1. {{Making evidence-based approaches to autism accessible}}. {Bull World Health Organ};2017 (Aug 01);95(8):552-553.
One of the greatest challenges for the public health response to autism is providing access to evidence-based care. Sally J Rogers tells Andreia Azevedo Soares how parents can help their children mitigate the disabilities associated with autism.
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2. Ahmad SF, Nadeem A, Ansari MA, Bakheet SA, Al-Ayadhi LY, Attia SM. {{Upregulation of IL-9 and JAK-STAT signaling pathway in children with autism}}. {Prog Neuropsychopharmacol Biol Psychiatry};2017 (Aug 09);79(Pt B):472-480.
Autism spectrum disorder (ASD) gradually develops predominantly neurodevelopmental disorders, which are socially diagnosed in early childhood. Though the etiopathology of ASD is not clear, immune alteration has been suggested as autism’s pathophysiological mechanism. Previous studies found that several cytokines and transcription factor activation pathways were significantly increased in ASD. IL-9 has been confirmed to play a significant role in the central nervous system (CNS). The aim of the present study was to investigate the understudied role of pro- and anti-inflammatory cytokines and the JAK-STAT signaling pathway in ASD. We examined the IL-1beta, IL-4, IFN-gamma, and IL-9 positive immunostaining in all cells, and CD4+ T cells, in ASD and normally developing control children (TD), on peripheral blood mononuclear cells (PBMCs), using flow cytometry. We explored PBMC mRNA expression levels for IL-1beta, IL-4, IFN-gamma, IL-9, JAK1, and STAT5, by using real-time PCR (RT-PCR). We also explored PBMC protein expression levels for IL-1beta, IL-4, IL-9, pJAK1, and pSTAT5 by using western blotting. We found that the children with ASD had increased IL-1beta, IL-4, IFN-gamma, and IL-9 positive immunostaining in all cells, and in CD4+ cells, relative to the TD controls. The mRNA and protein expression for IL-1beta, IL-4, IFN-gamma, IL-9, JAK1, pJAK1, STAT5, and pSTAT5 were also significantly elevated in ASD relative to TD controls. These results suggested that cytokines and JAK-STAT activation signaling have an essential role in immune dysfunction in ASD.
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3. Ayres M, Parr JR, Rodgers J, Mason D, Avery L, Flynn D. {{A systematic review of quality of life of adults on the autism spectrum}}. {Autism};2017 (Aug 01):1362361317714988.
Autism spectrum disorder is associated with co-existing conditions that may adversely affect an individual’s quality of life. No systematic review of quality of life of adults on the autism spectrum has been conducted. Our objectives were as follows: (1) review the evidence about quality of life for adults on the autism spectrum; (2) critically appraise current practice in assessing quality of life of adults on the autism spectrum. We searched bibliographic databases and other literature to identify studies using a direct measure of quality of life of adults on the autism spectrum. Hand searching of reference lists, citation searching and personal communication with field experts were also undertaken. In total, 827 studies were identified; 14 were included. Only one quality of life measure designed for use with the general autism spectrum population was identified. Quality of life of adults on the autism spectrum is lower than that of typically developing adults, when measured with tools designed for the general population. There are no comprehensive autism spectrum disorder-specific quality of life measurement tools validated for use with representative samples of adults on the autism spectrum. There is a pressing need to develop robust measures of quality of life of autistic adults.
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4. Bacon EC, Courchesne E, Barnes CC, Cha D, Pence S, Schreibman L, Stahmer AC, Pierce K. {{Rethinking the idea of late autism spectrum disorder onset}}. {Dev Psychopathol};2017 (Aug 14):1-17.
A common theory of autism spectrum disorder (ASD) symptom onset includes toddlers who do not display symptoms until well after age 2, which are termed late-onset ASD cases. Objectives were to analyze differences in clinical phenotype between toddlers identified as ASD at initial evaluations (early diagnosed) versus those initially considered nonspectrum, then later identified as ASD (late diagnosed). Two hundred seventy-three toddlers recruited from the general population based on a failed developmental screening form or parent or physician concerns were followed longitudinally from 12 months and identified as early- and late-diagnosed cases of ASD, language delayed, or typically developing. Toddlers completed common standardized assessments and experimental eye-tracking and observational measures every 9-12 months until age 3. Longitudinal performance on standardized assessments and experimental tests from initial evaluations were compared. Delay in social communication skills was seen in both ASD groups at early-age initial assessment, including increased preference for nonsocial stimuli, increased stereotypic play, reduced exploration, and use of gestures. On standardized psychometric assessments, early-diagnosed toddlers showed more impairment initially while late-diagnosed toddlers showed a slowing in language acquisition. Similar social communication impairments were present at very early ages in both early-detected ASD and so-called late-onset ASD. Data indicate ASD is present whether detected or not by current methods, and development of more sensitive tools is needed.
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5. Bhattacherjee A, Mu Y, Winter MK, Knapp JR, Eggimann LS, Gunewardena SS, Kobayashi K, Kato S, Krizsan-Agbas D, Smith PG. {{Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome}}. {Proc Natl Acad Sci U S A};2017 (Aug 15);114(33):E6952-e6961.
Children with Rett syndrome show abnormal cutaneous sensitivity. The precise nature of sensory abnormalities and underlying molecular mechanisms remain largely unknown. Rats with methyl-CpG binding protein 2 (MeCP2) mutation, characteristic of Rett syndrome, show hypersensitivity to pressure and cold, but hyposensitivity to heat. They also show cutaneous hyperinnervation by nonpeptidergic sensory axons, which include subpopulations encoding noxious mechanical and cold stimuli, whereas peptidergic thermosensory innervation is reduced. MeCP2 knockdown confined to dorsal root ganglion sensory neurons replicated this phenotype in vivo, and cultured MeCP2-deficient ganglion neurons showed augmented axonogenesis. Transcriptome analysis revealed dysregulation of genes associated with cytoskeletal dynamics, particularly those controlling actin polymerization and focal-adhesion formation necessary for axon growth and mechanosensory transduction. Down-regulation of these genes by topoisomerase inhibition prevented abnormal axon sprouting. We identified eight key affected genes controlling actin signaling and adhesion formation, including members of the Arhgap, Tiam, and cadherin families. Simultaneous virally mediated knockdown of these genes in Rett rats prevented sensory hyperinnervation and reversed mechanical hypersensitivity, indicating a causal role in abnormal outgrowth and sensitivity. Thus, MeCP2 regulates ganglion neuronal genes controlling cytoskeletal dynamics, which in turn determines axon outgrowth and mechanosensory function and may contribute to altered pain sensitivity in Rett syndrome.
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6. Broome K, McCabe P, Docking K, Doble M. {{A Systematic Review of Speech Assessments for Children With Autism Spectrum Disorder: Recommendations for Best Practice}}. {Am J Speech Lang Pathol};2017 (Aug 15);26(3):1011-1029.
Purpose: The purpose of this systematic review was to provide a summary and evaluation of speech assessments used with children with autism spectrum disorders (ASD). A subsequent narrative review was completed to ascertain the core components of an evidence-based pediatric speech assessment, which, together with the results of the systematic review, provide clinical and research guidelines for best practice. Method: A systematic search of eight databases was used to find peer-reviewed research articles published between 1990 and 2014 assessing the speech of children with ASD. Eligible articles were categorized according to the assessment methods used and the speech characteristics described. Results: The review identified 21 articles that met the inclusion criteria, search criteria, and confidence in ASD diagnosis. The speech of prelinguistic participants was assessed in seven articles. Speech assessments with verbal participants were completed in 15 articles with segmental and suprasegmental aspects of speech analyzed. Assessment methods included connected speech samples, single-word naming tasks, speech imitation tasks, and analysis of the production of words and sentences. Conclusions: Clinical and research guidelines for speech assessment of children with ASD are outlined. Future comparisons will be facilitated by the use of consistent reporting methods in research focusing on children with ASD.
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7. Chouinard B, Volden J, Cribben I, Cummine J. {{Neurological evaluation of the selection stage of metaphor comprehension in individuals with and without autism spectrum disorder}}. {Neuroscience};2017 (Aug 09);361:19-33.
Because of their difficulties with figurative language in conversation, it is commonly thought that individuals with autism spectrum disorder (ASD) do not understand figurative meaning. However, recent research indicates that individuals with and without ASD are similar in the first two stages of metaphor comprehension, up to and including successful generation of the figurative meaning. In the current study, we used a sentence decision task to evaluate the subsequent stage of metaphor comprehension, the selection stage, which requires suppression/inhibition of the unintended meaning as part of selecting the intended meaning. fMRI activation and functional connectivity were used to compare the selection stage of metaphor comprehension between high-functioning individuals with ASD and carefully matched controls. Cortical and subcortical regions of interest were selected based on the basal-ganglia model of cognitive control. Compared to controls, individuals with ASD recruited greater activation in regions related to verbal memory (thalamus), semantic associations (medial temporal gyrus), and basic visual processing (middle occipital gyrus). Functional connectivity analysis revealed fewer overall connections and cortical-subcortical connections in the ASD group compared to controls. There was a novel finding of maintenance of subcortical-subcortical connectivity in the ASD group, specific to the selection condition, despite differences in cortically involved connections. Reduced cortical-subcortical connectivity in the ASD group compared to controls may reflect a more global impairment in cognitive control pathways, while consistent subcortical-subcortical connectivity may reflect systemic inflexibility or preserved subcortical function and dissociation between subcortical and cortical systems. Further investigation is required.
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8. Conaughton RJ, Donovan CL, March S. {{Efficacy of an internet-based CBT program for children with comorbid High Functioning Autism Spectrum Disorder and anxiety: A randomised controlled trial}}. {J Affect Disord};2017 (Aug 15);218:260-268.
BACKGROUND: All trials conducted to date on BRAVE-ONLINE for youth anxiety disorders have excluded children with High Functioning Autism Spectrum Disorder (HFASD) and therefore it is unknown whether these programs might be beneficial to HFASD children. The aim of this study was to evaluate the efficacy of BRAVE-ONLINE in HFASD children with an anxiety disorder. METHODS: Forty-two HFASD children, aged 8-12 years, with an anxiety disorder, and their parents, were randomly assigned to either the BRAVE-ONLINE condition (NET) or a waitlist control (WLC). Diagnostic interviews and parent/child questionnaires were completed at pre-treatment, post-treatment and 3-month follow-up. RESULTS: At post- assessment, compared to children in the WLC condition, children in the NET condition demonstrated a significantly greater reduction in number of anxiety diagnoses, clinical severity of diagnosis, and self and parent reported anxiety symptoms, as well as significantly greater increases in overall functioning. However, loss of primary diagnosis in this sample was lower than in previous studies. LIMITATIONS: The small sample size, coupled with attrition rates, makes it difficult to generalise the findings of the study to HFASD population and to conduct analyses regarding mediators, moderators and predictors of outcomes. CONCLUSIONS: The BRAVE-ONLINE program may be useful in reducing anxiety symptoms in HFASD children, although the effects are less strong than those found in neurotypical children for a variety of reasons.
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9. Delaney KR. {{Restoring EEAquilibrium: rebalancing excitation and inhibition in Rett mouse model neurons with early endosome antigen-1}}. {J Physiol};2017 (Aug 15);595(16):5411.
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10. Dyer C. {{Private GP who ran autism clinic is banned from seeing patients pending investigation}}. {Bmj};2017 (Aug 15);358:j3899.
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11. Fukuyama H, Kumagaya SI, Asada K, Ayaya S, Kato M. {{Autonomic versus perceptual accounts for tactile hypersensitivity in autism spectrum disorder}}. {Sci Rep};2017 (Aug 15);7(1):8259.
Tactile atypicality in individuals with autism spectrum disorder (ASD) has harmful effects on their everyday lives including social interactions. However, whether tactile atypicality in ASD reflects perceptual and/or autonomic processes is unknown. Here, we show that adults with ASD have hypersensitivity to tactile stimuli in the autonomic but not perceptual domain. In particular, adults with ASD showed a greater skin conductance response (SCR) to tactile stimuli compared to typically developing (TD) adults, despite an absence of differences in subjective responses. Furthermore, the level of the SCR was correlated with sensory sensitivity in daily living. By contrast, in perceptual discriminative tasks that psychophysically measured thresholds to tactile stimuli, no differences were found between the ASD and TD groups. These results favor the hypothesis that atypical autonomic processing underlies tactile hypersensitivity in ASD.
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12. Gogoi M, Chatterjee A. {{Vaccines and Autism: A Misconception that Persists}}. {S D Med};2016 (Oct);69(10):465-467.
13. Hoang N, Cytrynbaum C, Scherer SW. {{Communicating complex genomic information: A counselling approach derived from research experience with Autism Spectrum Disorder}}. {Patient Educ Couns};2017 (Jul 29)
Individuals with Autism Spectrum Disorder (ASD) share characteristics (impairments in socialization and communication, and repetitive interests and behaviour), but differ in their developmental course, pattern of symptoms, and cognitive and language abilities. The development of standardized phenotyping has revealed ASD to clinically be vastly heterogeneous, ranging from milder presentations to more severe forms associated with profound intellectual disability. Some 100 genes have now been implicated in the etiology of ASD, and advances in genome-wide testing continue to yield new data at an unprecedented rate. As the translation of this data is incorporated into clinical care, genetic professionals/counsellors, as well as other health care providers, will benefit from guidelines and tools to effectively communicate such genomic information. Here, we present a model to facilitate communication regarding the complexities of ASD, where clinical and genetic heterogeneity, as well as overlapping neurological conditions are inherent. We outline an approach for counselling families about their genomic results grounded in our direct experience from counselling families participating in an ASD research study, and supported by rationale from the literature.
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14. Kamata A, Muramatsu K, Sawaura N, Makioka N, Ogata T, Kuwashima M, Arakawa H. {{Demyelinating neuropathy in a 6-year-old girl with autism spectrum disorder}}. {Pediatr Int};2017 (Aug);59(8):951-954.
Herein we report the case of a 6-year-old girl with autism spectrum disorder (ASD) and weakness in the distal portion of the right upper limb. Although difficult to perform, nerve conduction studies indicated demyelinating neuropathy. Magnetic resonance imaging (MRI) showed swelling a nd high-intensity signals in the right brachial plexus and cervical spinal roots. The symptoms recovered after a single course of i.v. immunoglobulin. Electrophysiological indices and MRI findings also improved after treatment. This case demonstrates the utility of neuroimaging in addition to electrophysiological assessments for the diagnosis of demyelinating neuropathy, particularly in young patients with ASD.
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15. Mackus M, de Kruijff D, Otten LS, Kraneveld AD, Garssen J, Verster JC. {{The 2D : 4D Digit Ratio as a Biomarker for Autism Spectrum Disorder}}. {Autism Res Treat};2017;2017:1048302.
It has been suggested that the second (2D, index finger) to fourth (4D, ring finger) digit ratio, 2D : 4D, may be a biomarker for the risk of developing autism. The aim of the current study was to determine the usefulness of the 2D : 4D digit ratio as biomarker for autistic traits. N = 401 healthy young volunteers participated in the study. For both hands, digit lengths were measured using digital Vernier calipers. In addition to demographics, the Autism Spectrum Quotient (AQ) questionnaire was completed, comprised of five subscales, assessing « social insights and behavior, » « attention switching, » « communication, » « imagination, » and « attention to detail. » Overall, no significant correlations were observed between the AQ total score, its subscales, and the 2D : 4D digit ratio. For women, the left hand 2D : 4D digit ratio correlated significantly with the subscale score « communication » (r = -0.142; p = 0.036). For men, a significant positive correlation was found between the left 2D : 4D digit ratio and the total AQ score (r = 0.157; p = 0.042) and AQ subscale « attention switching » (r = 0.182; p = 0.017). In conclusion, gender specific associations between the 2D : 4D digit ratio and specific autism traits were observed, which were stronger in men than in women. Future studies should be conducted in patients that are formally diagnosed with autism.
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16. Singal D, Chateau D, Brownell M. {{Prenatal Antidepressant Use and Autism Spectrum Disorder}}. {Jama};2017 (Aug 15);318(7):664-665.
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17. Sipowicz K, Pietras T. {{[The case of an adult man with savant syndrome in the course of autism spectrum disorder]}}. {Pol Merkur Lekarski};2017 (Jul 21);43(253):32-34.
The paper reports on a case of 57-year man with autism spectrum disorder and epilepsy with an unusual feature of calendar calculation. Namely, this is the case of savant syndrome, which appears rarely in the course of various neuropsychiatric disorders. Commorbidity of epilepsy and autism particularly predispose to the aforementioned syndrome. In the presented case, apart from the calendar calculation, the man has high language abilities. As previous studies suggest, the extraordinary abilities among persons with savant syndrome works similarly to the language module in healthy persons. Savant syndrome may appear in any patient with neuropsychiatric disorders, particularly in those suffering from autism spectrum disorder with comorbid epilepsy.
18. Soltani A, Lebrun S, Carpentier G, Zunino G, Chantepie S, Maiza A, Bozzi Y, Desnos C, Darchen F, Stettler O. {{Increased signaling by the autism-related Engrailed-2 protein enhances dendritic branching and spine density, alters synaptic structural matching, and exaggerates protein synthesis}}. {PLoS One};2017;12(8):e0181350.
Engrailed 1 (En1) and 2 (En2) code for closely related homeoproteins acting as transcription factors and as signaling molecules that contribute to midbrain and hindbrain patterning, to development and maintenance of monoaminergic pathways, and to retinotectal wiring. En2 has been suggested to be an autism susceptibility gene and individuals with autism display an overexpression of this homeogene but the mechanisms remain unclear. We addressed in the present study the effect of exogenously added En2 on the morphology of hippocampal cells that normally express only low levels of Engrailed proteins. By means of RT-qPCR, we confirmed that En1 and En2 were expressed at low levels in hippocampus and hippocampal neurons, and observed a pronounced decrease in En2 expression at birth and during the first postnatal week, a period characterized by intense synaptogenesis. To address a putative effect of Engrailed in dendritogenesis or synaptogenesis, we added recombinant En1 or En2 proteins to hippocampal cell cultures. Both En1 and En2 treatment increased the complexity of the dendritic tree of glutamatergic neurons, but only En2 increased that of GABAergic cells. En1 increased the density of dendritic spines both in vitro and in vivo. En2 had similar but less pronounced effect on spine density. The number of mature synapses remained unchanged upon En1 treatment but was reduced by En2 treatment, as well as the area of post-synaptic densities. Finally, both En1 and En2 elevated mTORC1 activity and protein synthesis in hippocampal cells, suggesting that some effects of Engrailed proteins may require mRNA translation. Our results indicate that Engrailed proteins can play, even at low concentrations, an active role in the morphogenesis of hippocampal cells. Further, they emphasize the over-regulation of GABA cell morphology and the vulnerability of excitatory synapses in a pathological context of En2 overexpression.
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19. Stadelmaier R, Nasri H, Deutsch CK, Bauman M, Hunt A, Stodgell CJ, Adams J, Holmes LB. {{Exposure to Sodium Valproate during Pregnancy: Facial Features and Signs of Autism}}. {Birth Defects Res};2017 (Aug 15);109(14):1134-1143.
BACKGROUND: Valproic acid (VPA) is the most teratogenic anticonvulsant drug in clinical use today. Children exposed prenatally to VPA have previously been shown to have dysmorphic craniofacial features, identified subjectively but not by anthropometric methods. Exposure to VPA has also been associated with an increased frequency of autism spectrum disorder (ASD). An increased cephalic index (the ratio of the cranial lateral width to the cranial anterior-posterior length) has been observed in children with ASD. METHODS: Forty-seven children exposed to VPA during the first trimester of pregnancy were evaluated for dysmorphic facial features, identified subjectively and by measurements. Each VPA-exposed child was evaluated for ASD using the Social Communication Questionnaire, Autism Diagnostic Interview-Revised, and Autism Diagnostic Observation Schedule. The same physical examination was carried out on an unexposed comparison group of 126 children. The unexposed children also had testing for cognitive performance by the Wechsler Intelligence Scale for Children. RESULTS: Several dysmorphic craniofacial features, including telecanthus, wide philtrum, and increased length of the upper lip were identified subjectively. Anthropometric measurements confirmed the increased intercanthal distance and documented additional findings, including an increased cephalic index and decreased head circumference/height index. There were no differences between the craniofacial features of VPA-exposed children with and without ASD. CONCLUSION: An increased frequency of dysmorphic craniofacial features was identified in children exposed to VPA during the first trimester of pregnancy. The most consistent finding was a larger cephalic index, which indicates a disproportion of increased width of the skull relative to the shortened anterior-posterior length. Birth Defects Research 109:1134-1143, 2017. (c) 2017 Wiley Periodicals, Inc.
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20. Vigod SN, Gomes T, Ray JG. {{Prenatal Antidepressant Use and Autism Spectrum Disorder-Reply}}. {Jama};2017 (Aug 15);318(7):665.
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21. Xu X, Pozzo-Miller L. {{EEA1 restores homeostatic synaptic plasticity in hippocampal neurons from Rett syndrome mice}}. {J Physiol};2017 (Aug 15);595(16):5699-5712.
KEY POINTS: Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Mecp2 deletion in mice results in an imbalance of excitation and inhibition in hippocampal neurons, which affects ‘Hebbian’ synaptic plasticity. We show that Mecp2-deficient neurons also lack homeostatic synaptic plasticity, likely due to reduced levels of EEA1, a protein involved in AMPA receptor endocytosis. Expression of EEA1 restored homeostatic synaptic plasticity in Mecp2-deficient neurons, providing novel targets of intervention in Rett syndrome. ABSTRACT: Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Deletion of Mecp2 in mice results in an imbalance of synaptic excitation and inhibition in hippocampal pyramidal neurons, which affects ‘Hebbian’ long-term synaptic plasticity. Since the excitatory-inhibitory balance is maintained by homeostatic mechanisms, we examined the role of MeCP2 in homeostatic synaptic plasticity (HSP) at excitatory synapses. Negative feedback HSP, also known as synaptic scaling, maintains the global synaptic strength of individual neurons in response to sustained alterations in neuronal activity. Hippocampal neurons from Mecp2 knockout (KO) mice do not show the characteristic homeostatic scaling up of the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and of synaptic levels of the GluA1 subunit of AMPA-type glutamate receptors after 48 h silencing with the Na+ channel blocker tetrodotoxin. This deficit in HSP is bidirectional because Mecp2 KO neurons also failed to scale down mEPSC amplitudes and GluA1 synaptic levels after 48 h blockade of type A GABA receptor (GABAA R)-mediated inhibition with bicuculline. Consistent with the role of synaptic trafficking of AMPA-type of glutamate receptors in HSP, Mecp2 KO neurons have lower levels of early endosome antigen 1 (EEA1), a protein involved in AMPA-type glutamate receptor endocytosis. In addition, expression of EEA1 in Mecp2 KO neurons reduced mEPSC amplitudes to wild-type levels, and restored synaptic scaling down of mEPSC amplitudes after 48 h blockade of GABAA R-mediated inhibition with bicuculline. The identification of a molecular deficit in HSP in Mecp2 KO neurons provides potentially novel targets of intervention for improving hippocampal function in Rett syndrome individuals.
