. 2017.

Repetitive sensory motor behaviors are a direct target for clinical treatment and a potential treatment endpoint for individuals with intellectual or developmental disabilities. By removing the burden associated with video annotation or direct observation, automated detection of stereotypy would allow for longer term monitoring in ecologic settings. We report automated detection of common stereotypical motor movements using commercially available accelerometers affixed to the body and a generalizable detection algorithm. The method achieved a sensitivity of 80% for body rocking and 93% for hand flapping without individualized algorithm training or foreknowledge of subject’s specific movements. This approach is well-suited for implementation in a continuous monitoring system outside of a clinical setting.

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12. Grossberg S. Acetylcholine Neuromodulation in Normal and Abnormal Learning and Memory : Vigilance Control in Waking, Sleep, Autism, Amnesia and Alzheimer’s Disease. Front Neural Circuits. 2017 ; 11 : 82.

Adaptive Resonance Theory, or ART, is a neural model that explains how normal and abnormal brains may learn to categorize and recognize objects and events in a changing world, and how these learned categories may be remembered for a long time. This article uses ART to propose and unify the explanation of diverse data about normal and abnormal modulation of learning and memory by acetylcholine (ACh). In ART, vigilance control determines whether learned categories will be general and abstract, or specific and concrete. ART models how vigilance may be regulated by ACh release in layer 5 neocortical cells by influencing after-hyperpolarization (AHP) currents. This phasic ACh release is mediated by cells in the nucleus basalis (NB) of Meynert that are activated by unexpected events. The article additionally discusses data about ACh-mediated tonic control of vigilance. ART proposes that there are often dynamic breakdowns of tonic control in mental disorders such as autism, where vigilance remains high, and medial temporal amnesia, where vigilance remains low. Tonic control also occurs during sleep-wake cycles. Properties of Up and Down states during slow wave sleep arise in ACh-modulated laminar cortical ART circuits that carry out processes in awake individuals of contrast normalization, attentional modulation, decision-making, activity-dependent habituation, and mismatch-mediated reset. These slow wave sleep circuits interact with circuits that control circadian rhythms and memory consolidation. Tonic control properties also clarify how Alzheimer’s disease symptoms follow from a massive structural degeneration that includes undermining vigilance control by ACh in cortical layers 3 and 5. Sleep disruptions before and during Alzheimer’s disease, and how they contribute to a vicious cycle of plaque formation in layers 3 and 5, are also clarified from this perspective.

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13. Hetzroni OE, Shalahevich K. Structure Mapping in Autism Spectrum Disorder : Levels of Information Processing and Relations to Executive Functions. J Autism Dev Disord. 2017.

Analogical reasoning was investigated among children with autism spectrum disorders (ASD) without intellectual disabilities and typical development (TD). Children were asked to select one of two targets in two conditions : (1) with and without spatial structure similarity ; (2) with and without a perceptual distractor. Results demonstrate that children with ASD were able to select targets based on structural similarity, but this ability decreased to chance level when presented with a perceptual distractor. Everyday executive functions were positively correlated with structural selections among children with ASD. Results suggest that although children with ASD were able to select based on systematicity principle, perceptual distractor decreased their selection so that their cognitive system produced less structure similarities, that negatively affects spatial analogical reasoning.

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14. Higuchi Y, Motoki T, Ishida H, Kanamitsu K, Washio K, Oyama T, Noda T, Tsurumaru Y, Okada A, Tsukahara H, Shimada A. Sorafenib treatment for papillary thyroid carcinoma with diffuse lung metastases in a child with autism spectrum disorder : a case report. BMC Cancer. 2017 ; 17(1) : 775.

BACKGROUND : Pediatric papillary thyroid carcinoma frequently presents with lymph node involvement and distant metastases. Sorafenib, an oral multikinase inhibitor, has been used to treat radioactive iodine (RAI) therapy-refractory thyroid carcinoma in adults ; however, pediatric experience is limited. Medical procedures and hospitalization for children with autism spectrum disorder may be challenging. CASE PRESENTATION : An 11-year-old boy with autism spectrum disorder and moderate intellectual impairment presented with dyspnea on exertion with thyroid carcinoma and diffuses lung metastases. Total thyroidectomy and adjuvant RAI therapy is the standard treatment ; however, the latter therapy was impractical because of his respiratory status and challenging behaviors. He was therefore started on sorafenib 200 mg/day (150 mg/m(2)/day) and this dosage was increased to 400 mg/day (300 mg/m(2)/day). The adverse effects were mild and tolerable. After administration of medication, his dyspnea improved and surgery was performed. We attempted to administer RAI therapy after surgery ; however, we abandoned it because he had difficulty taking care of himself according to isolation room rules. Thyrotropin suppression therapy was therefore started and sorafenib treatment (400 mg/day) resumed. Follow-up imaging showed regression of pulmonary metastases. The metastases have remained stable for over 24 months on continuous sorafenib treatment without serious adverse events. CONCLUSION : We inevitably used sorafenib as an alternative to standard therapy because of the patient’s specific circumstances. Individualized strategies for pediatric cancer patients with autism spectrum disorder are needed.

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15. Khatri N, Gilbert JP, Huo Y, Sharaflari R, Nee M, Qiao H, Man HY. The autism protein Ube3A/E6AP remodels neuronal dendritic arborization via caspase-dependent microtubule destabilization. J Neurosci. 2017.

UBE3A gene copy number variation and the resulting overexpression of the protein E6AP is directly linked to autism spectrum disorders (ASDs), however the underlying cellular and molecular neurobiology remains less clear. Here we report the role of ASD-related increased dosage of Ube3A/E6AP in dendritic arborization during brain development. We show that increased E6AP expression in primary cultured neurons leads to a reduction in dendritic branch number and length. The E6AP-dependent remodeling of dendritic arborization results from retraction of dendrites by thinning and fragmentation at the tips of dendrite branches, leading to shortening or removal of dendrites. This remodeling effect is mediated by the ubiquitination and degradation of XIAP by E6AP, which leads to activation of caspase-3 and cleavage of microtubules. In vivo, male and female Ube3A 2X ASD mice show decreased XIAP levels, increased caspase-3 activation, and elevated levels of tubulin cleavage. Consistently, dendritic branching and spine density are reduced in cortical neurons of Ube3A 2X ASD mice. Our findings reveal an important role for Ube3A/E6AP in ASD-related developmental alteration in dendritic arborization and synapse formation, which provide new insights into the pathogenesis of Ube3A/E6AP-dependent ASD.SIGNIFICANCE STATEMENTCopy number variation of the UBE3A gene and aberrant overexpression of the gene product E6AP protein is a common cause in autism spectrum disorders (ASDs). As a major event during brain development, dendritic growth and remodeling play a crucial role in neuronal connectivity and information integration. We found that in primary neurons and in Ube3A transgenic autism mouse brain, overexpression of E6AP leads to significant loss of dendritic arborization. This effect is mediated by the ubiquitination of XIAP by E6AP, subsequent activation of caspases, and the eventual cleavage of microtubules, leading to local degeneration and retraction at the tips of dendritic branches. These findings demonstrate dysregulation in neuronal structural stability as a major cellular neuropathology in ASD.

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16. Kuhn J, Ford K, Dawalt LS. Brief Report : Mapping Systems of Support and Psychological Well-Being of Mothers of Adolescents with Autism Spectrum Disorders. J Autism Dev Disord. 2017.

Parents of children with autism spectrum disorders are generally known to experience elevated levels of stress and poorer psychological well-being. To provide treatments and resources that most effectively support parent mental health, it is critical to understand how parents’ connections with various networks and systems impact their well-being. This study examined the relationship between the psychological well-being of mothers of adolescents with ASD (n = 20) and their systems of support from an ecological systems theoretical framework. Findings indicated that most connections across mothers’ ecosystems were strong in nature. However, the presence of strong connections was not significantly related to psychological well-being. In contrast, stressful/weak connections were significantly related to elevated levels of depressive symptoms, perceived stress, and sense of burden.

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17. Lee M, Krishnamurthy J, Susi A, Sullivan C, Gorman GH, Hisle-Gorman E, Erdie-Lalena CR, Nylund CM. Association of Autism Spectrum Disorders and Inflammatory Bowel Disease. J Autism Dev Disord. 2017.

Autism spectrum disorders (ASD) and inflammatory bowel disease (IBD) both have multifactorial pathogenesis with an increasing number of studies demonstrating gut-brain associations. We aim to examine the association between ASD and IBD using strict classification criteria for IBD. We conducted a retrospective case-cohort study using records from the Military Health System database with IBD defined as having one encounter with an ICD-9-CM diagnostic code for IBD and at least one outpatient prescription dispensed for a medication to treat IBD. Children with ASD were more likely to meet criteria for Crohn’s disease (CD) and Ulcerative colitis (UC) compared to controls. This higher prevalence of CD and UC in children with ASD compared to controls confirms the association of ASD with IBD.

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18. Manor E, Jabareen A, Magal N, Kofman A, Hagerman RJ, Tassone F. Prenatal Diagnosis of Fragile X : Can a Full Mutation Allele in the FMR1 Gene Contract to a Normal Size ?. Front Genet. 2017 ; 8 : 158.

Here we describe a case of a prenatal diagnosis of a male fetus that inherited the unstable allele from his full mutation mosaic mother (29, 160, >200 CGG repeats) reduced to a normal size range (19 CGG repeats). Haplotype analysis showed that the fetus 19 CGG repeats allele derived from the maternal unstable allele which was inherited from his maternal grandmother. No size mosaicism was detected by testing the DNA from in vitro cultured samples, including seventh passage culture as well as from two amniocentesis samples. Sequence analysis confirmed that the allele was 19 CGG repeats long. Methylation assay showed no methylation. Although none of the techniques used in this study can provide with absolute certainty the diagnosis, the results strongly indicate the presence in the fetus of an allele with a CGG repeat number in the normal range. Because this is a prenatal diagnosis case, the crucial question is whether the 19 CGG allele derived from the maternal unstable expanded allele, which contracted to the normal range, became a normal stable allele or a normal unstable allele which could expand in the next generation. It is also possible that allele size mosaicism of the FMR1 gene that went undetected exists. Because this is a prenatal diagnosis case, we cannot with certainty exclude the presence of an undetected expanded allele of the FMR1 gene, in addition to the 19 CGG allele derived from an unstable expanded allele, which contracted to the normal range.

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19. Mayes SD. Brief Report : Checklist for Autism Spectrum Disorder : Most Discriminating Items for Diagnosing Autism. J Autism Dev Disord. 2017.

The smallest subset of items from the 30-item Checklist for Autism Spectrum Disorder (CASD) that differentiated 607 referred children (3-17 years) with and without autism with 100% accuracy was identified. This 6-item subset (CASD-Short Form) was cross-validated on an independent sample of 397 referred children (1-18 years) with and without autism and on data from 1417 children in the CASD standardization sample and 1052 children in the CASD normative sample, resulting in 98.5, 97.6, and 99.8% diagnostic accuracy, respectively. Diagnostic agreement was high between the CASD-Short Form and the Autism Diagnostic Interview-Revised (96%), and the Child Autism Rating Scale (98%). Diagnostic accuracy for the CASD-SF was similar to accuracy for the 30-item CASD full form.

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20. Nordahl-Hansen A, Oien RA, Fletcher-Watson S. Pros and Cons of Character Portrayals of Autism on TV and Film. J Autism Dev Disord. 2017.

Portrayals of characters with autism spectrum disorder (ASD) and/or with autistic traits on film and in TV-series are increasing. Such portrayals may contribute in increasing awareness of the condition but can also increase stereotypes. Thus, these character portrayals are subject to heated debate within the ASD-community, but also in the general public at large. Following our recent published study on character portrayals of ASD on film and TV we here address some central issues related advantages and disadvantage of such portrayals.

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21. Pedersen KA, Santangelo SL, Gabriels RL, Righi G, Erard M, Siegel M. Behavioral Outcomes of Specialized Psychiatric Hospitalization in the Autism Inpatient Collection (AIC) : A Multisite Comparison. J Autism Dev Disord. 2017.

Psychiatric hospitalization of children with autism spectrum disorder (ASD) is relatively common and occurs at a higher rate than in non-ASD youth. This study compared changes in the severity of serious problem behaviors in 350 youth with ASD enrolled in the autism inpatient collection during and after hospitalization in six specialized child psychiatry units. There was a significant reduction in serious problem behaviors from admission (aberrant behavior checklist-irritability subscale M = 29.7, SD 9.6) to discharge (M = 15.0, SD 10.3) and 2-month follow-up (M = 19.3, SD 10.3). Between discharge and 2-month follow-up, tantrum-like behaviors but not self-injurious behaviors increased slightly. Improvement in the severity of problem behaviors was not uniform across sites, even after controlling for measured site differences.

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22. Schieve LA, Tian LH, Drews-Botsch C, Windham GC, Newschaffer C, Daniels JL, Lee LC, Croen LA, Danielle Fallin M. Autism spectrum disorder and birth spacing : Findings from the study to explore early development (SEED). Autism Res. 2017.

Previous studies of autism spectrum disorder (ASD) and birth spacing had limitations ; few examined phenotypic case subtypes or explored underlying mechanisms for associations and none assessed whether other (non-ASD) developmental disabilities (DDs) were associated with birth spacing. We assessed associations between inter-pregnancy interval (IPI) and both ASD and other DDs using data from the Study to Explore Early Development, a multi-site case-control study with rigorous case-finding and case-classification methods and detailed data collection on maternal reproductive history. Our sample included 356 ASD cases, 627 DD cases, and 524 population (POP) controls born in second or later births. ASD and DD cases were further sub-divided according to whether the child had intellectual disability (ID). ASD cases were also sub-divided by ASD symptom severity, and DD cases were subdivided by presence of some ASD symptoms (indicated on an autism screener). Odds ratios, adjusted for maternal-child sociodemographic factors, (aORs) and 95% confidence intervals were derived from logistic regression models. Among term births, ASD was associated with both IPI <18 months (aOR 1.5 [1.1-2.2]) and >/=60 months (1.5 [0.99-2.4]). Both short and long IPI associations were stronger among ASD cases with high severity scores (aORs 2.0 [1.3-3.3] and 1.8 [0.99-3.2], respectively). Associations were unchanged after adding several factors potentially related to the causal pathway to regression models. DD was not associated with either short or long IPI-overall, among term births, or in any subgroup examined. These findings extend those from previous studies and further inform recommendations on optimal pregnancy spacing. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : We investigated whether the amount of time between pregnancies was associated autism spectrum disorder (ASD) or other developmental disabilities (DD) in children. ASD was increased in second and later-born children who were conceived less than 18 months or 60 or more months after the mother’s previous birth. Other DDs were not associated with birth spacing.

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23. Servadio M, Manduca A, Melancia F, Leboffe L, Schiavi S, Campolongo P, Palmery M, Ascenzi P, di Masi A, Trezza V. Impaired repair of DNA damage is associated with autistic-like traits in rats prenatally exposed to valproic acid. Eur Neuropsychopharmacol. 2017.

Prenatal exposure to the antiepileptic and mood stabilizer valproic acid (VPA) is an environmental risk factor for autism spectrum disorders (ASD), although recent epidemiological studies show that the public awareness of this association is still limited. Based on the clinical findings, prenatal VPA exposure in rodents is a widely used preclinical model of ASD. However, there is limited information about the precise biochemical mechanisms underlying the link between ASD and VPA. Here, we tested the effects of increasing doses of VPA on behavioral features resembling core and secondary symptoms of ASD in rats. Only when administered prenatally at the dose of 500mg/kg, VPA induced deficits in communication and social discrimination in rat pups, and altered social behavior and emotionality in the adolescent and adult offspring in the absence of gross malformations. This dose of VPA inhibited histone deacetylase in rat embryos and favored the formation of DNA double strand breaks (DSB), but impaired their repair. The defective DSB response was no more visible in one-day-old pups, thus supporting the hypothesis that unrepaired VPA-induced DNA damage at the time of neural tube closure may underlie the autistic-like traits displayed in the course of development by rats prenatally exposed to VPA. These experiments help to understand the neurodevelopmental trajectories affected by prenatal VPA exposure and identify a biochemical link between VPA exposure during gestation and ASD.

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24. Spector V, Charlop MH. A Sibling-Mediated Intervention for Children with Autism Spectrum Disorder : Using the Natural Language Paradigm (NLP). J Autism Dev Disord. 2017.

We taught three typically developing siblings to occasion speech by implementing the Natural Language Paradigm (NLP) with their brothers with autism spectrum disorder (ASD). A non-concurrent multiple baseline design across children with ASD and sibling dyads was used. Ancillary behaviors of happiness, play, and joint attention for the children with ASD were recorded. Generalization of speech for the children with ASD across setting and peers was also measured. During baseline, the children with ASD displayed few target speech behaviors and the siblings inconsistently occasioned speech from their brothers. After sibling training, however, they successfully delivered NLP, and in turn, for two of the brothers with ASD, speech reached criterion. Implications of this research suggest the inclusion of siblings in interventions.

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25. T WV, A RM, J AK, A CB, E SM. A Randomized Controlled Trial of the Social Tools And Rules for Teens (START) Program : An Immersive Socialization Intervention for Adolescents with Autism Spectrum Disorder. J Autism Dev Disord. 2017.

Adolescents with ASD face numerous personal and contextual barriers that impede the development of social motivation and core competencies, warranting the need for targeted intervention. A randomized controlled trial was conducted with 40 adolescents to evaluate the merits of a multi-component socialization intervention that places emphasis on experiential learning. This investigation evaluated the impact of the 20-week START program on the social functioning of adolescents with ASD. Significant Group x Time differences between START and waitlist control groups were found across multiple measures. Secondary analyses of the entire program cohort also yielded significant improvement trends across all measures. These findings may be an important step in identifying optimal strategies to target the complex factors limiting optimal social development in ASD.

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26. Tanaka AJ, Cho MT, Willaert R, Retterer K, Zarate YA, Bosanko K, Stefans V, Oishi K, Williamson A, Wilson GN, Basinger A, Barbaro-Dieber T, Ortega L, Sorrentino S, Gabriel MK, Anderson IJ, Sacoto MJG, Schnur RE, Chung WK. De novo variants in EBF3 are associated with hypotonia, developmental delay, intellectual disability, and autism. Cold Spring Harb Mol Case Stud. 2017 ; 3(6).

Using whole-exome sequencing, we identified seven unrelated individuals with global developmental delay, hypotonia, dysmorphic facial features, and an increased frequency of short stature, ataxia, and autism with de novo heterozygous frameshift, nonsense, splice, and missense variants in the Early B-cell Transcription Factor Family Member 3 (EBF3) gene. EBF3 is a member of the collier/olfactory-1/early B-cell factor (COE) family of proteins, which are required for central nervous system (CNS) development. COE proteins are highly evolutionarily conserved and regulate neuronal specification, migration, axon guidance, and dendritogenesis during development and are essential for maintaining neuronal identity in adult neurons. Haploinsufficiency of EBF3 may affect brain development and function, resulting in developmental delay, intellectual disability, and behavioral differences observed in individuals with a deleterious variant in EBF3.

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27. Turcotte P, Shea LL, Mandell D. School Discipline, Hospitalization, and Police Contact Overlap Among Individuals with Autism Spectrum Disorder. J Autism Dev Disord. 2017.

The objective was to examine the frequency, correlates, and overlap of school disciplinary actions, psychiatric hospitalizations, and police contact among children and adolescents with autism. Survey results from 2525 caregivers of individuals with autism in elementary through high school were examined. Logistic regression was used to examine predictors of each outcome. Youth with autism most frequently experienced school disciplinary action (15.0%), followed by police contact (7.9%) and hospitalization (7.8%). Experiencing any one of the three events increased risk of experiencing either of the other events. Strong associations between traumatic experiences such as police contact and hospitalizations (OR 9.2), need to be explored to determine risk factors for potential intervention. Further research is needed to determine the temporal ordering of these outcomes.

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28. Vasa RA, Keefer A, Reaven J, South M, White SW. Priorities for Advancing Research on Youth with Autism Spectrum Disorder and Co-occurring Anxiety. J Autism Dev Disord. 2017.

Research on anxiety disorders in youth with autism spectrum disorder (ASD) has burgeoned in the past two decades. Yet, critical gaps exist with respect to measuring and treating anxiety in this population. This study used the nominal group technique to identify the most important research priorities on co-occurring anxiety in ASD. An international group of researchers and clinicians with experience in ASD and anxiety participated in the process. Topics ranked as most important focused on understanding how ASD symptoms affect treatment response, implementing treatments in real world settings, developing methods to disentangle overlapping symptoms between anxiety and ASD, and developing objective measures to assess anxiety. Collectively, these priorities can lead to collaborative studies to accelerate research in the field.

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29. Wang J, Ding G, Li Y, Hua N, Wei N, Qi X, Ning Y, Zhang Y, Li X, Li J, Song L, Qian X. Refractive Status and Amblyopia Risk Factors in Chinese Children with Autism Spectrum Disorder. J Autism Dev Disord. 2017.

Amblyopia risk factors in children with autism spectrum disorders (ASD) are usually hard to detect in early childhood due to poor cooperation and has not been reported in the Chinese population. We screened 168 Chinese children with ASD, aged between 3 and 8 years, and 264 age-matched neurotypical children with Spot photoscreener and basic ophthalmologic examinations. Children with ASD were found to have normal refractive status but significantly higher incidence of strabismus (16.1%), compared with control children (1.5%) (p < 0.01). Most of the cases of strabismus found in children with ASD were classified as esodeviation. Strabismus in children with ASD should be considered more seriously as an amblyopia risk factor by ophthalmologists and other healthcare professionals.

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30. Zeidler S, de Boer H, Hukema RK, Willemsen R. Combination Therapy in Fragile X Syndrome ; Possibilities and Pitfalls Illustrated by Targeting the mGluR5 and GABA Pathway Simultaneously. Front Mol Neurosci. 2017 ; 10 : 368.

Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability and autism. The disorder is characterized by altered synaptic plasticity in the brain. Synaptic plasticity is tightly regulated by a complex balance of different synaptic pathways. In FXS, various synaptic pathways are disrupted, including the excitatory metabotropic glutamate receptor 5 (mGluR5) and the inhibitory gamma-aminobutyric acid (GABA) pathways. Targeting each of these pathways individually, has demonstrated beneficial effects in animal models, but not in patients with FXS. This lack of translation might be due to oversimplification of the disease mechanisms when targeting only one affected pathway, in spite of the complexity of the many pathways implicated in FXS. In this report we outline the hypothesis that targeting more than one pathway simultaneously, a combination therapy, might improve treatment effects in FXS. In addition, we present a glance of the first results of chronic combination therapy on social behavior in Fmr1 KO mice. In contrast to what we expected, targeting both the mGluR5 and the GABAergic pathways simultaneously did not result in a synergistic effect, but in a slight worsening of the social behavior phenotype. This does implicate that both pathways are interconnected and important for social behavior. Our results underline the tremendous fine-tuning that is needed to reach the excitatory-inhibitory balance in the synapse in relation to social behavior. We believe that alternative strategies focused on combination therapy should be further explored, including targeting pathways in different cellular compartments or cell-types.

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