Pubmed du 22/07/19

lundi 22 juillet 2019

1. Brandenburg C, Blatt GJ. Differential serotonin transporter (5-HTT) and 5-HT2 receptor density in limbic and neocortical areas of adults and children with ASD : implications for SSRI efficacy. J Neurochem ;2019 (Jul 20)

As selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed medications in autism, we aimed to determine whether targets for SSRIs are differentially affected in three cortical areas in children and adults with autism compared to neurotypical individuals. Utilizing a large cohort of postmortem brain tissue (n=14-19 per group), saturation ligand binding assays were conducted on sections from the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC) and fusiform gyrus (FG). Specific binding to the 5-HT transporter (5-HTT) as well as to 5-HT2 and 1A receptors (5-HT(2), 5-HT1A ) was quantified in superficial and deep layers of each region using the ligands [(3) H]-citalopram (5-HTT), [(3) H]-ketanserin (5-HT2 ) and [(3) H]-8-OH-DPAT (5-HT1A ). A Welch’s t-test was utilized to compare receptor densities (Bmax ), revealing a statistically significant decrease in 5-HTT within the ACC of the entire autism cohort. There was also a decrease in 5-HT2 receptor density in the ACC in the adult cohort, but not in child postmortem autism cases as compared to controls. Comparing linear regression lines of Bmax values plotted against age, shows a significantly lower intercept for 5-HTT in autism (p=0.025). 5-HT(2) density increases with age in control cases, whereas in autism there is a decrease with age and significantly different slopes between regression lines (p=0.032). This suggests a deficit in 5-HTT within the ACC in individuals with autism, while decreases in 5-HT(2) density are age-dependent. There were no differences in receptor densities in the PCC or FG in autism and no differences in ligand affinity (KD ) across all regions and ligands examined. This article is protected by copyright. All rights reserved.

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2. Butera G, Sturla F, Pluchinotta FR, Caimi A, Carminati M. Holographic Augmented Reality and 3D Printing for Advanced Planning of Sinus Venosus ASD/Partial Anomalous Pulmonary Venous Return Percutaneous Management. JACC Cardiovasc Interv ;2019 (Jul 22) ;12(14):1389-1391.

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3. Di Nanni N, Bersanelli M, Cupaioli FA, Milanesi L, Mezzelani A, Mosca E. Network-Based Integrative Analysis of Genomics, Epigenomics and Transcriptomics in Autism Spectrum Disorders. Int J Mol Sci ;2019 (Jul 9) ;20(13)

Current studies suggest that autism spectrum disorders (ASDs) may be caused by many genetic factors. In fact, collectively considering multiple studies aimed at characterizing the basic pathophysiology of ASDs, a large number of genes has been proposed. Addressing the problem of molecular data interpretation using gene networks helps to explain genetic heterogeneity in terms of shared pathways. Besides, the integrative analysis of multiple omics has emerged as an approach to provide a more comprehensive view of a disease. In this work, we carry out a network-based meta-analysis of the genes reported as associated with ASDs by studies that involved genomics, epigenomics, and transcriptomics. Collectively, our analysis provides a prioritization of the large number of genes proposed to be associated with ASDs, based on genes’ relevance within the intracellular circuits, the strength of the supporting evidence of association with ASDs, and the number of different molecular alterations affecting genes. We discuss the presence of the prioritized genes in the SFARI (Simons Foundation Autism Research Initiative) database and in gene networks associated with ASDs by other investigations. Lastly, we provide the full results of our analyses to encourage further studies on common targets amenable to therapy.

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4. Kasari C. Time to rethink pre-emptive interventions for infants with early signs of autism spectrum disorder. Lancet Child Adolesc Health ;2019 (Jul 15)

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5. Lin TC, Lo YC, Lin HC, Li SJ, Lin SH, Wu HF, Chu MC, Lee CW, Lin IC, Chang CW, Liu YC, Chen TC, Lin YJ, Ian Shih YY, Chen YY. MR imaging central thalamic deep brain stimulation restored autistic-like social deficits in the rat. Brain Stimul ;2019 (Jul 6)

BACKGROUND : Social deficit is a core symptom in autism spectrum disorder (ASD). Although deep brain stimulation (DBS) has been proposed as a potential treatment for ASD, an ideal target nucleus is yet to be identified. DBS at the central thalamic nucleus (CTN) is known to alter corticostriatal and limbic circuits, and subsequently increase the exploratory motor behaviors, cognitive performance, and skill learning in neuropsychiatric and neurodegenerative disorders. OBJECTIVE : We first investigated the ability of CTN-DBS to selectively engage distinct brain circuits and compared the spatial distribution of evoked network activity and modulation. Second, we investigated whether CTN-DBS intervention improves social interaction in a valproic acid-exposed ASD rat offspring model. METHODS : Brain regions activated through CTN-DBS by using a magnetic resonance (MR)-compatible neural probe, which is capable of inducing site-selective microstimulations during functional MRI (fMRI), were investigated. We then performed functional connectivity MRI, the three-chamber social interaction test, and Western blotting analyses to evaluate the therapeutic efficacy of CTN-DBS in an ASD rat offspring model. RESULTS : The DBS-evoked fMRI results indicated that the activated brain regions were mainly located in cortical areas, limbic-related areas, and the dorsal striatum. We observed restoration of brain functional connectivity (FC) in corticostriatal and corticolimbic circuits after CTN-DBS, accompanied with increased social interaction and decreased social avoidance in the three-chamber social interaction test. The dopamine D2 receptor decreased significantly after CTN-DBS treatment, suggesting changes in synaptic plasticity and alterations in the brain circuits. CONCLUSIONS : Applying CTN-DBS to ASD rat offspring increased FC and altered the synaptic plasticity in the corticolimbic and the corticostriatal circuits. This suggests that CTN-DBS could be an effective treatment for improving the social behaviors of individuals with ASD.

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6. Miryounesi M, Bahari S, Salehpour S, Alipour N, Ghafouri-Fard S. ELMO Domain Containing 1 (ELMOD1) Gene Mutation Is Associated with Mental Retardation and Autism Spectrum Disorder. J Mol Neurosci ;2019 (Jul 20)

ELMO domain containing 1 (ELMOD1) encodes a protein with GTPase-activating functions. Previous studies have confirmed its overexpression in brain tissues. Although no previous study has reported mutations in this gene in human subjects, spontaneous inactivating mutations in the mouse homolog of this gene have been associated with deafness and balance problems. In the current study, we have performed whole exome sequencing (WES) in a patient with intellectual disability. We found a novel mutation in ELMOD1 gene (c.571delG, p.D191MfsTer25) in the proband and two other affected cases in the family. Segregation analysis showed that parents carried the mutation in the heterozygote state. Consequently, the current study reports the first case of mutation in ELMOD1 in human subjects and demonstrates the significant difference in the phenotypes associated with ELMOD1 mutations in humans and mice.

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7. Rafi SK, Fernandez-Jaen A, Alvarez S, Nadeau OW, Butler MG. High Functioning Autism with Missense Mutations in Synaptotagmin-Like Protein 4 (SYTL4) and Transmembrane Protein 187 (TMEM187) Genes : SYTL4- Protein Modeling, Protein-Protein Interaction, Expression Profiling and MicroRNA Studies. Int J Mol Sci ;2019 (Jul 9) ;20(13)

We describe a 7-year-old male with high functioning autism spectrum disorder (ASD) and maternally-inherited rare missense variant of Synaptotagmin-like protein 4 (SYTL4) gene (Xq22.1 ; c.835C>T ; p.Arg279Cys) and an unknown missense variant of Transmembrane protein 187 (TMEM187) gene (Xq28 ; c.708G>T ; p. Gln236His). Multiple in-silico predictions described in our study indicate a potentially damaging status for both X-linked genes. Analysis of predicted atomic threading models of the mutant and the native SYTL4 proteins suggest a potential structural change induced by the R279C variant which eliminates the stabilizing Arg279-Asp60 salt bridge in the N-terminal half of the SYTL4, affecting the functionality of the protein’s critical RAB-Binding Domain. In the European (Non-Finnish) population, the allele frequency for this variant is 0.00042. The SYTL4 gene is known to directly interact with several members of the RAB family of genes, such as, RAB27A, RAB27B, RAB8A, and RAB3A which are known autism spectrum disorder genes. The SYTL4 gene also directly interacts with three known autism genes : STX1A, SNAP25 and STXBP1. Through a literature-based analytical approach, we identified three of five (60%) autism-associated serum microRNAs (miRs) with high predictive power among the total of 298 mouse Sytl4 associated/predicted microRNA interactions. Five of 13 (38%) miRs were differentially expressed in serum from ASD individuals which were predicted to interact with the mouse equivalent Sytl4 gene. TMEM187 gene, like SYTL4, is a protein-coding gene that belongs to a group of genes which host microRNA genes in their introns or exons. The novel Q236H amino acid variant in the TMEM187 in our patient is near the terminal end region of the protein which is represented by multiple sequence alignments and hidden Markov models, preventing comparative structural analysis of the variant harboring region. Like SYTL4, the TMEM187 gene is expressed in the brain and interacts with four known ASD genes, namely, HCFC1 ; TMLHE ; MECP2 ; and GPHN. TMM187 is in linkage with MECP2, which is a well-known determinant of brain structure and size and is a well-known autism gene. Other members of the TMEM gene family, TMEM132E and TMEM132D genes are associated with bipolar and panic disorders, respectively, while TMEM231 is a known syndromic autism gene. Together, TMEM187 and SYTL4 genes directly interact with recognized important ASD genes, and their mRNAs are found in extracellular vesicles in the nervous system and stimulate target cells to translate into active protein. Our evidence shows that both these genes should be considered as candidate genes for autism. Additional biological testing is warranted to further determine the pathogenicity of these gene variants in the causation of autism.

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8. Whitehouse AJO, Varcin KJ, Alvares GA, Barbaro J, Bent C, Boutrus M, Chetcuti L, Cooper MN, Clark A, Davidson E, Dimov S, Dissanayake C, Doyle J, Grant M, Iacono T, Maybery M, Pillar S, Renton M, Rowbottam C, Sadka N, Segal L, Slonims V, Taylor C, Wakeling S, Wan MW, Wray J, Green J, Hudry K. Pre-emptive intervention versus treatment as usual for infants showing early behavioural risk signs of autism spectrum disorder : a single-blind, randomised controlled trial. Lancet Child Adolesc Health ;2019 (Jul 15)

BACKGROUND : Great interest exists in the potential efficacy of prediagnostic interventions within the autism spectrum disorder prodrome, but available evidence relates to children at high familial risk. We aimed to test the efficacy of a pre-emptive intervention designed for infants showing early behavioural signs of autism spectrum disorder. METHODS : In this single-blind, randomised controlled trial done at two specialist centres in Australia, infants aged 9-14 months were enrolled if they were showing at least three early behavioural signs of autism spectrum disorder on the Social Attention and Communication Surveillance-Revised (SACS-R) 12-month checklist. Infants were randomly assigned (1:1) to receive a parent-mediated video-aided intervention (iBASIS-VIPP) or treatment as usual. Group allocation was done by minimisation, stratified by site, sex, age, and the number of SACS-R risk behaviours. Assessments were done at baseline (before treatment allocation) and at the 6 month endpoint. The primary outcome was Autism Observation Scale for Infants (AOSI), which measures early behavioural signs associated with autism spectrum disorder. Secondary outcomes were a range of infant and caregiver outcomes measured by Manchester Assessment of Caregiver-Infant interaction (MACI), Mullen Scales of Early Learning (MSEL), Vineland Adaptive Behaviour Scales, 2nd edition (VABS-2), MacArthur-Bates Communicative Development Inventory (MCDI), and Parenting Sense of Competence (PSOC) scale. This trial is registered with Australian New Zealand Clinical Trials Registry, number ANZCTR12616000819426. FINDINGS : Between June 9, 2016, and March 30, 2018, 103 infants were randomly assigned, 50 to the iBASIS-VIPP group and 53 to the treatment-as-usual group. After the intervention, we observed no significant differences between groups on early autism spectrum disorder behavioural signs measured by the AOSI (difference estimate -0.74, 95% CI -2.47 to 0.98). We also observed no significant differences on secondary outcomes measuring caregiver non-directiveness (0.16, -0.33 to 0.65), caregiver sensitive responding (0.24, -0.15 to 0.63), and infant attentiveness (-0.19, -0.63 to 0.25) during parent-child interactions (MACI), as well as on researcher-administered measures of receptive (1.30, -0.48 to 3.08) and expressive language (0.54, -0.73 to 1.80), visual reception (0.31, -0.77 to 1.40), and fine motor skills (0.55, -0.32 to 1.41) using the MSEL. Compared with the treatment-as-usual group, the iBASIS-VIPP group had lower infant positive affect (-0.69, -1.27 to -0.10) on the MACI, but higher caregiver-reported receptive (37.17, 95% CI 10.59 to 63.75) and expressive vocabulary count (incidence rate ratio 2.31, 95% CI 1.22 to 4.33) on MCDI, and functional language use (difference estimate 6.43, 95% CI 1.06 to 11.81) on VABS. There were no significant group differences on caregiver-reported measures of MCDI infant gesture use (3.22, -0.60 to 7.04) and VABS social behaviour (3.28, -1.43 to 7.99). We observed no significant differences between groups on self-reported levels of parenting satisfaction (difference estimate 0.21, 95% CI -0.09 to 0.52), interest (-0.23, -0.62 to 0.16) and efficacy (-0.08, -0.38 to 0.22) on PSOC. INTERPRETATION : A pre-emptive intervention for the autism spectrum disorder prodrome had no immediate treatment effect on early autism spectrum disorder symptoms, the quality of parent-child interactions, or researcher-administered measures of developmental skills. However, we found a positive effect on parent-rated infant communication skills. Ongoing follow-up of this infant cohort will assess longer-term developmental effects. FUNDING : Western Australia Children’s Research Fund, Autism Cooperative Research Centre, La Trobe University, and Angela Wright Bennett Foundation.

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