1. {{Correction: The Little Prince: is not a glimpse into the world of autism}}. {Arch Dis Child};2018 (Mar 29)
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2. Broder-Fingert S, Walls M, Augustyn M, Beidas R, Mandell D, Wiltsey-Stirman S, Silverstein M, Feinberg E. {{A hybrid type I randomized effectiveness-implementation trial of patient navigation to improve access to services for children with autism spectrum disorder}}. {BMC Psychiatry};2018 (Mar 27);18(1):79.
BACKGROUND: Significant racial, ethnic, and socioeconomic disparities exist in access to evidence-based treatment services for children with autism spectrum disorder (ASD). Patient Navigation (PN) is a theory-based care management strategy designed to reduce disparities in access to care. The purpose of this study is to test the effectiveness of PN a strategy to reduce disparities in access to evidence-based services for vulnerable children with ASD, as well as to explore factors that impact implementation. METHODS: This study uses a hybrid type I randomized effectiveness/implementation design to test effectiveness and collect data on implementation concurrently. It is a two-arm comparative effectiveness trial with a target of 125 participants per arm. Participants are families of children age 15-27 months who receive a positive screen for ASD at a primary care visit at urban clinics in Massachusetts (n = 6 clinics), Connecticut (n = 1), and Pennsylvania (n = 2). The trial measures diagnostic interval (number of days from positive screen to diagnostic determination) and time to receipt of evidence-based ASD services/recommended services (number of days from date of diagnosis to receipt of services) in those with PN compared to and activated control -Conventional Care Management – which is similar to care management received in a high quality medical home. At the same time, a mixed-method implementation evaluation is being carried out. DISCUSSION: This study will examine the effectiveness of PN to reduce the time to and receipt of evidence-based services for vulnerable children with ASD, as well as factors that influence implementation. Findings will tell us both if PN is an effective approach for improving access to evidence-based care for children with ASD, and inform future strategies for dissemination. TRIAL REGISTRATION: NCT02359084 Registered February 1, 2015.
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3. Demily C, Lesca G, Poisson A, Till M, Barcia G, Chatron N, Sanlaville D, Munnich A. {{Additive Effect of Variably Penetrant 22q11.2 Duplication and Pathogenic Mutations in Autism Spectrum Disorder: To Which Extent Does the Tree Hide He Forest?}}. {J Autism Dev Disord};2018 (Mar 27)
The 22q11.2 duplication is a variably penetrant copy number variant (CNV) associated with a broad spectrum of clinical manifestations including autism spectrum disorders (ASD), and epilepsy. Here, we report on pathogenic HUWE1 and KIF1A mutations in two severely affected ASD/ID participants carrying a 22q11.2 duplication. Based on previous studies, this CNV was originally considered as disease-causing. Yet, owing to their clinical severity, the participants were further investigated by next generation sequencing and eventually found to carry pathogenic mutations in HUWE1 and KIF1A respectively. We suggest giving consideration to additive effect of 22q11.2 duplication and pathogenic mutations when clinical presentation is either unusually severe or associated with atypical features. Caution should be exercised when delivering genetic counseling for variably penetrant CNVs, as uncertain penetrance of this CNV may lead to ignore additive pathogenic mutations. Systematic panel or exome sequencing of known ASD genes should be recommended when counseling families of patients carrying variably penetrant CNV.
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4. Dickter CL, Burk JA, Fleckenstein K, Kozikowski CT. {{Autistic traits and social anxiety predict differential performance on social cognitive tasks in typically developing young adults}}. {PLoS One};2018;13(3):e0195239.
The current work examined the unique contribution that autistic traits and social anxiety have on tasks examining attention and emotion processing. In Study 1, 119 typically-developing college students completed a flanker task assessing the control of attention to target faces and away from distracting faces during emotion identification. In Study 2, 208 typically-developing college students performed a visual search task which required identification of whether a series of 8 or 16 emotional faces depicted the same or different emotions. Participants with more self-reported autistic traits performed more slowly on the flanker task in Study 1 than those with fewer autistic traits when stimuli depicted complex emotions. In Study 2, participants higher in social anxiety performed less accurately on trials showing all complex faces; participants with autistic traits showed no differences. These studies suggest that traits related to autism and to social anxiety differentially impact social cognitive processing.
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5. Dong Q, Liu Q, Li R, Wang A, Bu Q, Wang KH, Chang Q. {{Mechanism and consequence of abnormal calcium homeostasis in Rett syndrome astrocytes}}. {Elife};2018 (Mar 29);7
Astrocytes play an important role in Rett syndrome (RTT) disease progression. Although the non-cell-autonomous effect of RTT astrocytes on neurons was documented, cell-autonomous phenotypes and mechanisms within RTT astrocytes are not well understood. We report that spontaneous calcium activity is abnormal in RTT astrocytes in vitro, in situ, and in vivo. Such abnormal calcium activity is mediated by calcium overload in the endoplasmic reticulum caused by abnormal store operated calcium entry, which is in part dependent on elevated expression of TRPC4. Furthermore, the abnormal calcium activity leads to excessive activation of extrasynaptic NMDA receptors (eNMDARs) on neighboring neurons and increased network excitability in Mecp2 knockout mice. Finally, both the abnormal astrocytic calcium activity and the excessive activation of eNMDARs are caused by Mecp2 deletion in astrocytes in vivo. Our findings provide evidence that abnormal calcium homeostasis is a key cell-autonomous phenotype in RTT astrocytes, and reveal its mechanism and consequence.
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6. Fein D. {{Jill Boucher: Autism Spectrum Disorder (2nd ed.) : Sage Publications, London, 2017, viii + 356 pp., ISBN 978-1-4462-9567-0, $46.65}}. {J Autism Dev Disord};2018 (Mar 27)
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7. Greene RK, Spanos M, Alderman C, Walsh E, Bizzell J, Mosner MG, Kinard JL, Stuber GD, Chandrasekhar T, Politte LC, Sikich L, Dichter GS. {{The effects of intranasal oxytocin on reward circuitry responses in children with autism spectrum disorder}}. {J Neurodev Disord};2018 (Mar 27);10(1):12.
BACKGROUND: Intranasal oxytocin (OT) has been shown to improve social communication functioning of individuals with autism spectrum disorder (ASD) and, thus, has received considerable interest as a potential ASD therapeutic agent. Although preclinical research indicates that OT modulates the functional output of the mesocorticolimbic dopamine system that processes rewards, no clinical brain imaging study to date has examined the effects of OT on this system using a reward processing paradigm. To address this, we used an incentive delay task to examine the effects of a single dose of intranasal OT, versus placebo (PLC), on neural responses to social and nonsocial rewards in children with ASD. METHODS: In this placebo-controlled double-blind study, 28 children and adolescents with ASD (age: M = 13.43 years, SD = 2.36) completed two fMRI scans, one after intranasal OT administration and one after PLC administration. During both scanning sessions, participants completed social and nonsocial incentive delay tasks. Task-based neural activation and connectivity were examined to assess the impact of OT relative to PLC on mesocorticolimbic brain responses to social and nonsocial reward anticipation and outcomes. RESULTS: Central analyses compared the OT and PLC conditions. During nonsocial reward anticipation, there was greater activation in the right nucleus accumbens (NAcc), left anterior cingulate cortex (ACC), bilateral orbital frontal cortex (OFC), left superior frontal cortex, and right frontal pole (FP) during the OT condition relative to PLC. Alternatively, during social reward anticipation and outcomes, there were no significant increases in brain activation during the OT condition relative to PLC. A Treatment Group x Reward Condition interaction revealed relatively greater activation in the right NAcc, right caudate nucleus, left ACC, and right OFC during nonsocial relative to social reward anticipation during the OT condition relative to PLC. Additionally, these analyses revealed greater activation during nonsocial reward outcomes during the OT condition relative to PLC in the right OFC and left FP. Finally, functional connectivity analyses generally revealed changes in frontostriatal connections during the OT condition relative to PLC in response to nonsocial, but not social, rewards. CONCLUSIONS: The effects of intranasal OT administration on mesocorticolimbic brain systems that process rewards in ASD were observable primarily during the processing of nonsocial incentive salience stimuli. These findings have implications for understanding the effects of OT on neural systems that process rewards, as well as for experimental trials of novel ASD treatments developed to ameliorate social communication impairments in ASD.
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8. Hannon E, Schendel D, Ladd-Acosta C, Grove J, Hansen CS, Andrews SV, Hougaard DM, Bresnahan M, Mors O, Hollegaard MV, Baekvad-Hansen M, Hornig M, Mortensen PB, Borglum AD, Werge T, Pedersen MG, Nordentoft M, Buxbaum J, Daniele Fallin M, Bybjerg-Grauholm J, Reichenberg A, Mill J. {{Elevated polygenic burden for autism is associated with differential DNA methylation at birth}}. {Genome Med};2018 (Mar 28);10(1):19.
BACKGROUND: Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviors, interests, or activities. The etiology of ASD involves both inherited and environmental risk factors, with epigenetic processes hypothesized as one mechanism by which both genetic and non-genetic variation influence gene regulation and pathogenesis. The aim of this study was to identify DNA methylation biomarkers of ASD detectable at birth. METHODS: We quantified neonatal methylomic variation in 1263 infants-of whom ~ 50% went on to subsequently develop ASD-using DNA isolated from archived blood spots taken shortly after birth. We used matched genotype data from the same individuals to examine the molecular consequences of ASD-associated genetic risk variants, identifying methylomic variation associated with elevated polygenic burden for ASD. In addition, we performed DNA methylation quantitative trait loci (mQTL) mapping to prioritize target genes from ASD GWAS findings. RESULTS: We identified robust epigenetic signatures of gestational age and prenatal tobacco exposure, confirming the utility of DNA methylation data generated from neonatal blood spots. Although we did not identify specific loci showing robust differences in neonatal DNA methylation associated with later ASD, there was a significant association between increased polygenic burden for autism and methylomic variation at specific loci. Each unit of elevated ASD polygenic risk score was associated with a mean increase in DNA methylation of – 0.14% at two CpG sites located proximal to a robust GWAS signal for ASD on chromosome 8. CONCLUSIONS: This study is the largest analysis of DNA methylation in ASD undertaken and the first to integrate genetic and epigenetic variation at birth. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with disease, and of using mQTL to refine the functional and regulatory variation associated with ASD risk variants.
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9. Hine JF, Herrington CG, Rothman AM, Mace RL, Patterson BL, Carlson KL, Warren ZE. {{Embedding Autism Spectrum Disorder Diagnosis Within the Medical Home: Decreasing Wait Times Through Streamlined Assessment}}. {J Autism Dev Disord};2018 (Mar 27)
Long waits for diagnostic assessment prevent early identification of children suspected of having autism spectrum disorder. We evaluated the benefit of embedded diagnostic consultation within primary care clinics. Using a streamlined diagnostic model, 119 children with concerns for autism spectrum disorder were seen over 14 months. Diagnostic clarity was determined through streamlined assessment for 59% of the children, while others required follow-up. Latency from first concern to diagnosis was 55 days and median age at diagnosis was 32 months: considerably lower than national averages or comparable tertiary clinics. Findings support that embedded processes for effective triage and diagnosis within the medical home is a viable mechanism for efficient access to diagnostic services and assists in bypassing a common barrier to specialized services.
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10. Jacquemont S, Pacini L, Jonch AE, Cencelli G, Rozenberg I, He Y, D’Andrea L, Pedini G, Eldeeb M, Willemsen R, Gasparini F, Tassone F, Hagerman R, Gomez-Mancilla B, Bagni C. {{Protein synthesis levels are increased in a subset of individuals with Fragile X syndrome}}. {Hum Mol Genet};2018 (Mar 24)
Fragile X syndrome (FXS) is a monogenic form of intellectual disability and autism spectrum disorder caused by the absence of the fragile X mental retardation protein (FMRP). In biological models for the disease, this leads to upregulated mRNA translation and as a consequence, deficits in synaptic architecture and plasticity. Preclinical studies revealed that pharmacological interventions restore those deficits, which are thought to mediate the FXS cognitive and behavioral symptoms. Here we characterized the de novo rate of protein synthesis in patients with FXS and their relationship with clinical severity. We measured the rate of protein synthesis in fibroblasts derived from 32 individuals with FXS and from 17 controls as well as in fibroblasts and primary neurons of 27 Fmr1 KO mice and 20 controls. Here we show that levels of protein synthesis are increased in fibroblasts of individuals with FXS and Fmr1 KO mice. However, this cellular phenotype displays a broad distribution and a proportion of fragile X individuals and Fmr1 KO mice do not show increased levels of protein synthesis, having measures in the normal range. Because the same Fmr1 KO animal measures in fibroblasts predict those in neurons we suggest the validity of this peripheral biomarker. Our study offers a potential explanation for the comprehensive drug development program undertaken thus far yielding negative results and suggests that a significant proportion, but not all individuals with FXS, may benefit from the reduction of excessive levels of protein synthesis.
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11. Muhle RA, Reed HE, Stratigos KA, Veenstra-VanderWeele J. {{The Emerging Clinical Neuroscience of Autism Spectrum Disorder: A Review}}. {JAMA Psychiatry};2018 (Mar 28)
Importance: Autism spectrum disorder (ASD) is a highly prevalent disorder, and community psychiatrists are likely to treat many individuals with ASD during their clinical practice. This clinical case challenge describes a routine evaluation of irritability and self-injury in a preschool-aged child who meets the criteria for ASD. The case also illustrates the importance of known risk factors for ASD, such as chromosomal deletion and prematurity. This clinical neuroscience article seeks to educate the clinician of current avenues of research that can inform and may already affect clinical practice for this patient, while providing a preview of research that may yield biological treatments for ASD within the next decade. Observations: A diagnosis of ASD is defined behaviorally; therefore, many genetic and environmental risk factors, working singly or in concert, are linked to ASD. The prenatal period of brain development is particularly sensitive to risk factors such as gene mutation or drug exposure that affect brain development and circuitry formation. Currently, neuroimaging researchers can detect changes in brain connectivity of children with ASD as young as 6 months, followed by an atypical trajectory of brain development through preschool age and ongoing connectivity inefficiencies across the lifespan. Animal and cellular model systems have provided a means for defining the molecular and cellular changes associated with risk factors for ASD. The ability to connect specific treatments to particular subgroups of people with ASD is the defining hope of precision medicine initiatives. Conclusions and Relevance: The advent of next-generation sequencing technology, advanced imaging techniques, and cutting-edge molecular techniques for modeling ASD has allowed researchers to define ASD risk-related biological pathways and circuits that may, for the first time, unify the effects of disparate risk factors into common neurobiological mechanisms. The path from these mechanisms to biological treatments that improve the lives of individuals with autism remains unclear, but the cumulative output of multiple lines of research suggests that subtyping by genetic risk factors may be a particularly tractable way to capitalize on individual differences amenable to specific treatments.
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12. Rodgers J, Herrema R, Honey E, Freeston M. {{Towards a Treatment for Intolerance of Uncertainty for Autistic Adults: A Single Case Experimental Design Study}}. {J Autism Dev Disord};2018 (Mar 27)
Intolerance of uncertainty (IU) is indicated as an important transdiagnostic process variable in a range of anxiety disorders. Anxiety is very common in autistic adults. This study evaluates a manualised treatment programme for autistic adults, which focused on IU. An eight session programme (CUES-A(c)) was developed and delivered to four autistic adults on an individual basis. A single case experimental design was used to provide a preliminary evaluation of the feasibility, acceptability and preliminary effectiveness of the programme. Data regarding retention, acceptability and feasibility indicate that the participants valued the programme. Analyses of outcome measures indicate that the programme has promise as a treatment option for autistic adults experiencing IU.
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13. Wang Q, Hu Y, Shi D, Zhang Y, Zou X, Li S, Fang F, Yi L. {{Children with Autism Spectrum Disorder Prefer Looking at Repetitive Movements in a Preferential Looking Paradigm}}. {J Autism Dev Disord};2018 (Mar 27)
The present study aimed to investigate the visual preference for repetitive movements in children with autism spectrum disorder (ASD). Young children with ASD and typically-developing (TD) children were presented simultaneously with cartoons depicting repetitive and random movements respectively, while their eye-movements were recorded. We found that: (1) the children with ASD spent more time fixating on the repetitive movements than the random movements, whereas the TD children showed no preference for either type of movements; (2) the children’s preference for the repetitive movements was correlated with the parent reports of their repetitive behaviors. Our findings show a promise in using the preferential looking as a potential indicator for the repetitive behaviors and aiding early screening of ASD in future investigations.
