1. Bowling H, Bhattacharya A, Zhang G, Alam D, Lebowitz JZ, Bohm-Levine N, Lin D, Singha P, Mamcarz M, Puckett R, Zhou L, Aryal S, Sharp K, Kirshenbaum K, Berry-Kravis E, Neubert TA, Klann E. {{Altered steady state and activity-dependent de novo protein expression in fragile X syndrome}}. {Nat Commun}. 2019; 10(1): 1710.
Whether fragile X mental retardation protein (FMRP) target mRNAs and neuronal activity contributing to elevated basal neuronal protein synthesis in fragile X syndrome (FXS) is unclear. Our proteomic experiments reveal that the de novo translational profile in FXS model mice is altered at steady state and in response to metabotropic glutamate receptor (mGluR) stimulation, but the proteins expressed differ under these conditions. Several altered proteins, including Hexokinase 1 and Ras, also are expressed in the blood of FXS model mice and pharmacological treatments previously reported to ameliorate phenotypes modify their abundance in blood. In addition, plasma levels of Hexokinase 1 and Ras differ between FXS patients and healthy volunteers. Our data suggest that brain-based de novo proteomics in FXS model mice can be used to find altered expression of proteins in blood that could serve as disease-state biomarkers in individuals with FXS.
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2. DuBois D, Renwick R, Chowdhury M, Eisen S, Cameron D. {{Engagement in community life: perspectives of youths with intellectual and developmental disabilities on families’ roles}}. {Disabil Rehabil}. 2019: 1-12.
PURPOSE: The main objectives of this study were to learn from youths with intellectual and developmental disabilities about the ways their families were involved in their engagement in community life and to capture how they felt about such involvement. METHOD: The current study is a secondary analysis of a larger study, the Voices of Youths Research Project, framed by inclusive research methods. Thirty-eight semi-structured interviews that discussed perspectives on friendship, social inclusion, and quality of life from 20 participants (ages 13 to 24 years) were included in this paper. All interviews were video-recorded and coded using NVivo 10. Thematic analysis of the coded segments was guided by a constructivist grounded theory approach. RESULTS: Three major themes emerged from the experiences of youths with intellectual and developmental disabilities on family involvement in their social and community engagement: (1) complex of supports and influences, (2) community engagement with and through family, and (3) points of tension. CONCLUSIONS: These thematic findings offer insights into the lived experiences of youths with intellectual and developmental disabilities about engagement in community life. These findings provide an understanding, outside of conventional schemas, of transition into young adulthood for these youths. IMPLICATIONS FOR REHABILITATION Rehabilitation professionals often work with youths with intellectual and developmental disabilities who face barriers to reaching transition goals identified either by themselves or others. Family members’ views that may focus on goals of maximizing functional independence and/or decreasing caregiver demands can often overshadow the goals or views of youths with intellectual and developmental disabilities themselves. Rehabilitation professionals should find ways to explore with youth their family’s roles in engagement and belonging in community life so that they can link youths to appropriate community resources and plan optimal interventions/programs. Rehabilitation professionals need to be aware of and respond to points of tension that can emerge between youths with intellectual and developmental disabilities and their family during transition.
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3. Funke A. {{Improving the quality of life of parents of children with developmental disabilities}}. {Dev Med Child Neurol}. 2019.
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4. Ibrahim K, Eilbott JA, Ventola P, He G, Pelphrey KA, McCarthy G, Sukhodolsky DG. {{Reduced Amygdala-Prefrontal Functional Connectivity in Children With Autism Spectrum Disorder and Co-occurring Disruptive Behavior}}. {Biol Psychiatry Cogn Neurosci Neuroimaging}. 2019.
BACKGROUND: Disruptive behaviors are prevalent in children with autism spectrum disorder (ASD) and often cause substantial impairments. However, the underlying neural mechanisms of disruptive behaviors remain poorly understood in ASD. In children without ASD, disruptive behavior is associated with amygdala hyperactivity and reduced connectivity with the ventrolateral prefrontal cortex (vlPFC). This study examined amygdala reactivity and connectivity in children with ASD with and without co-occurring disruptive behavior disorders. We also investigated differential contributions of externalizing behaviors and callous-unemotional traits to variance in amygdala connectivity and reactivity. METHODS: This cross-sectional study involved behavioral assessments and neuroimaging in three groups of children 8 to 16 years of age: 18 children had ASD and disruptive behavior, 20 children had ASD without disruptive behavior, and 19 children were typically developing control participants matched for age, gender, and IQ. During functional magnetic resonance imaging, participants completed an emotion perception task of fearful versus calm faces. Task-specific changes in amygdala reactivity and connectivity were examined using whole-brain, psychophysiological interaction, and multiple regression analyses. RESULTS: Children with ASD and disruptive behavior showed reduced amygdala-vlPFC connectivity compared with children with ASD without disruptive behavior. Externalizing behaviors and callous-unemotional traits were associated with amygdala reactivity to fearful faces in children with ASD after controlling for suppressor effects. CONCLUSIONS: Reduced amygdala-vlPFC connectivity during fear processing may differentiate children with ASD and disruptive behavior from children with ASD without disruptive behavior. The presence of callous-unemotional traits may have implications for identifying differential patterns of amygdala activity associated with increased risk of aggression in ASD. These findings suggest a neural mechanism of emotion dysregulation associated with disruptive behavior in children with ASD.
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5. Liu YW, Liong MT, Chung YE, Huang HY, Peng WS, Cheng YF, Lin YS, Wu YY, Tsai YC. {{Effects of Lactobacillus plantarum PS128 on Children with Autism Spectrum Disorder in Taiwan: A Randomized, Double-Blind, Placebo-Controlled Trial}}. {Nutrients}. 2019; 11(4).
This four-week, randomized, double-blind, placebo-controlled study investigated the effects of Lactobacillus plantarum PS128 (PS128) on boys with autism spectrum disorder (ASD) aged 7-15 in Taiwan. All subjects fulfilled the criteria for ASD diagnosis of DSM-V and the Autism Diagnostic Interview-Revised (ADI-R). Questionnaires used for the primary outcome measure include the Autism Behavior Checklist-Taiwan version (ABC-T), the Social Responsiveness Scale (SRS) and the Child Behavior Checklist (CBCL). The Swanson, Nolan, and Pelham-IV-Taiwan version (SNAP-IV) and the Clinical Global Impression-improvement (CGI-I) were used for the secondary outcome measure. The results showed that PS128 ameliorated opposition/defiance behaviors, and that the total score of SNAP-IV for younger children (aged 712) improved significantly compared with the placebo group. Additionally, several elements were also notably improved in the PS128 group after 28-day consumption of PS128. Further studies are needed to better clarify the effects of PS128 for younger children with ASD on broader symptoms.
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6. Mahdavinasab SM, Saghazadeh A, Motamed-Gorji N, Vaseghi S, Mohammadi MR, Alichani R, Akhondzadeh S. {{Baclofen as an adjuvant therapy for autism: a randomized, double-blind, placebo-controlled trial}}. {Eur Child Adolesc Psychiatry}. 2019.
Increasing evidence suggests that the function of the GABAergic system is abnormally low in autism spectrum disorder (ASD). Baclofen, which functions as a selective agonist for GABAB receptors, does appear promising for the treatment of ASD. We conducted a 10-week randomized-controlled study aimed at evaluating the potential of baclofen as an adjuvant therapy to enhance the effect of risperidone in children with ASD. Sixty-four children (3-12 years) with moderate-to-severe irritability symptoms of ASD were included. We used the Aberrant Behavior Checklist-Community Edition (ABC-C) for the outcome measures on each of the follow-up visits (weeks 0, 5, and 10). Analysis of the combined data revealed significant improvement for all the ABC subscales (irritability: F = 51.644, df = 1.66, p < 0.001, lethargy: F = 39.734, df = 1.38, p < 0.001, stereotypic behavior: F = 25.495, df = 1.56, p < 0.001, hyperactivity: F = 54.135, df = 1.35, p < 0.001, and inappropriate speech: F = 19.277, df = 1.47, p = 0.004). Combined treatment with baclofen and risperidone exerted a greater effect on improvement of hyperactivity symptoms at both midpoint [Cohen's d, 95% confidence interval (CI) = - 3.14, - 5.56 to - 0.72] and endpoint (d, 95% CI = - 4.45, - 8.74 to - 0.16) when compared with treatment with placebo plus risperidone. The two treatments achieved comparable results for other outcome measures. Our data support safety and efficacy of baclofen as an adjuvant to risperidone for improvement of hyperactivity symptoms in children with ASD. Lien vers le texte intégral (Open Access ou abonnement)
7. Symons FJ, Barney CC, Byiers BJ, McAdams BD, Foster S, Feyma TJ, Wendelschafer-Crabb G, Kennedy WR. {{A clinical case-control comparison of epidermal innervation density in Rett syndrome}}. {Brain and behavior}. 2019: e01285.
INTRODUCTION: Rett syndrome (RTT), a rare neurodevelopmental disorder occurring primarily in females (1:10-15,000 female live births), is most often caused by loss-of-function mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). Clinical observations and preclinical findings indicate apparent abnormal sensory and nociceptive function. There have been no direct investigations of epidermal sensory innervation in patients with RTT. METHODS: We compared 3 mm epidermal punch biopsy specimens from adolescent female RTT patients (N = 4, aged 12-19 years) against an archived approximate age-, sex-, body-site matched comparison sample of healthy adolescent females (N = 8, ages 11-17). RESULTS: Confocal imaging revealed, on average, statistically significant increased epidermal nerve fiber (ENF) peptidergic (co-stained calcitonin gene-related protein [CGRP]) innervation density compared with healthy female control individuals. CONCLUSIONS: Given the clinical phenotype of disrupted sensory function along with diagnostic criteria specific to cold hands/feet and insensitivity to pain, our preliminary observations of ENF peptidergic fiber density differences warrants further investigation of the peripheral neurobiology in RTT.
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8. Walker SJ, Langefeld CD, Zimmerman K, Schwartz MZ, Krigsman A. {{A molecular biomarker for prediction of clinical outcome in children with ASD, constipation, and intestinal inflammation}}. {Sci Rep}. 2019; 9(1): 5987.
In children with autism spectrum disorder (ASD) who present to the gastroenterologist with chronic constipation on a background of colonic inflammation, we have identified two distinct clinical subtypes: (1) patients who experience a sustained state of GI symptomatic remission while on maintenance anti-inflammatory therapy (fast responders) and, (2) those with recurrent right-sided fecal loading requiring regular colon cleanouts during treatment for enterocolitis (slow responders). We hypothesized that a detailed molecular analysis of tissue from the affected region of the colon would provide mechanistic insights regarding the fast versus slow response to anti-inflammatory therapy. To test this, ascending colon biopsy tissues from 35 children with ASD (20 slow responders and 15 fast responders) were analyzed by RNAseq. Hierarchical cluster analysis was performed to assign samples to clusters and gene expression analysis was performed to identify differentially expressed transcripts (DETs) between samples within the clusters. Significant differences were found between the two clusters with fast responder-predominant cluster showing an upregulation of transcripts involved in the activation of immune and inflammatory response and the slow responder-predominant cluster showing significant over-representation of pathways impacting colonic motility (e.g. genes involved in tryptophan and serotonin degradation and mitochondrial dysfunction). Regression analysis identified a single long non-coding RNA that could predict cluster assignment with a high specificity (0.88), sensitivity (0.89) and accuracy (0.89). Comparison of gene expression profiles in the ascending colon from a subset of patients with ASD, chronic right-sided fecal loading constipation and a slow versus fast response to therapy has identified molecular mechanisms that likely contribute to this differential response following the primary therapeutic intervention (i.e. treatment for colonic inflammation with brief induction immunosuppression followed by maintenance non-steroidal anti-inflammatory therapy). Importantly, we have identified a transcript that, if validated, may provide a biomarker that can predict from the outset which patients will be slow responders who would benefit from an alternate therapeutic strategy in treating their constipation.
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9. Zhang X, Piano I, Messina A, D’Antongiovanni V, Cro F, Provenzano G, Bozzi Y, Gargini C, Casarosa S. {{Retinal Defects in Mice Lacking the Autism-Associated Gene Engrailed-2}}. {Neuroscience}. 2019.
Defective cortical processing of visual stimuli and altered retinal function have been described in autism spectrum disorder (ASD) patients. In keeping with these findings, anatomical and functional defects have been found in the visual cortex and retina of mice bearing mutations for ASD-associated genes. Here we sought to investigate the anatomy and function of the adult retina of Engrailed 2 knockout (En2(-/-)) mice, a model for ASD. Our results showed that En2 is expressed in all three nuclear layers of the adult retina. When compared to age-matched En2(+/+) controls, En2(-/-) adult retinas showed a significant decrease in the number of calbindin(+) horizontal cells, and a significant increase in calbindin(+) amacrine/ganglion cells. The total number of ganglion cells was not altered in the adult En2(-/-) retina, as shown by Brn3a(+) cell counts. In addition, En2(-/-) adult mice showed a significant reduction of photoreceptor (rhodopsin) and bipolar cell (Pcp2, PKCalpha) markers. Functional defects were also present in the retina of En2 mutants, as indicated by electroretinogram recordings showing a significant reduction in both a-wave and b-wave amplitude in En2(-/-) mice as compared to controls. These data show for the first time that anatomical and functional defects are present in the retina of the En2 ASD mouse model.
