1. Barone R, Sturiale L, Fiumara A, Palmigiano A, Bua RO, Rizzo R, Zappia M, Garozzo D. {{CSF N-glycan profile reveals sialylation deficiency in a patient with GM2 gangliosidosis presenting as childhood disintegrative disorder}}. {Autism research : official journal of the International Society for Autism Research}. 2015 Aug 19.
Protein N-glycosylation consists in the synthesis and processing of the oligosaccharide moiety (N-glycan) linked to a protein and it serves several functions for the proper central nervous system (CNS) development and function. Previous experimental and clinical studies have shown the importance of proper glycoprotein sialylation for the synaptic function and the occurrence of autism spectrum disorders (ASD) in the presence of sialylation deficiency in the CNS. Late-onset Tay Sachs disease (LOTSD) is a lysosomal disorder caused by mutations in the HEXA gene resulting in GM2-ganglioside storage in the CNS. It is characterized by progressive neurological impairment and high co-occurrence of psychiatric disturbances. We studied the N-glycome profile of the cerebrospinal fluid (CSF) in a 14 year-old patient with GM2-gangliosidosis (LOTSD). At the age of 4, the patient presented regressive autism fulfilling criteria for childhood disintegrative disorder (CDD). A CSF sample was obtained in the course of diagnostic work-up for the suspicion of an underlying neurodegenerative disorder. We found definite changes of CSF N-glycans due to a dramatic decrease of sialylated biantennary and triantennary structures and an increase of asialo-core fucosylated bisected N-glycans. No changes of total plasma N-glycans were found. Herein findings highlight possible relationships between the early onset psychiatric disturbance featuring CDD in the patient and defective protein sialylation in the CNS. In conclusion, the study first shows aberrant N-glycan structures of CSF proteins in LOTSD; unveils possible pathomechanisms of GM2-gangliosidosis; supports existing relationships between neuropsychiatric disorders and unproper protein glycosylation in the CNS. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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2. Bourgeron T. {{From the genetic architecture to synaptic plasticity in autism spectrum disorder}}. {Nature reviews Neuroscience}. 2015 Aug 20;16(9):551-63.
Genetics studies of autism spectrum disorder (ASD) have identified several risk genes that are key regulators of synaptic plasticity. Indeed, many of the risk genes that have been linked to these disorders encode synaptic scaffolding proteins, receptors, cell adhesion molecules or proteins that are involved in chromatin remodelling, transcription, protein synthesis or degradation, or actin cytoskeleton dynamics. Changes in any of these proteins can increase or decrease synaptic strength or number and, ultimately, neuronal connectivity in the brain. In addition, when deleterious mutations occur, inefficient genetic buffering and impaired synaptic homeostasis may increase an individual’s risk for ASD.
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3. Durieux AM, Horder J, Mendez MA, Egerton A, Williams SC, Wilson CE, Spain D, Murphy C, Robertson D, Barker GJ, Murphy DG, McAlonan GM. {{Cortical and subcortical glutathione levels in adults with autism spectrum disorder}}. {Autism research : official journal of the International Society for Autism Research}. 2015 Aug 20.
Increased oxidative stress has been postulated to contribute to the pathogenesis of autism spectrum disorder (ASD). However, reports of alterations in oxidation markers including glutathione (GSH), the major endogenous antioxidant, are indirect, coming from blood plasma level measurements and postmortem studies. Therefore we used in-vivo 3 Tesla proton magnetic resonance spectroscopy ([1H]MRS) to directly measure GSH concentrations in the basal ganglia (BG) and the dorsomedial prefrontal cortex of 21 normally intelligent adult males with ASD and 29 controls who did not differ in age or IQ. There was no difference in brain GSH between patients and controls in either brain area; neither did GSH levels correlate with measures of clinical severity in patients. Thus [1H]MRS measures of cortical and subcortical GSH are not a biomarker for ASD in intellectually able adult men. Autism Res 2015. (c) 2015 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.
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4. Iannuzzi D, Kopecky K, Broder-Fingert S, Connors SL. {{Addressing the Needs of Individuals with Autism: Role of Hospital-Based Social Workers in Implementation of a Patient-Centered Care Plan}}. {Health & social work}. 2015 Aug;40(3):245-8.
5. Jingru L, Shasha M, Weihui Z. {{Functional analysis of autism-associated NRXN1beta gene promoter}}. {Yi chuan = Hereditas / Zhongguo yi chuan xue hui bian ji}. 2015 Aug 20;37(8):801-10.
Neurexins are neuron-specific synaptic proteins, and abnormal structure of Neurexin1beta is closely associated with autism. To characterize the minimal promoter of autism-associated NRXN1beta gene and identify functional elements regulating its transcription, luciferase reporter plasmids containing different regulatory regions upstream of NRXN1beta gene were constructed. After transfecting HEK293 cells with these plasmids, the minimal promoter region of NRXN1beta gene was determined by detecting the transcriptional activity of luciferase reporter genes while the corresponding functional elements that significantly enhance or inhibit the activity of reporter genes were further screened out. To identify cis-acting elements, continuous nucleotide mutation within the functional regions and adjacent DNA sequences were generated using site-directed mutagenesis techniques and then transcriptional regulatory elements in corresponding regions were analyzed using transcription factor binding prediction tool. Our results showed for the first time that the minimal promoter region of human NRXN1beta gene is located between positions ?88 and +156 (-88/+156); two regions -88/-73 and +156/+149 enhance while the region +229/+419 inhibits promoter activity. The region -84/-63 significantly enhances promoter activity as cis-acting elements, suggesting the presence of DBP and ABF1 transcription factor binding sites in this region.
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6. Li HH, Shan L, Du L, Jia FY. {{[Research advances in the management of autism spectrum disorders in children]}}. {Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics}. 2015 Aug;17(8):886-92.
Autism spectrum disorders (ASD) are a group of developmental dysfuntion of nervous system characterized by social interaction and communication disorders, restricted interests and repetitive stereotyped behaviors. The incidence of ASD has been increasing through the world. Some studies have shown that early reasonable individualized comprehensive intervention can obviously improve the prognosis of children with ASD. The etiology of ASD is unclear now, and behavioral and developmental intervention is the main therapy for ASD. The reasonable application of some drugs can improve the efficacy of the behavioral intervention for concomitant symptoms in ASD. With the in-depth study of the pathogenesis of ASD, bumetanide, oxytocin, vitamin D and hyperbaric oxygen therapy have been found to be promising for the improvement of core symptoms of ASD. This article reviews the research advances in the behavioral and developmental intervention and drug therapy for ASD.
7. Matlis S, Boric K, Chu CJ, Kramer MA. {{Erratum: Robust disruptions in electroencephalogram cortical oscillations and large-scale functional networks in autism}}. {BMC neurology}. 2015;15:142.
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8. Ngounou Wetie AG, Wormwood KL, Charette L, Ryan JP, Woods AG, Darie CC. {{Comparative two-dimensional polyacrylamide gel electrophoresis of the salivary proteome of children with autism spectrum disorder}}. {Journal of cellular and molecular medicine}. 2015 Aug 20.
In the last decades, prevalence of autism spectrum disorder (ASD) has been on the rise. However, clear aetiology is still elusive and improvements in early diagnosis are needed. To uncover possible biomarkers present in ASD, we used two-dimensional polyacrylamide gel electrophoresis and nanoliquid chromatography-tandem mass spectrometry (nanoLC-MS/MS), to compare salivary proteome profiling of children with ASD and controls. A total of 889 spots were compared and only those spots with a fold change >/=1.7 and a P-value <0.05 or a fold change of >/=3.0 between ASD cases and controls were analysed by nanoLC-MS/MS. Alpha-amylase, CREB-binding protein, p532, Transferrin, Zn alpha2 glycoprotein, Zymogen granule protein 16, cystatin D and plasminogen were down-regulated in ASD. Increased expression of proto-oncogene Frequently rearranged in advanced T-cell lymphomas 1 (FRAT1), Kinesin family member 14, Integrin alpha6 subunit, growth hormone regulated TBC protein 1, parotid secretory protein, Prolactin-inducible protein precursor, Mucin-16, Ca binding protein migration inhibitory factor-related protein 14 (MRP14) was observed in individuals with ASD. Many of the identified proteins have previously been linked to ASD or were proposed as risk factors of ASD at the genetic level. Some others are involved in pathological pathways implicated in ASD causality such as oxidative stress, lipid and cholesterol metabolism, immune system disturbances and inflammation. These data could contribute to protein signatures for ASD presence, risk and subtypes, and advance understanding of ASD cause as well as provide novel treatment targets for ASD.
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9. Qin LY, Dai XF. {{[Effect of sulindac on improving autistic behaviors in rats]}}. {Nan fang yi ke da xue xue bao = Journal of Southern Medical University}. 2015 Aug 20;35(8):1162-5.
OBJECTIVE: To test the effect of sulindac on autistic behaviors in a rat model and explore the possible mechanisms. METHODS: Autistic rat models were established by a single intraperitoneal injection of sodium valproate (VPA) at 12.5 days of pregnancy. The pregnant rats were treated with oral sulindac at a daily dose of 80 mg/kg until weaning of the newborn rats (23 days after being born), which were divided into control, VPA treatment, sulindac treatment, and VPA+ sulindac treatment groups. The social interaction and neuroethology of the newborn rats were evaluated at 35 days, and the levels of beta-catenin and phosphorylated Gsk3beta in the brain tissues were investigated by Western blotting. RESULTS: Compared with the control rats, the rats treated with VPA showed lower social interaction, longer moving time in central area, and reduced standing times. Treatment with sulindac alone resulted in no obvious changes in the social interaction or neuroethology of the newborn rats, but sulindac treatment corrected VPA-induced autistic-like behaviors. Sulindac also attenuated VPA-triggered p-Gsk3beta downregulation and beta-catenin upregulation in the prefrontal lobe, seahorse and cerebellum. CONCLUSION: ulindac can improve the behaviors of autistic rats possibly by suppressing Wnt signaling pathway.
10. Scremin OU, Roch M, Norman KM, Djazayeri S, Liu YY. {{Brain acetylcholine and choline concentrations and dynamics in a murine model of the Fragile X syndrome: Age, sex and region-specific changes}}. {Neuroscience}. 2015 Aug 20;301:520-8.
Fragile X syndrome is a learning disability caused by excess of CGG repeats in the 5′ untranslated region of the Fragile X gene (FMR1) silencing its transcription and translation. We used a murine model of this condition, Fmr1 knock-out mice (KO) to study acetylcholine (ACh) metabolism and compared it to that of wild-type control mice (WT). Brain endogenous ACh (D0ACh), free choline (D0Ch), their deuterated variants D4ACh and D4Ch and mole ratios (AChMR and ChMR) were measured by gas chromatography-mass spectrometry in the cerebral hemisphere, cerebral cortex, hippocampus and cerebellum, following D4Ch administration. Regression analysis indicated a significant decrease with age (negative slope) of D4ACh, AChMR, D4Ch and ChMR in WT mice. Age dependence was only present for D4ACh and AChMR in KO mice. Analysis of variance with age as covariate indicated a significant greater D4Ch in the cerebral cortex of KO females when compared to WT females. Contrasts between sexes within genotypes indicated lower D0Ch in cortex and cerebellum of female KO mice but not in WT and lower D4Ch in hippocampus of female KO and WT mice. In conclusion, after adjusting for age, D0ACh concentrations and synthesis from deuterium-labeled Ch were similar in KO and control WT mice in all brain regions. In contrast, significant changes in Ch dynamics were found in hippocampus and cerebral cortex of KO mice that might contribute to the pathogenesis of FXS.
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11. Shen Y, Xun G, Guo H, He Y, Ou J, Dong H, Xia K, Zhao J. {{Association and gene-gene interactions study of reelin signaling pathway related genes with autism in the Han Chinese population}}. {Autism research : official journal of the International Society for Autism Research}. 2015 Aug 19.
Autism is a neurodevelopmental disorder with unclear etiology. Reelin had been proposed to participate in the etiology of autism due to its important role in brain development. The goal of this study was to explore the association and gene-gene interactions of reelin signaling pathway related genes (RELN, VLDLR, LRP8, DAB1, FYN, and CDK5) with autism in Han Chinese population. Genotyping data of the six genes were obtained from a recent genome-wide association study performed in 430 autistic children who fulfilled the DSM-IV-TR criteria for autistic disorder, and 1,074 healthy controls. Single marker case-control association analysis and haplotype case-control association analysis were conducted after the data was screened. Multifactor dimensionality reduction (MDR) was applied to further test gene-gene interactions. Neither the single marker nor the haplotype association tests found any significant difference between the autistic group and the control group after permutation test of 1,000 rounds. The 4-locus MDR model (comprising rs6143734, rs1858782, rs634500, and rs1924267 which belong to RELN and DAB1) was determined to be the model with the highest cross-validation consistency (CVC) and testing balanced accuracy. The results indicate that an interaction between RELN and DAB1 may increase the risk of autism in the Han Chinese population. Furthermore, it can also be inferred that the involvement of RELN in the etiology of autism would occur through interaction with DAB1. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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12. Vieira JP, Lopes F, Silva-Fernandes A, Sousa MV, Moura S, Sousa S, Costa BM, Barbosa M, Ylstra B, Temudo T, Lourenco T, Maciel P. {{Variant Rett syndrome in a girl with a pericentric X-chromosome inversion leading to epigenetic changes and overexpression of the MECP2 gene}}. {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience}. 2015 Aug 10.
Rett syndrome is a neurodevelopmental disorder caused by mutations in the MECP2 gene. We investigated the genetic basis of disease in a female patient with a Rett-like clinical. Karyotype analysis revealed a pericentric inversion in the X chromosome -46,X,inv(X)(p22.1q28), with breakpoints in the cytobands where the MECP2 and CDKL5 genes are located. FISH analysis revealed that the MECP2 gene is not dislocated by the inversion. However, and in spite of a balanced pattern of X inactivation, this patient displayed hypomethylation and an overexpression of the MECP2 gene at the mRNA level in the lymphocytes (mean fold change: 2.55+/-0.38) in comparison to a group of control individuals; the expression of the CDKL5 gene was similar to that of controls (mean fold change: 0.98+/-0.10). No gains or losses were detected in the breakpoint regions encompassing known or suspected transcription regulatory elements. We propose that the de-regulation of MECP2 expression in this patient may be due to alterations in long-range genomic interactions caused by the inversion and hypothesize that this type of epigenetic de-regulation of the MECP2 may be present in other RTT-like patients.
