1. Babbs C, Lloyd D, Pagnamenta AT, Twigg SR, Green J, McGowan SJ, Mirza G, Naples R, Sharma VP, Volpi EV, Buckle VJ, Wall SA, Knight SJ, Parr JR, Wilkie AO. {{De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder}}. {J Med Genet};2014 (Sep 16)
BACKGROUND: Autism spectrum disorders (ASDs) are common and have a strong genetic basis, yet the cause of approximately 70-80% ASDs remains unknown. By clinical cytogenetic testing, we identified a family in which two brothers had ASD, mild intellectual disability and a chromosome 22 pericentric inversion, not detected in either parent, indicating de novo mutation with parental germinal mosaicism. We hypothesised that the rearrangement was causative of their ASD and localised the chromosome 22 breakpoints. METHODS: The rearrangement was characterised using fluorescence in situ hybridisation, Southern blotting, inverse PCR and dideoxy-sequencing. Open reading frames and intron/exon boundaries of the two physically disrupted genes identified, TCF20 and TNRC6B, were sequenced in 342 families (260 multiplex and 82 simplex) ascertained by the International Molecular Genetic Study of Autism Consortium (IMGSAC). RESULTS: IMGSAC family screening identified a de novo missense mutation of TCF20 in a single case and significant association of a different missense mutation of TCF20 with ASD in three further families. Through exome sequencing in another project, we independently identified a de novo frameshifting mutation of TCF20 in a woman with ASD and moderate intellectual disability. We did not identify a significant association of TNRC6B mutations with ASD. CONCLUSIONS: TCF20 encodes a transcriptional coregulator (also termed SPBP) that is structurally and functionally related to RAI1, the critical dosage-sensitive protein implicated in the behavioural phenotypes of the Smith-Magenis and Potocki-Lupski 17p11.2 deletion/duplication syndromes, in which ASD is frequently diagnosed. This study provides the first evidence that mutations in TCF20 are also associated with ASD.
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2. Bhat S, Acharya UR, Adeli H, Bairy GM, Adeli A. {{Autism: cause factors, early diagnosis and therapies}}. {Rev Neurosci};2014 (Sep 12)
Abstract Autism spectrum disorder (ASD) is a complex neurobiological disorder characterized by neuropsychological and behavioral deficits. Cognitive impairment, lack of social skills, and stereotyped behavior are the major autistic symptoms, visible after a certain age. It is one of the fastest growing disabilities. Its current prevalence rate in the U.S. estimated by the Centers for Disease Control and Prevention is 1 in 68 births. The genetic and physiological structure of the brain is studied to determine the pathology of autism, but diagnosis of autism at an early age is challenging due to the existing phenotypic and etiological heterogeneity among ASD individuals. Volumetric and neuroimaging techniques are explored to elucidate the neuroanatomy of the ASD brain. Nuroanatomical, neurochemical, and neuroimaging biomarkers can help in the early diagnosis and treatment of ASD. This paper presents a review of the types of autism, etiologies, early detection, and treatment of ASD.
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3. Chiocchetti AG, Kopp M, Waltes R, Haslinger D, Duketis E, Jarczok TA, Poustka F, Voran A, Graab U, Meyer J, Klauck SM, Fulda S, Freitag CM. {{Variants of the CNTNAP2 5′ promoter as risk factors for autism spectrum disorders: a genetic and functional approach}}. {Mol Psychiatry};2014 (Sep 16)
Contactin-associated protein-like 2 gene (CNTNAP2), a member of the Neurexin gene superfamily, is one of the best-replicated risk genes for autism spectrum disorders (ASD). ASD are predominately genetically determined neurodevelopmental disorders characterized by impairments of language development, social interaction and communication, as well as stereotyped behavior and interests. Although CNTNAP2 expression levels were proposed to alter ASD risk, no study to date has focused on its 5′ promoter. Here, we directly sequenced the CNTNAP2 5′ promoter region of 236 German families with one child with ASD and detected four novel variants. Furthermore, we genotyped the three most frequent variants (rs150447075, rs34712024, rs71781329) in an additional sample of 356 families and found nominal association of rs34712024G with ASD and rs71781329GCG[7] with language development. The four novel and the three known minor alleles of the identified variants were predicted to alter transcription factor binding sites (TFBS). At the functional level, the respective sequences spanning these seven variants were bound by nuclear factors. In a luciferase promoter assay, the respective minor alleles showed cell line-specific and differentiation stage-dependent effects at the level of promoter activation. The novel potential rare risk-variant M2, a G>A mutation -215 base pairs 5′ of the transcriptional start site, significantly reduced promoter efficiency in HEK293T and in undifferentiated and differentiated neuroblastoid SH-SY5Y cells. This variant was transmitted to a patient with autistic disorder. The under-transmitted, protective minor G allele of the common variant rs34712024, in contrast, increased transcriptional activity. These results lead to the conclusion that the pathomechanism of CNTNAP2 promoter variants on ASD risk is mediated by their effect on TFBSs, and thus confirm the hypothesis that a reduced CNTNAP2 level during neuronal development increases liability for ASD.Molecular Psychiatry advance online publication, 16 September 2014; doi:10.1038/mp.2014.103.
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4. Ciranna L, Catania MV. {{5-HT7 receptors as modulators of neuronal excitability, synaptic transmission and plasticity: physiological role and possible implications in autism spectrum disorders}}. {Front Cell Neurosci};2014;8:250.
Serotonin type 7 receptors (5-HT7) are expressed in several brain areas, regulate brain development, synaptic transmission and plasticity, and therefore are involved in various brain functions such as learning and memory. A number of studies suggest that 5-HT7 receptors could be potential pharmacotherapeutic target for cognitive disorders. Several abnormalities of serotonergic system have been described in patients with autism spectrum disorder (ASD), including abnormal activity of 5-HT transporter, altered blood and brain 5-HT levels, reduced 5-HT synthesis and altered expression of 5-HT receptors in the brain. A specific role for 5-HT7 receptors in ASD has not yet been demonstrated but some evidence implicates their possible involvement. We have recently shown that 5-HT7 receptor activation rescues hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome, a monogenic cause of autism. Several other studies have shown that 5-HT7 receptors modulate behavioral flexibility, exploratory behavior, mood disorders and epilepsy, which include core and co-morbid symptoms of ASD. These findings further suggest an involvement of 5-HT7 receptors in ASD. Here, we review the physiological roles of 5-HT7 receptors and their implications in Fragile X Syndrome and other ASD.
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5. Crider A, Thakkar R, Ahmed AO, Pillai A. {{Dysregulation of estrogen receptor beta (ERbeta), aromatase (CYP19A1), and ER co-activators in the middle frontal gyrus of autism spectrum disorder subjects}}. {Mol Autism};2014;5(1):46.
BACKGROUND: Autism spectrum disorders (ASD) are much more common in males than in females. Molecular alterations within the estrogen receptor (ER) signaling pathway may contribute to the sex difference in ASD, but the extent of such abnormalities in the brain is not known. METHODS: Postmortem middle frontal gyrus tissues (13 ASD and 13 control subjects) were used. The protein levels were examined by western blotting. The gene expression was determined by qRT-PCR. RESULTS: Gene expression analysis identified a 35% decrease in ERbeta mRNA expression in the middle frontal gyrus of ASD subjects. In addition, a 38% reduction in aromatase (CYP19A1) mRNA expression was observed in ASD subjects. We also found significant decreases in ER co-activators that included a 34% decrease in SRC-1, a 77% decrease in CBP, and a 52% decrease in P/CAF mRNA levels in ASD subjects relative to controls. There were no differences in the mRNA levels of TIF-2, AIB-1 (ER co-activators), ER co-repressors (SMRT and nCoR) and ERalpha in the middle frontal gyrus of ASD subjects as compared to controls. We observed significant correlations between ERbeta, CYP19A1, and co-activators in the study subjects. Immunoblot analysis further confirmed the changes in ERbeta and aromatase at the protein level in the control and ASD subjects. CONCLUSIONS: These results, for the first time, provide the evidence of the dysregulation of ERbeta and co-factors in the brain of subjects with ASD.
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6. Ford TC, Crewther DP. {{Factor Analysis Demonstrates a Common Schizoidal Phenotype within Autistic and Schizotypal Tendency: Implications for Neuroscientific Studies}}. {Front Psychiatry};2014;5:117.
Behavioral and cognitive dysfunction, particularly social and communication impairments, are shared between autism and schizophrenia spectrum disorders, while evidence for a diametric autism-positive schizophrenia symptom profile is inconsistent. We investigated the shared phenotype at a personality trait level, particularly its resemblance to schizoid personality disorder, as well as differential aspects of the autism-schizophrenia model. Items of the autism spectrum quotient (AQ) and schizotypal personality questionnaire (SPQ) were pseudo-randomly combined, and were completed by 449 (162 male, 287 female) non-clinical participants aged 18-40. A factor analysis revealed three factors; the first represented a shared social disorganization phenotype, the second reflected perceptual oddities specific to schizotypy while the third reflected social rigidity specific to autism. The AQ and SPQ were strongly correlated with Factor 1 (AQ: r = 0.75, p < 0.001; SPQ: r = 0.96, p < 0.001), SPQ score was correlated with Factor 2 (r = 0.51, p < 0.001), particularly in cognitive-perceptual features (r = 0.66, p < 0.001), and AQ score was strongly correlated with Factor 3 (r = 0.76, p < 0.001). Furthermore, there was no relationship between Factor 1 and Factor 2. Thus, there is robust evidence for a shared social disorganization phenotype in autistic and schizotypal tendency, which reflects the schizoid phenotype. Discriminating and independent dimensions of schizotypal and autistic tendency exist in Factors 2 and 3, respectively. Current diagnostic protocols could result in different diagnoses depending on the instrument used, suggesting the need for neuromarkers that objectively differentiate autistic and schizotypal traits and resolve the question of commonality versus co-morbidity.
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7. Fung LK, Hardan AY. {{Autism in DSM-5 under the microscope: Implications to patients, families, clinicians, and researchers}}. {Asian J Psychiatr};2014 (Sep 3)
The changes in the diagnostic classification of the pervasive developmental disorders from the 4th edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV) to DSM-5 are expected to affect patients with autism, their families, as well as clinicians and researchers in the field of autism. This article reviews the new DSM-5 diagnostic criteria for Autism Spectrum Disorder (ASD) and Social Communication Disorder (SCD), and discusses potential consequences in the perspectives of major stakeholders.
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8. Grant N, Rodger S, Hoffmann T. {{Evaluation of Autism-Related Health Information on the Web}}. {J Appl Res Intellect Disabil};2014 (Sep 16)
BACKGROUND: The Internet is a frequently accessed source of information for parents of a child with autism. To help parents make informed decisions about treatment options, websites should contain accurate information. This study aimed to evaluate the quality of information in a sample of autism-relevant websites. MATERIALS AND METHODS: Autism-related keywords were entered into three widely used search engines in April 2013 and the 20 most frequently appearing sites identified. Website quality was rated, by two independent raters, using the DISCERN tool. Websites were also coded according to the type of references/sources provided to support the intervention content presented. RESULTS: The mean DISCERN score was 46.5 (range 23-67.5), of a possible 80. Information about treatment risks and no treatment as an option was rarely described. Only six (30%) websites provided research references when describing intervention options. CONCLUSIONS: Many websites did not meet criteria for quality health information and failed to cite evidence supporting described interventions. Implications of these findings are discussed.
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9. Hill AP, Zuckerman KE, Hagen AD, Kriz DJ, Duvall SW, van Santen J, Nigg J, Fair D, Fombonne E. {{Aggressive Behavior Problems in Children with Autism Spectrum Disorders: Prevalence and Correlates in a Large Clinical Sample}}. {Res Autism Spectr Disord};2014 (Sep 1);8(9):1121-1133.
Aggressive behavior problems (ABP) are frequent yet poorly understood in children with Autism Spectrum Disorders (ASD) and are likely to co-vary significantly with comorbid problems. We examined the prevalence and sociodemographic correlates of ABP in a clinical sample of children with ASD (N = 400; 2-16.9 years). We also investigated whether children with ABP experience more intensive medical interventions, greater impairments in behavioral functioning, and more severe comorbid problems than children with ASD who do not have ABP. One in four children with ASD had Child Behavior Checklist scores on the Aggressive Behavior scale in the clinical range (T-scores >/= 70). Sociodemographic factors (age, gender, parent education, race, ethnicity) were unrelated to ABP status. The presence of ABP was significantly associated with increased use of psychotropic drugs and melatonin, lower cognitive functioning, lower ASD severity, and greater comorbid sleep, internalizing, and attention problems. In multivariate models, sleep, internalizing, and attention problems were most strongly associated with ABP. These comorbid problems may hold promise as targets for treatment to decrease aggressive behavior and proactively identify high-risk profiles for prevention.
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10. Joyce HD, Hoffman J, Anderson-Butcher D, Moodie-Dyer A. {{Fiscal Mapping Autism Spectrum Disorder Funds: A Case Study of Ohio}}. {J Soc Work Disabil Rehabil};2014 (Sep 15)
Individuals with autism spectrum disorders (ASD) have complex needs requiring regular service utilization. Policymakers, administrators, and community leaders are looking for ways to finance ASD services and systems. Understanding the fiscal resources that support ASD services is essential. This paper uses fiscal mapping to explore ASD funding streams in Ohio. Fiscal mapping steps are overviewed to assist ASD stakeholders in identifying and examining ASD-related funding. Implications are drawn related to how fiscal mapping may be used to identify and leverage funding for ASD services. The resulting information is critical to utilizing existing resources, advocating for resources, and leveraging available funds.
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11. Kumari D, Bhattacharya A, Nadel J, Moulton K, Zeak NM, Glicksman A, Dobkin C, Brick DJ, Schwartz PH, Smith CB, Klann E, Usdin K. {{Identification of Fragile X Syndrome-Specific Molecular Markers in Human Fibroblasts: A Useful Model to Test the Efficacy of Therapeutic Drugs}}. {Hum Mutat};2014 (Sep 16)
Fragile X Syndrome (FXS) is the most frequent cause of inherited intellectual disability and autism. It is caused by the absence of the fragile X mental retardation 1 (FMR1) gene product, FMRP, an RNA-binding protein involved in the regulation of translation of a subset of brain mRNAs. In Fmr1 knockout (KO) mice, the absence of FMRP results in elevated protein synthesis in the brain as well as increased signaling of many translational regulators. Whether protein synthesis is also dysregulated in FXS patients is not firmly established. Here, we demonstrate that fibroblasts from FXS patients have significantly elevated rates of basal protein synthesis along with increased levels of phosphorylated mechanistic target of rapamycin (p-mTOR), phosphorylated extracellular signal regulated kinase 1/2 (p-ERK 1/2) and phosphorylated p70 ribosomal S6 kinase 1 (p-S6K1). Treatment with small molecules that inhibit S6K1, and a known FMRP target, phosphoinositide 3-kinase (P13K) catalytic subunit p110beta, lowered the rates of protein synthesis in both control and patient fibroblasts. Our data thus demonstrate that fibroblasts from FXS patients may be a useful in vitro model to test the efficacy and toxicity of potential therapeutics prior to clinical trials, as well as for drug screening and designing personalized treatment approaches. This article is protected by copyright. All rights reserved.
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12. Lassalle A, Itier RJ. {{Autistic traits influence gaze-oriented attention to happy but not fearful faces}}. {Soc Neurosci};2014 (Sep 15):1-19.
The relationship between autistic traits and gaze-oriented attention to fearful and happy faces was investigated at the behavioral and neuronal levels. Upright and inverted dynamic face stimuli were used in a gaze-cueing paradigm while event related potentials (ERPs) were recorded. Participants responded faster to gazed-at than to non-gazed-at targets, and this gaze orienting effect (GOE) diminished with inversion, suggesting it relies on facial configuration. It was also larger for fearful than happy faces but only in participants with high autism-spectrum quotient (AQ) scores. While the GOE to fearful faces was of similar magnitude regardless of AQ scores, a diminished GOE to happy faces was found in participants with high AQ scores. At the ERP level, a congruency effect on target-elicited P1 component reflected enhanced visual processing of gazed-at targets. In addition, cue-triggered early directing attention negativity and anterior directing attention negativity reflected, respectively, attention orienting and attention holding at gazed-at locations. These neural markers of spatial attention orienting were not modulated by emotion and were not found in participants with high AQ scores. Together, these findings suggest that autistic traits influence attention orienting to gaze and its modulation by social emotions such as happiness.
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13. Santos AR, Kanellopoulos AK, Bagni C. {{Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us}}. {Learn Mem};2014 (Oct);21(10):543-555.
The Fragile X syndrome (FXS) is the most frequent form of inherited mental disability and is considered a monogenic cause of autism spectrum disorder. FXS is caused by a triplet expansion that inhibits the expression of the FMR1 gene. The gene product, the Fragile X Mental Retardation Protein (FMRP), regulates mRNA metabolism in brain and nonneuronal cells. During brain development, FMRP controls the expression of key molecules involved in receptor signaling, cytoskeleton remodeling, protein synthesis and, ultimately, spine morphology. Symptoms associated with FXS include neurodevelopmental delay, cognitive impairment, anxiety, hyperactivity, and autistic-like behavior. Twenty years ago the first Fmr1 KO mouse to study FXS was generated, and several years later other key models including the mutant Drosophila melanogaster, dFmr1, have further helped the understanding of the cellular and molecular causes behind this complex syndrome. Here, we review to which extent these biological models are affected by the absence of FMRP, pointing out the similarities with the observed human dysfunction. Additionally, we discuss several potential treatments under study in animal models that are able to partially revert some of the FXS abnormalities.
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14. Tabata K, Yoshida T, Naoe J. {{P-4three cases of alcoholism with autism spectrum disorder}}. {Alcohol Alcohol};2014 (Sep);49 Suppl 1:i54.
INTRODUCTION: The relationship between alcoholism and autism spectrum disorder (ASD) has been the subject of much recent research. We report herein three patients with alcoholism and a history of ASD. ETHICAL CONSIDERATIONS: Consent was directly obtained from Patients 1 and 2. Care was taken to protect the identities of all three patients. CASE REPORTS: Patient 1 was a 34-year-old man. From adolescence onwards,he had few friends and tended to isolate himself. At 21 years old, he began drinking alcohol due to the stress of interpersonal communication. At 29 years old, he was admitted with alcohol withdrawal symptoms. Post-discharge, no relapse has occurred. ASD was confirmed on psychological testing. Patient 2 was a 38-year-old man with a long-term history of anthropophobia. He entered employment at the age 19, but quit employment at age 30 due to the stress of interpersonal communication. After turning to alcohol in order to reduce anxiety, he became an alcoholic. He was admitted at 36 years old. Post-discharge, no relapse has occurred. ASD was confirmed on psychological testing. Patient 3 was a 28-year-old woman with a long-term history of stranger anxiety. She began drinking excessively in order to reduce the stress of interpersonal communication. At 26 years old, she was admitted for alcohol epilepsy. Post-discharge, no relapse has occurred. ASD was confirmed on psychological testing. DISCUSSION: The following characteristics were common to all three patients: ASD; interpersonal communication disorder from a young age; development of alcoholism at a young age; and no difficulty maintaining abstinence after successfully quitting. In connection with alcohol consumption, ASD traits, including strong preferences, obsessive-compulsive behaviors, and stereotypies, reportedly result in early addiction, but also work favorably to enable maintained abstinence. These characteristics are consistent with the present patients. The identification of a history of ASD is important for the successful management of alcoholism.
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15. Thackeray LA, Eatough V. {{‘Well the Future, that is Difficult’: A Hermeneutic Phenomenological Analysis Exploring the Maternal Experience of Parenting a Young Adult with a Developmental Disability}}. {J Appl Res Intellect Disabil};2014 (Sep 15)
BACKGROUND: The predominant focus of extant literature exploring maternal experience of developmental disability has been stress, adaptation, efficacy of interventions and the burden of care. Most studies involve mothers of children, with scant attention given to what life is like later. This study qualitatively explores the experience of mothers of young adults (aged 19-28). MATERIALS AND METHODS: Semi-structured interviews conducted with six women aged 48-60 were transcribed and analysed using interpretative phenomenological analysis. RESULTS: Three themes illustrate how mothers are confronted with their adult children’s continuing need for support and how a lack of trust in social care creates anxiety about the future, increasing awareness of mortality. CONCLUSIONS: Vulnerability represents a useful concept for understanding these findings theoretically. Galvin & Todres’ (2013) conceptual framework for the humanization of care provides the opportunity to prioritize the needs of individuals by highlighting dimensions of existence which confer meaning.
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16. Tjeerdema H. {{[Reaction on ‘The stigmatising of schizophrenia and autism in the Flemish daily papers’]}}. {Tijdschr Psychiatr};2014;56(9):629-631.
17. Wong K, Leonard H, Jacoby P, Ellaway C, Downs J. {{The trajectories of sleep disturbances in Rett syndrome}}. {J Sleep Res};2014 (Sep 14)
Rett syndrome is a rare neurodevelopmental disorder usually affecting females, and is associated with a mutation in the MECP2 gene. Sleep problems occur commonly and we investigated the trajectories and influences of age, mutation and treatments. Data were collected at six time points over 12 years from 320 families registered with the Australian Rett Syndrome Database. Regression analysis was used to investigate relationships between sleep disturbances, age, mutation type and use of treatment, and latent class growth analysis was performed to identify sleep problem phenotypes and model the effect of mutation type. The age range of subjects was 2.0-35.8 years. The study showed that sleep problems occurred in more than 80% of individuals and the prevalence decreased with age. Night laughing and night screaming occurred in 77 and 49%, respectively, when younger. Those with a large deletion had a higher prevalence of night laughing, which often occurred frequently. Treatment was associated with a 1.7% reduction in risk of further sleep problems. High and low baseline prevalence groups were identified. Approximately three-quarters of girls and women with sleep disturbances were in the high baseline group and problems persisted into adulthood. Conversely, 57% with night laughing and 42% with night screaming in the high baseline group exhibited mild improvement over time. Mutation type was not found to be a significant predictor of group membership. In conclusion, the evolution of sleep problems differed between subgroups of girls and women with Rett syndrome, in part explained by age and genotype. Treatment was not associated with improvement in sleep problems.
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18. Xiong XX, He M, Chen XQ. {{[Progress in autism: de novo mutation and CHD8 functions]}}. {Sheng Li Ke Xue Jin Zhan};2014 (Jun);45(3):185-189.
Autism or autism spectrum disorders is the most common central nervous system developmental disorder in children. Until now, there is still no effective drug for autism. The latest breakthrough advance in autism study is the discovery of autism-related gene de novo mutation by the whole exon sequencing. Among multiple de novo gene mutations identified in autism, the chromodomain helicase DNA-binding protein 8 (CHD8) is the most frequently mutated gene, suggesting that CHD8 is an important candidate gene for autism. CHD8 binds to various other proteins such as p53 and beta-catenin to regulate gene expression. The discovery of autism-candidate genes provides novel molecular targets for the diagnosis and treatment of autism.
