Pubmed du 13/09/19

vendredi 13 septembre 2019

1. Abraham JR, Szoko N, Barnard J, Rubin RA, Schlatzer D, Lundberg K, Li X, Natowicz MR. Proteomic Investigations of Autism Brain Identify Known and Novel Pathogenetic Processes. Sci Rep ;2019 (Sep 11) ;9(1):13118.

Autism Spectrum Disorder (ASD) is a set of heterogeneous neurodevelopmental conditions defined by impairments in social communication and restricted, repetitive behaviors, interests or activities. Only a minority of ASD cases are determined to have a definitive etiology and the pathogenesis of most ASD is poorly understood. We hypothesized that a global analysis of the proteomes of human ASD vs. control brain, heretofore not done, would provide important data with which to better understand the underlying neurobiology of autism. In this study, we characterized the proteomes of two brain regions, Brodmann area 19 (BA19) and posterior inferior cerebellum (CB), from carefully selected idiopathic ASD cases and matched controls using label-free HPLC-tandem mass spectrometry. The data revealed marked differences between ASD and control brain proteomes for both brain regions. Unlike earlier transcriptomic analyses using frontal and temporal cortex, however, our proteomic analysis did not support ASD attenuating regional gene expression differences. Bioinformatic analyses of the differentially expressed proteins between cases and controls highlighted canonical pathways involving glutamate receptor signaling and glutathione-mediated detoxification in both BA19 and CB ; other pathways such as Sertoli cell signaling and fatty acid oxidation were specifically enriched in BA19 or CB, respectively. Network analysis of both regions of ASD brain showed up-regulation of multiple pre- and post-synaptic membrane or scaffolding proteins including glutamatergic ion channels and related proteins, up-regulation of proteins involved in intracellular calcium signaling, and down-regulation of neurofilament proteins, with DLG4 and MAPT as major hub proteins in BA19 and CB protein interaction networks, respectively. Upstream regulator analysis suggests neurodegeneration-associated proteins drive the differential protein expression for ASD in both BA19 and CB. Overall, the proteomic data provide support for shared dysregulated pathways and upstream regulators for two brain regions in human ASD brain, suggesting a common ASD pathophysiology that has distinctive regional expression.

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2. Bertollo JR, Strang JF, Anthony LG, Kenworthy L, Wallace GL, Yerys BE. Adaptive Behavior in Youth with Autism Spectrum Disorder : The Role of Flexibility. J Autism Dev Disord ;2019 (Sep 13)

Cognitive and behavioral flexibility are important predictors of adaptive behavior in school-age autistic youth. While prior research has utilized broad measures of flexibility, the current study uses the multi-dimensional Flexibility Scale-Revised to examine which specific flexibility skills relate to adaptive functioning. Through parent-report measures on 216 autistic youth, flexibility explained 22.2% of variance in adaptive socialization skills (p < 0.001). Specifically, Social Flexibility accounted for significant variance in adaptive socialization skills, while Transitions/Change approached significance. In exploratory analyses, flexibility explained 11.5% of variance in Communication skills (p < 0.001). This pattern remained after controlling for co-occurring ADHD symptoms. The current study helps to refine the relationship between flexibility and adaptive behavior, which may ultimately help to inform more targeted interventions.

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3. Case L, Yun J. The Effect of Different Intervention Approaches on Gross Motor Outcomes of Children With Autism Spectrum Disorder : A Meta-Analysis. Adapt Phys Activ Q ;2019 (Sep 13):1-26.

Despite the rising interest in intervention for children with autism spectrum disorder, the extent to which interventions are effective on gross motor outcomes is currently unknown. The purpose of this study was to analyze the effect of different intervention approaches on gross motor outcomes among children with autism spectrum disorder using meta-analysis. A total of 18 studies met the inclusion criteria for quantitative analysis. Pre- and posttest means and SDs were extracted to calculate effect sizes. Potential moderator variables were chosen based on important intervention characteristics. The results suggest that interventions have a large effect on gross motor outcomes among children with autism spectrum disorder (delta = 0.99, SE = 0.19, p < .001, 95% confidence interval [0.62, 1.36]). The interventions that were 16 total hours or longer had a significantly larger effect than those less than 16 hr. In addition, the interventions in experimental settings had significantly larger effects than the interventions in practical settings. Future interventions should consider intensity, including not only the duration of the intervention but also the intensity in which specific intervention goals are targeted.

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4. Friedman BH, Scarpa A, Patriquin MA. The Biopsychology of Autism Spectrum Disorder : Theory, Methods, and Evidence. Biol Psychol ;2019 (Sep 13):107770.

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5. Gabard-Durnam LJ, Wilkinson C, Kapur K, Tager-Flusberg H, Levin AR, Nelson CA. Longitudinal EEG power in the first postnatal year differentiates autism outcomes. Nat Commun ;2019 (Sep 13) ;10(1):4188.

An aim of autism spectrum disorder (ASD) research is to identify early biomarkers that inform ASD pathophysiology and expedite detection. Brain oscillations captured in electroencephalography (EEG) are thought to be disrupted as core ASD pathophysiology. We leverage longitudinal EEG power measurements from 3 to 36 months of age in infants at low- and high-risk for ASD to test how and when power distinguishes ASD risk and diagnosis by age 3-years. Power trajectories across the first year, second year, or first three years postnatally were submitted to data-driven modeling to differentiate ASD outcomes. Power dynamics during the first postnatal year best differentiate ASD diagnoses. Delta and gamma frequency power trajectories consistently distinguish infants with ASD diagnoses from others. There is also a developmental shift across timescales towards including higher-frequency power to differentiate outcomes. These findings reveal the importance of developmental timing and trajectory in understanding pathophysiology and classifying ASD outcomes.

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6. Hare-Harris AE, Mitchel MW, Myers SM, Mitchel AD, King BR, Ruocco BG, Martin CL, Flax JF, Brzustowicz LM. Within-task variability on standardized language tests predicts autism spectrum disorder : a pilot study of the Response Dispersion Index. J Neurodev Disord ;2019 (Sep 13) ;11(1):21.

BACKGROUND : Qualitatively atypical language development characterized by non-sequential skill acquisition within a developmental domain, which has been called developmental deviance or difference, is a common characteristic of autism spectrum disorder (ASD). We developed the Response Dispersion Index (RDI), a measure of this phenomenon based on intra-subtest scatter of item responses on standardized psychometric assessments, to assess the within-task variability among individuals with language impairment (LI) and/or ASD. METHODS : Standard clinical assessments of language were administered to 502 individuals from the New Jersey Language and Autism Genetics Study (NJLAGS) cohort. Participants were divided into four diagnostic groups : unaffected, ASD-only, LI-only, and ASD + LI. For each language measure, RDI was defined as the product of the total number of test items and the sum of the weight (based on item difficulty) of test items missed. Group differences in RDI were assessed, and the relationship between RDI and ASD diagnosis among individuals with LI was investigated for each language assessment. RESULTS : Although standard scores were unable to distinguish the LI-only and ASD/ASD + LI groups, the ASD/ASD + LI groups had higher RDI scores compared to LI-only group across all measures of expressive, pragmatic, and metalinguistic language. RDI was positively correlated with quantitative ASD traits across all subgroups and was an effective predictor of ASD diagnosis among individuals with LI. CONCLUSIONS : The RDI is an effective quantitative metric of developmental deviance/difference that correlates with ASD traits, supporting previous associations between ASD and non-sequential skill acquisition. The RDI can be adapted to other clinical measures to investigate the degree of difference that is not captured by standard performance summary scores.

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7. Hartley SL, DaWalt LS, Hong J, Greenberg JS, Mailick MR. Positive Emotional Support in Premutation Carrier Mothers of Adolescents and Adults With Fragile X Syndrome : Gene by Environment Interactions. Am J Intellect Dev Disabil ;2019 (Sep) ;124(5):411-426.

We examined the benefit of emotional support on daily health in premutation carrier mothers of adolescents and adults with fragile X syndrome (n = 114), and whether this benefit was moderated by the mother’s genetic status (FMR1 CGG repeat length). In an 8-day daily diary, maternal daily health was assessed subjectively through self-reported number of physical health symptoms and physiologically via cortisol awakening response. Multilevel lagged-day models indicated that premutation carrier mothers with midrange CGG repeats derived less health benefit from a day with high positive emotional support than those with lower or higher numbers of repeats within the premutation range. The data support the influence of both genetic and environmental influences on the health of this population.

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8. 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 ;2019 (Sep 13) ;29(10):4415-4425.

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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9. Jagtap S, Thanos JM, Fu T, Wang J, Lalonde J, Dial TO, Feiglin A, Chen J, Kohane I, Lee JT, Sheridan SD, Perlis RH. Aberrant mitochondrial function in patient-derived neural cells from CDKL5 deficiency disorder and Rett Syndrome. Hum Mol Genet ;2019 (Sep 13)

The X-linked neurodevelopmental diseases CDKL5 deficiency disorder (CDD) and Rett syndrome (RTT) are associated with intellectual disability, infantile spasms, and seizures. Although mitochondrial dysfunction has been suggested in RTT, less is understood about mitochondrial function in CDD. A comparison of bioenergetics and mitochondrial function between isogenic wild type and mutant neural progenitor (NPC) lines revealed increased oxygen consumption in CDD mutant lines, which is associated with altered mitochondrial function and structure. Transcriptomic analysis revealed differential expression of genes related to mitochondrial and REDOX function in NPCs expressing the mutant CDKL5. Furthermore, a similar increase in oxygen consumption specific to RTT-patient-derived isogenic mutant NPCs was observed, though the pattern of mitochondrial functional alterations was distinct from CDKL5-mutant-expressing NPCs. We propose that aberrant neural bioenergetics is a common feature between CDD and RTT disorders. The observed changes in oxidative stress and mitochondrial function may facilitate the development of therapeutic agents for CDD and related disorders.

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10. Li MY, Ye J, Huang ZY, Lin YC, Liu AH, Li LP, Chen J, Wang YP. [Clinical analysis of five cases of autism spectrum disorder complicated with epilepsy with chromosome copy number variation]. Zhonghua Yi Xue Za Zhi ;2019 (Sep 3) ;99(33):2615-2618.

Objective : To explore the clinical features and genetic causes of autism spectrum disorder (ASD) patients with epilepsy. Methods : The clinical data of five patients with ASD and epilepsy admitted to Xuanwu Hospital between September 2017 and September 2018 were collected, including medical history, intelligence level, developmental level, physical examination, neuroimaging and electroencephalogram. High-throughput whole-genome sequencing was applied to five patients and their parents. Results : Of five patients, four were male and one was female. All five patients had mild mental retardation, and one patient had significant growth retardation and craniofacial deformity. The average epilepsy onset age was 6.3 years old (7 months to 16 years). The main epileptic type was tonic-clonic seizure with abnormal EEG results. All patients have a favorable response to anti-epileptic drugs. Whole-exome sequencing (WES) revealed copy number variation in all 5 patients. Among them, 3 cases were reported to be pathogenic, and 2 cases were not reported (chromosome 16p13.3 duplication and chromosome 21q22.3 deletion). Conclusions : The results of current study support that autism spectrum disorders with seizures is often associated with copy number variations, such as Williams-Beuren region duplication syndrome, chromosome 15q11.2 duplication syndrome and chromosome 15q11.2 deletion syndrome. We reported two novel copy number variations (chromosome 16p13.3 duplication and chromosome 21q22.3 deletion) in two autism spectrum disorder patients with epileptic seizures.

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11. Ni HC, Lin HY, Chen YC, Tseng WI, Gau SS. Boys with autism spectrum disorder have distinct cortical folding patterns underpinning impaired self-regulation : a surface-based morphometry study. Brain Imaging Behav ;2019 (Sep 11)

Although impaired self-regulation (dysregulation) in autism spectrum disorder (ASD) garnered increasing awareness, the neural mechanism of dysregulation in ASD are far from conclusive. To complement our previous voxel-based morphometry findings, we estimated the cortical thickness, surface area, and local gyrification index based on the surface-based morphometry from structural MRI images in 85 ASD and 65 typically developing control (TDC) boys, aged 7-17 years. Levels of dysregulation were measured by the sum of T-scores of Attention, Aggression, and Anxiety/Depression subscales on the Child Behavior Checklist. We found both ASD and TDC shared similar relationships between dysregulation and cortical folding patterns in the left superior and inferior temporal gyri and the left premotor cortex. Significant diagnosis by dysregulation interactions in cortical folding patterns were identified over the right middle frontal and right lateral orbitofrontal regions. The statistical significance of greater local gyrification index in ASD than TDC in several brain regions disappeared when the level of dysregulation was considered. The findings of shared and distinct neural correlates underpinning dysregulation between ASD and TDC may facilitate the development of targeted interventions in the future. The present work also demonstrates that inter-subject variations in self-regulation may explain some extents of ASD-associated brain morphometric differences, likely suggesting that dysregulation is one of the yardsticks for dissecting the heterogeneity of ASD.

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12. Rosenbloom R, Wills HP, Mason R, Huffman JM, Mason BA. The Effects of a Technology-Based Self-monitoring Intervention on On-Task, Disruptive, and Task-Completion Behaviors for Adolescents with Autism. J Autism Dev Disord ;2019 (Sep 11)

Individuals with autism spectrum disorders (ASD) often present with difficulty in sustaining engagement, attention, and have disruptive behavior in classroom settings. Without appropriate intervention, these challenging behaviors often persist and negatively impact educational outcomes. Self-monitoring is a well-supported evidence-based practice for addressing challenging behaviors and improving pro-social behaviors for individuals with ASD. Self-monitoring procedures utilizing a handheld computer-based technology is an unobtrusive and innovative way of implementing the intervention. A withdrawal design was employed to assess the effectiveness of a technologically-delivered self-monitoring intervention (I-Connect) in improving on-task and task completion behaviors and decreasing disruptive behavior with four adolescents with ASD. Results demonstrated improvements in on-task and task completion behaviors across all four participants and disruptive behavior improved for two participants.

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13. Shivers CM. Self-Reported Guilt Among Adult Siblings of People With Intellectual and Developmental Disabilities. Am J Intellect Dev Disabil ;2019 (Sep) ;124(5):470-477.

As more siblings become responsible for their aging brothers and sisters with intellectual and developmental disabilities, it becomes increasingly important to understand these siblings’ emotional needs, including potential negative emotions such as guilt. This study examined the presence and correlates of self-reported guilt among 1,021 adult siblings of people with intellectual and developmental disabilities. Respondents completed the Adult Sibling Questionnaire, a national survey examining characteristics of adult health, depression, and feelings of guilt. Over 50% of siblings reported feeling increased guilt. Siblings who experienced increased guilt (versus those who did not) experienced less close sibling relationships, more depressive symptoms, and lower levels of well-being. Siblings experiencing more guilt also had brothers/sisters with more severe emotional/behavioral problems.

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14. Wall CA, Hogan AL, Will EA, McQuillin S, Kelleher BL, Roberts JE. Early negative affect in males and females with fragile X syndrome : implications for anxiety and autism. J Neurodev Disord ;2019 (Sep 13) ;11(1):22.

BACKGROUND : Fragile X syndrome (FXS) is a genetic disorder that is highly comorbid with anxiety and autism spectrum disorder (ASD). Elevated negative affect in young children has been associated with increased risk for both anxiety and ASD ; however, these relations remain poorly understood in FXS. METHODS : The present prospective longitudinal study examined the trajectory of negative affect from infancy through preschool in males and females with FXS and typical development and its relation to anxiety and ASD. RESULTS : Results indicate a complex association reflecting group, developmental, and sex effects. Specifically, the group with FXS displayed a trajectory of increasing negative affect across age that was distinct from the typical controls. This atypical trajectory of negative affect in FXS was driven by sex effects in that males showed lower negative affect during infancy followed by steep increases across the toddler and preschool years whereas the females displayed a flatter trajectory. Finally, elevated negative affect predicted anxiety symptoms in males, but not females, with no relationship to ASD in males or females with FXS. CONCLUSIONS : The current work addresses the importance of studying the development of psychopathology in a specific neurogenetic population. Temperamental negative affect was shown to be an important early marker for anxiety in young children with FXS, with subtle differences observed between males and females.

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15. Wang J, Zhang Q, Chen Y, Yu S, Wu X, Bao X. Rett and Rett-like syndrome : Expanding the genetic spectrum to KIF1A and GRIN1 gene. Mol Genet Genomic Med ;2019 (Sep 11):e968.

BACKGROUND : This study aimed to investigate the new genetic etiologies of Rett syndrome (RTT) or Rett-like phenotypes. METHODS : Targeted next-generation sequencing (NGS) was performed on 44 Chinese patients with RTT or Rett-like phenotypes, in whom genetic analysis of MECP2, CDKL5, and FOXG1 was negative. RESULTS : The detection rate was 31.8% (14/44). A de novo pathogenic variant (c.275_276ins AA, p. Cys92*) of KIF1A was identified in a girl with all core features of typical RTT. A patient with atypical RTT was detected having de novo GRIN1 pathogenic variant (c.2337C > A, p. Val793Phe). Additionally, compound heterozygous pathogenic variants of PPT1 gene were detected in a girl, who initially displayed typical RTT features, but progressed into neuronal ceroid lipofuscinoses (NCL) afterwards. Pathogenic variants in KCNQ2, MEF2C, WDR45, TCF4, IQSEC2, and SDHA were also found in our cohort. CONCLUSIONS : It is the first time that pathogenic variants of GRIN1 and KIF1A were linked to RTT and Rett-like profiles. Our findings expanded the genetic heterogeneity of Chinese RTT or Rett-like patients, and also suggest that some patients with genetic metabolic disease such as NCL, might displayed Rett features initially, and clinical follow-up is essential for the diagnosis.

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16. Wang ZJ, Zhong P, Ma K, Seo JS, Yang F, Hu Z, Zhang F, Lin L, Wang J, Liu T, Matas E, Greengard P, Yan Z. Correction : Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice. Mol Psychiatry ;2019 (Sep 13)

A correction to this paper has been published and can be accessed via a link at the top of the paper.

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17. Wieckowski AT, White SW. Attention Modification to Attenuate Facial Emotion Recognition Deficits in Children with Autism : A Pilot Study. J Autism Dev Disord ;2019 (Sep 13)

Diminished attending to faces may contribute to the impairments in emotion recognition and expression in autism spectrum disorder (ASD). The current study evaluated the acceptability, feasibility, and preliminary efficacy of an attention modification intervention designed to attenuate deficits in facial emotion recognition (FER). During the 10-session experimental treatment, children (n = 8) with ASD watched dynamic videos of people expressing different emotions with the facial features highlighted to guide children’s attention. Children and their parents generally rated the treatment as acceptable and helpful. Although FER improvement was not apparent on task-based measures, parents reported slight improvements and decreased socioemotional problems following treatment. Results suggest that further research on visual attention retraining for ASD, within an experimental therapeutic program, may be promising.

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18. Winkler M, Biswas S, Berger SM, Kuchler M, Preisendorfer L, Choo M, Fruh S, Rem PD, Enkel T, Arnold B, Komljenovic D, Sticht C, Goerdt S, Bettler B, von Bohlen Und Halbach O, Bartsch D, Geraud C. Pianp deficiency links GABAB receptor signaling and hippocampal and cerebellar neuronal cell composition to autism-like behavior. Mol Psychiatry ;2019 (Sep 11)

Pianp (also known as Leda-1) is a type I transmembrane protein with preferential expression in the mammalian CNS. Its processing is characterized by proteolytic cleavage by a range of proteases including Adam10, Adam17, MMPs, and the gamma-secretase complex. Pianp can interact with Pilralpha and the GB1a subunit of the GABAB receptor (GBR) complex. A recent case description of a boy with global developmental delay and homozygous nonsense variant in PIANP supports the hypothesis that PIANP is involved in the control of behavioral traits in mammals. To investigate the physiological functions of Pianp, constitutive, global knockout mice were generated and comprehensively analyzed. Broad assessment did not indicate malformation or malfunction of internal organs. In the brain, however, decreased sizes and altered cellular compositions of the dentate gyrus as well as the cerebellum, including a lower number of cerebellar Purkinje cells, were identified. Functionally, loss of Pianp led to impaired presynaptic GBR-mediated inhibition of glutamate release and altered gene expression in the cortex, hippocampus, amygdala, and hypothalamus including downregulation of Erdr1, a gene linked to autism-like behavior. Behavioral phenotyping revealed that Pianp deficiency leads to context-dependent enhanced anxiety and spatial learning deficits, an altered stress response, severely impaired social interaction, and enhanced repetitive behavior, which all represent characteristic features of an autism spectrum disorder-like phenotype. Altogether, Pianp represents a novel candidate gene involved in autism-like behavior, cerebellar and hippocampal pathology, and GBR signaling.

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