1. Ashwood KL, Gillan N, Horder J, Hayward H, Woodhouse E, McEwen FS, Findon J, Eklund H, Spain D, Wilson CE, Cadman T, Young S, Stoencheva V, Murphy CM, Robertson D, Charman T, Bolton P, Glaser K, Asherson P, Simonoff E, Murphy DG. {{Predicting the diagnosis of autism in adults using the Autism-Spectrum Quotient (AQ) questionnaire}}. {Psychol Med}. 2016: 1-10.
BACKGROUND: Many adults with autism spectrum disorder (ASD) remain undiagnosed. Specialist assessment clinics enable the detection of these cases, but such services are often overstretched. It has been proposed that unnecessary referrals to these services could be reduced by prioritizing individuals who score highly on the Autism-Spectrum Quotient (AQ), a self-report questionnaire measure of autistic traits. However, the ability of the AQ to predict who will go on to receive a diagnosis of ASD in adults is unclear. METHOD: We studied 476 adults, seen consecutively at a national ASD diagnostic referral service for suspected ASD. We tested AQ scores as predictors of ASD diagnosis made by expert clinicians according to International Classification of Diseases (ICD)-10 criteria, informed by the Autism Diagnostic Observation Schedule-Generic (ADOS-G) and Autism Diagnostic Interview-Revised (ADI-R) assessments. RESULTS: Of the participants, 73% received a clinical diagnosis of ASD. Self-report AQ scores did not significantly predict receipt of a diagnosis. While AQ scores provided high sensitivity of 0.77 [95% confidence interval (CI) 0.72-0.82] and positive predictive value of 0.76 (95% CI 0.70-0.80), the specificity of 0.29 (95% CI 0.20-0.38) and negative predictive value of 0.36 (95% CI 0.22-0.40) were low. Thus, 64% of those who scored below the AQ cut-off were ‘false negatives’ who did in fact have ASD. Co-morbidity data revealed that generalized anxiety disorder may ‘mimic’ ASD and inflate AQ scores, leading to false positives. CONCLUSIONS: The AQ’s utility for screening referrals was limited in this sample. Recommendations supporting the AQ’s role in the assessment of adult ASD, e.g. UK NICE guidelines, may need to be reconsidered.
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2. Bourgeois JA. {{Neuropsychiatry of fragile X-premutation carriers with and without fragile X-associated tremor-ataxia syndrome: implications for neuropsychology}}. {Clin Neuropsychol}. 2016: 1-16.
OBJECTIVES: Clinical neuropsychologists benefit from clinical currency in recently ascertained neuropsychiatric illness, such as fragile X premutation (FXPM) disorders. The author reviewed the clinical literature through 2016 for neuropsychiatric phenotypes in FXPM disorders, including patients with fragile X-associated tremor/ataxia syndrome (FXTAS). METHODS: A PubMed search using the search terms ‘Fragile X,’ ‘Premutation,’ ‘Carriers,’ ‘Psychiatric,’ ‘Dementia,’ ‘Mood,’ and ‘Anxiety’ for citations in the clinical literature through 2016 was reviewed for studies specifically examining the neuropsychiatric phenotype in FXPM patients. The relevant articles were classified according to specific neuropsychiatric syndromes, including child onset, adult onset with and without FXTAS, as well as common systemic comorbidities in FXPM patients. RESULTS: Eighty-six articles were reviewed for the neuropsychiatric and other phenotypes in FXPM patients. The neuropsychiatric phenotype in FXPM patients is distinct from that of full mutation (Fragile X Syndrome) patients. FXTAS is associated with a specific cortical-subcortical major or mild neurocognitive disorder (NCD). CONCLUSIONS: FXPM patients are at risk for neuropsychiatric illness. In addition, FXPM patients are at risk for other systemic conditions that should raise suspicion for FXPM-associated illnesses. Clinicians should consider a diagnosis of FXPM-associated neuropsychiatric illness when patients with specific clinical scenarios are encountered; especially in patient pedigrees consistent with a typical (often multigenerational) presentation of fragile X-associated conditions, confirmatory genetic testing should be considered. Clinical management should take into account the psychological challenges of a multigenerational genetic neuropsychiatric illness with a variable CNS and systemic clinical phenotype.
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3. Carther-Krone TA, Shomstein S, Marotta JJ. {{Looking without Perceiving: Impaired Preattentive Perceptual Grouping in Autism Spectrum Disorder}}. {PLoS One}. 2016; 11(6): e0158566.
Before becoming aware of a visual scene, our perceptual system has organized and selected elements in our environment to which attention should be allocated. Part of this process involves grouping perceptual features into a global whole. Individuals with autism spectrum disorders (ASD) rely on a more local processing strategy, which may be driven by difficulties perceptually grouping stimuli. We tested this notion using a line discrimination task in which two horizontal lines were superimposed on a background of black and white dots organized so that, on occasion, the dots induced the Ponzo illusion if perceptually grouped together. Results showed that even though neither group was aware of the illusion, the ASD group was significantly less likely than typically developing group to make perceptual judgments influenced by the illusion, revealing difficulties in preattentive grouping of visual stimuli. This may explain why individuals with ASD rely on local processing strategies, and offers new insight into the mechanism driving perceptual grouping in the typically developing human brain.
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4. Constantino JN. {{Data from the Baby Siblings Research Consortium confirm and specify the nature of the female protective effect in autism: A commentary on Messinger et al}}. {Mol Autism}. 2016; 7: 32.
Sibling recurrence data from the Baby Siblings Research Consortium (BSRC) recapitulate results from very large clinical family studies that demonstrate the absence of the Carter effect and provide clarification of the nature of the female protective effect in ASD. This legacy prospective data collection confirmed marked differences in the proportions of males versus females who lie along deviant trajectories of social development in the setting of inherited liability to autism-a phenomenon which defines the female protective effect-and demonstrate that among affected children, sex differences are modest and homologous to those observed among non-ASD children.
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5. Filley CM. {{Fragile X tremor ataxia syndrome and white matter dementia}}. {Clin Neuropsychol}. 2016: 1-12.
OBJECTIVE: Fragile X tremor ataxia syndrome (FXTAS) is an inherited neurodegenerative disease in which dementia is common and disabling. The pathogenesis of dementia in FXTAS is poorly understood, but the salience of executive dysfunction and slowed processing speed, the frequent presence of the middle cerebellar peduncle sign on magnetic resonance imaging (MRI), and striking neuropathological alterations of white matter all suggest that myelinated tracts are significantly involved. This paper considers the role of white matter disease in FXTAS dementia, particularly with regard to the concept of white matter dementia (WMD). METHOD: A focused review of FXTAS in relation to known white matter disorders is provided to propose that the concept of WMD may illuminate the basis of dementia in FXTAS. The putative pathogenetic contribution of white matter involvement in other neurodegenerative diseases is also considered. RESULTS: Considerable evidence supports the importance of white matter disease in the pathogenesis of dementia in FXTAS. Whereas, gray matter regions are also involved, white matter degeneration is prominent, even early in the disease, and correlates with executive dysfunction and slowed processing speed. Evidence for white matter involvement in other neurodegenerative diseases lends additional support to the relevance of white matter in FXTAS. CONCLUSION: The dementia of FXTAS is closely related to the profile of WMD, and white matter involvement is also supported by MRI and neuropathological observations. White matter pathology is also relevant to the pathogenesis of other neurodegenerative diseases. Further study of white matter promises to clarify the origin of dementia in FXTAS.
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6. Fluegge K. {{Maternal infection during pregnancy, risk of offspring autism, and the role of bacterial denitrification}}. {Brain Behav Immun}. 2016.
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7. Foote MM, Careaga M, Berman RF. {{What has been learned from mouse models of the Fragile X Premutation and Fragile X-associated tremor/ataxia syndrome?}}. {Clin Neuropsychol}. 2016: 1-13.
OBJECTIVE: To describe in this review how research using mouse models developed to study the Fragile X premutation (PM) and Fragile X-associated tremor/ataxia syndrome (FXTAS) have contributed to understanding these disorders. PM carriers bear an expanded CGG trinucleotide repeat on the Fragile X Mental Retardation 1 (FMR1) gene, and are at risk for developing the late onset neurodegenerative disorder FXTAS. CONCLUSIONS: Much has been learned about these genetic disorders from the development and study of mouse models. This includes new insights into the early cellular and molecular events that occur in PM carriers and in FXTAS, the presence of multiorgan pathology beyond the CNS, immunological dysregulation, unexpected synthesis of a potentially toxic peptide in FXTAS (i.e., FMRpolyG), and evidence that the disease process may be halted or reversed by appropriate molecular therapies given early in the course of disease.
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8. Furey H. {{Aristotle and Autism: Reconsidering a Radical Shift to Virtue Ethics in Engineering}}. {Sci Eng Ethics}. 2016.
Virtue-based approaches to engineering ethics have recently received considerable attention within the field of engineering education. Proponents of virtue ethics in engineering argue that the approach is practically and pedagogically superior to traditional approaches to engineering ethics, including the study of professional codes of ethics and normative theories of behavior. This paper argues that a virtue-based approach, as interpreted in the current literature, is neither practically or pedagogically effective for a significant subpopulation within engineering: engineers with high functioning autism spectrum disorder (ASD). Because the main argument for adopting a character-based approach is that it could be more successfully applied to engineering than traditional rule-based or algorithmic ethical approaches, this oversight is problematic for the proponents of the virtue-based view. Furthermore, without addressing these concerns, the wide adoption of a virtue-based approach to engineering ethics has the potential to isolate individuals with ASD and to devalue their contributions to moral practice. In the end, this paper gestures towards a way of incorporating important insights from virtue ethics in engineering that would be more inclusive of those with ASD.
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9. Grigsby J. {{The fragile X mental retardation 1 gene (FMR1): historical perspective, phenotypes, mechanism, pathology, and epidemiology}}. {Clin Neuropsychol}. 2016: 1-19.
OBJECTIVES: To provide an historical perspective and overview of the phenotypes, mechanism, pathology, and epidemiology of the fragile X-associated tremor/ataxia syndrome (FXTAS) for neuropsychologists. METHODS: Selective review of the literature on FXTAS. RESULTS: FXTAS is an X-linked neurodegenerative disorder of late onset. One of several phenotypes associated with different mutations of the fragile X mental retardation 1 gene (FMR1), FXTAS involves progressive action tremor, gait ataxia, and impaired executive functioning, among other features. It affects carriers of the FMR1 premutation, which may expand when passed from a mother to her children, in which case it is likely to cause fragile X syndrome (FXS), the most common inherited developmental disability. CONCLUSION: This review briefly summarizes current knowledge of the mechanisms, epidemiology, and mode of transmission of FXTAS and FXS, as well as the neuropsychological, neurologic, neuropsychiatric, neuropathologic, and neuroradiologic phenotypes of FXTAS. Because it was only recently identified, FXTAS is not well known to most practitioners, and it remains largely misdiagnosed, despite the fact that its prevalence may be relatively high.
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10. Grigsby J, Brega AG, Bennett RE, Bourgeois JA, Seritan AL, Goodrich GK, Hagerman RJ. {{Clinically significant psychiatric symptoms among male carriers of the fragile X premutation, with and without FXTAS, and the mediating influence of executive functioning}}. {Clin Neuropsychol}. 2016: 1-16.
OBJECTIVES: To clarify the neuropsychiatric phenotype of fragile X-associated tremor/ataxia syndrome (FXTAS), and assess the extent to which it is mediated by the dysexecutive syndrome that is a major feature of the disorder. METHODS: We examined the prevalence of clinically meaningful psychiatric symptoms among male carriers of the fragile X premutation, with and without FXTAS, in comparison with men with a normal allele. Measures included the Neuropsychiatric Inventory (NPI), Symptom Checklist-90-R (SCL-90-R), and the Behavioral Dyscontrol Scale, a measure of executive functioning. Between-group differences were evaluated using logistic regression, followed by a mediation analysis with ordinary least squares regression to assess the contribution of dysexecutive syndrome to the observed psychiatric domains. RESULTS: Men with FXTAS showed higher rates of clinically significant symptoms overall and in specific domains: somatization, obsessive compulsive, depression, anxiety, psychoticism, agitation/aggression, apathy/indifference, irritability, and nighttime behavior problems. Post hoc analyses suggested that findings of psychoticism among men with FXTAS may be associated with participants’ accurate acknowledgment of cognitive and physical dysfunction, rather than reflecting psychosis. Asymptomatic carriers showed no evidence of clinically significant psychiatric symptoms, but when all carriers were compared with men having a normal FMR1 allele, executive function deficits were found to mediate scores in several domains on both NPI and SCL-90-R. CONCLUSIONS: Building on prior research, the results provide evidence that the psychiatric phenotype for men includes clinically meaningful depression, hostility, and irritability, in association with behavioral and attentional disinhibition. It is likely that these problems reflect the effects of impaired executive functioning.
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11. Halbach N, Smeets EE, Julu P, Witt-Engerstrom I, Pini G, Bigoni S, Hansen S, Apartopoulos F, Delamont R, van Roozendaal K, Scusa MF, Borelli P, Candel M, Curfs L. {{Neurophysiology versus clinical genetics in Rett syndrome: A multicenter study}}. {Am J Med Genet A}. 2016.
Many studies have attempted to establish the genotype-phenotype correlation in Rett syndrome (RTT). Cardiorespiratory measurements provide robust objective data, to correlate with each of the different clinical phenotypes. It has important implications for the management and treatment of this syndrome. The aim of this study was to correlate the genotype with the quantitative cardiorespiratory data obtained by neurophysiological measurement combined with a clinical severity score. This international multicenter study was conducted in four European countries from 1999 to 2012. The study cohort consisted of a group of 132 well-defined RTT females aged between 2 and 43 years with extended clinical, molecular, and neurophysiological assessments. Diagnosis of RTT was based on the consensus criteria for RTT and molecular confirmation. Genotype-phenotype analyses of clinical features and cardiorespiratory data were performed after grouping mutations by the same type and localization or having the same putative biological effect on the MeCP2 protein, and subsequently on eight single recurrent mutations. A less severe phenotype was seen in females with CTS, p.R133C, and p.R294X mutations. Autonomic disturbances were present in all females, and not restricted to nor influenced by one specific group or any single recurrent mutation. The objective information from non-invasive neurophysiological evaluation of the disturbed central autonomic control is of great importance in helping to organize the lifelong care for females with RTT. Further research is needed to provide insights into the pathogenesis of autonomic dysfunction, and to develop evidence-based management in RTT. (c) 2016 Wiley Periodicals, Inc.
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12. Hessl D, Grigsby J. {{Fragile X-associated tremor/ataxia syndrome: another phenotype of the fragile X gene}}. {Clin Neuropsychol}. 2016: 1-5.
OBJECTIVE: Neuropsychologists have an important role in evaluating patients with fragile X-associated disorders, but most practitioners are unaware of the recently identified neurodegenerative movement disorder known as fragile X-associated tremor ataxia syndrome (FXTAS). The objective of this editorial is to orient the reader to FXTAS and highlight the importance of clinical neuropsychology in describing the fragile X premutation phenotype and the role practitioners may have in assessing and monitoring patients with or at risk for neurodegeneration. METHOD: We issued a call for papers for the special issue, highlighting the primary objective of familiarizing clinical neuropsychologists with FXTAS, and with the neuropsychological phenotype of both male and female asymptomatic carriers. RESULTS: Eight papers are included, including an overview of the fragile X-associated disorders (Grigsby), a review of the neuroradiological and neurological aspects of FXTAS and how the disorder compares to other movement disorders (O’Keefe et al.), a perspective on the prominence of white matter disease and dementia in FXTAS (Filley), and a review of mouse models of FXTAS (Foote). There are four research papers, including one on self-reported memory problems in FXTAS (Birch et al.), and three papers focused on the neuropsychiatric aspects of the fragile X premutation, a review (Bourgeois), an examination of autism-related traits (Schneider), and a research paper on executive functioning and psychopathology (Grigsby). CONCLUSIONS: The issue highlights the importance of awareness of fragile X-associated disorders for neuropsychologists, an awareness that must reach beyond neurodevelopmental aspects related to fragile X syndrome into the realm of neurodegenerative disease and aging.
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13. Jiang HY, Zhou K, Ruan B. {{Re: Maternal infection during pregnancy, risk of offspring autism, and the role of bacterial denitrification}}. {Brain Behav Immun}. 2016.
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14. Karaminis T, Cicchini GM, Neil L, Cappagli G, Aagten-Murphy D, Burr D, Pellicano E. {{Central tendency effects in time interval reproduction in autism}}. {Sci Rep}. 2016; 6: 28570.
Central tendency, the tendency of judgements of quantities (lengths, durations etc.) to gravitate towards their mean, is one of the most robust perceptual effects. A Bayesian account has recently suggested that central tendency reflects the integration of noisy sensory estimates with prior knowledge representations of a mean stimulus, serving to improve performance. The process is flexible, so prior knowledge is weighted more heavily when sensory estimates are imprecise, requiring more integration to reduce noise. In this study we measure central tendency in autism to evaluate a recent theoretical hypothesis suggesting that autistic perception relies less on prior knowledge representations than typical perception. If true, autistic children should show reduced central tendency than theoretically predicted from their temporal resolution. We tested autistic and age- and ability-matched typical children in two child-friendly tasks: (1) a time interval reproduction task, measuring central tendency in the temporal domain; and (2) a time discrimination task, assessing temporal resolution. Central tendency reduced with age in typical development, while temporal resolution improved. Autistic children performed far worse in temporal discrimination than the matched controls. Computational simulations suggested that central tendency was much less in autistic children than predicted by theoretical modelling, given their poor temporal resolution.
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15. Ko C, Kim N, Kim E, Song DH, Cheon KA. {{The effect of epilepsy on autistic symptom severity assessed by the social responsiveness scale in children with autism spectrum disorder}}. {Behav Brain Funct}. 2016; 12(1): 20.
BACKGROUND: As the prevalence of autism spectrum disorders in people with epilepsy ranges from 15 to 47 % (Clarke et al. in Epilepsia 46:1970-1977, 2005), it is speculated that there is a special relationship between the two disorders, yet there has been a lack of systematic studies comparing the behavioral phenotype between autistic individuals and autistic individuals with epilepsy. This study aims to investigate how the co-occurrence of epilepsy and Autism Spectrum Disorder (ASD) affects autistic characteristics assessed by the Social Responsiveness Scale (SRS), which has been used as a measure of autism symptoms in previous studies. In this research we referred to all individuals with Autism or Autistic Disorder as individuals with ASD. METHODS: We reviewed the complete medical records of 182 participants who presented to a single tertiary care referral center from January 1, 2013 to July 28, 2015, and subsequently received complete child and adolescent psychiatric assessments. Of the 182 participants, 22 were diagnosed with Autism Spectrum Disorder and epilepsy. Types of epilepsy observed in these individuals included complex partial seizure, generalized tonic-clonic seizure, or infantile spasm. Using ‘Propensity Score Matching’ we selected 44 children, diagnosed with only Autism Spectrum Disorder, whose age, gender, and intelligence quotient (IQ) were closely matched with the 22 children diagnosed with Autism Spectrum Disorder and epilepsy. Social functioning of participants was assessed by the social responsiveness scale, which consists of five categories: social awareness, social cognition, social communication, social motivation, and autistic mannerisms. Bivariate analyses were conducted to compare the ASD participants with epilepsy group with the ASD-only group on demographic and clinical characteristics. Chi square and t test p values were calculated when appropriate. RESULTS: There was no significant difference in age (p = 0.172), gender (p > 0.999), IQ (FSIQ, p = 0.139; VIQ, p = 0.114; PIQ, p = 0.295) between the two groups. ASD participants with epilepsy were significantly more impaired than ASD participants on some measures of social functioning such as social awareness (p = 0.03) and social communication (p = 0.027). ASD participants with epilepsy also scored significantly higher on total SRS t-score than ASD participants (p = 0.023). CONCLUSIONS: Understanding the relationship between ASD and epilepsy is critical for appropriate management (e.g. social skills training, seizure control) of ASD participants with co-occurring epilepsy. Results of this study suggest that mechanisms involved in producing epilepsy may play a role in producing or augmenting autistic features such as poor social functioning. Prospective study with larger sample sizes is warranted to further explore this association.
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16. Ku KM, Weir RK, Silverman JL, Berman RF, Bauman MD. {{Behavioral Phenotyping of Juvenile Long-Evans and Sprague-Dawley Rats: Implications for Preclinical Models of Autism Spectrum Disorders}}. {PLoS One}. 2016; 11(6): e0158150.
The laboratory rat is emerging as an attractive preclinical animal model of autism spectrum disorder (ASD), allowing investigators to explore genetic, environmental and pharmacological manipulations in a species exhibiting complex, reciprocal social behavior. The present study was carried out to compare two commonly used strains of laboratory rats, Sprague-Dawley (SD) and Long-Evans (LE), between the ages of postnatal day (PND) 26-56 using high-throughput behavioral phenotyping tools commonly used in mouse models of ASD that we have adapted for use in rats. We detected few differences between young SD and LE strains on standard assays of exploration, sensorimotor gating, anxiety, repetitive behaviors, and learning. Both SD and LE strains also demonstrated sociability in the 3-chamber social approach test as indexed by spending more time in the social chamber with a constrained age/strain/sex matched novel partner than in an identical chamber without a partner. Pronounced differences between the two strains were, however, detected when the rats were allowed to freely interact with a novel partner in the social dyad paradigm. The SD rats in this particular testing paradigm engaged in play more frequently and for longer durations than the LE rats at both juvenile and young adult developmental time points. Results from this study that are particularly relevant for developing preclinical ASD models in rats are threefold: (i) commonly utilized strains exhibit unique patterns of social interactions, including strain-specific play behaviors, (ii) the testing environment may profoundly influence the expression of strain-specific social behavior and (iii) simple, automated measures of sociability may not capture the complexities of rat social interactions.
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17. Li R, Dong Q, Yuan X, Zeng X, Gao Y, Chiao C, Li H, Zhao X, Keles S, Wang Z, Chang Q. {{Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome}}. {PLoS Genet}. 2016; 12(6): e1006129.
Mutations in the human MECP2 gene cause Rett syndrome (RTT), a severe neurodevelopmental disorder that predominantly affects girls. Despite decades of work, the molecular function of MeCP2 is not fully understood. Here we report a systematic identification of MeCP2-interacting proteins in the mouse brain. In addition to transcription regulators, we found that MeCP2 physically interacts with several modulators of RNA splicing, including LEDGF and DHX9. These interactions are disrupted by RTT causing mutations, suggesting that they may play a role in RTT pathogenesis. Consistent with the idea, deep RNA sequencing revealed misregulation of hundreds of splicing events in the cortex of Mecp2 knockout mice. To reveal the functional consequence of altered RNA splicing due to the loss of MeCP2, we focused on the regulation of the splicing of the flip/flop exon of Gria2 and other AMPAR genes. We found a significant splicing shift in the flip/flop exon toward the flop inclusion, leading to a faster decay in the AMPAR gated current and altered synaptic transmission. In summary, our study identified direct physical interaction between MeCP2 and splicing factors, a novel MeCP2 target gene, and established functional connection between a specific RNA splicing change and synaptic phenotypes in RTT mice. These results not only help our understanding of the molecular function of MeCP2, but also reveal potential drug targets for future therapies.
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18. Liu X, Campanac E, Cheung HH, Ziats MN, Canterel-Thouennon L, Raygada M, Baxendale V, Pang AL, Yang L, Swedo S, Thurm A, Lee TL, Fung KP, Chan WY, Hoffman DA, Rennert OM. {{Idiopathic Autism: Cellular and Molecular Phenotypes in Pluripotent Stem Cell-Derived Neurons}}. {Mol Neurobiol}. 2016.
Autism spectrum disorder is a complex neurodevelopmental disorder whose pathophysiology remains elusive as a consequence of the unavailability for study of patient brain neurons; this deficit may potentially be circumvented by neural differentiation of induced pluripotent stem cells. Rare syndromes with single gene mutations and autistic symptoms have significantly advanced the molecular and cellular understanding of autism spectrum disorders; however, in aggregate, they only represent a fraction of all cases of autism. In an effort to define the cellular and molecular phenotypes in human neurons of non-syndromic autism, we generated induced pluripotent stem cells (iPSCs) from three male autism spectrum disorder patients who had no identifiable clinical syndromes, and their unaffected male siblings and subsequently differentiated these patient-specific stem cells into electrophysiologically active neurons. iPSC-derived neurons from these autistic patients displayed decreases in the frequency and kinetics of spontaneous excitatory postsynaptic currents relative to controls, as well as significant decreases in Na+ and inactivating K+ voltage-gated currents. Moreover, whole-genome microarray analysis of gene expression identified 161 unique genes that were significantly differentially expressed in autistic patient iPSC-derived neurons (>twofold, FDR < 0.05). These genes were significantly enriched for processes related to synaptic transmission, such as neuroactive ligand-receptor signaling and extracellular matrix interactions, and were enriched for genes previously associated with autism spectrum disorder. Our data demonstrate aberrant voltage-gated currents and underlying molecular changes related to synaptic function in iPSC-derived neurons from individuals with idiopathic autism as compared to unaffected siblings controls. Lien vers le texte intégral (Open Access ou abonnement)
19. Mikita N, Simonoff E, Pine DS, Goodman R, Artiges E, Banaschewski T, Bokde AL, Bromberg U, Buchel C, Cattrell A, Conrod PJ, Desrivieres S, Flor H, Frouin V, Gallinat J, Garavan H, Heinz A, Ittermann B, Jurk S, Martinot JL, Paillere Martinot ML, Nees F, Papadopoulos Orfanos D, Paus T, Poustka L, Smolka MN, Walter H, Whelan R, Schumann G, Stringaris A. {{Disentangling the autism-anxiety overlap: fMRI of reward processing in a community-based longitudinal study}}. {Transl Psychiatry}. 2016; 6(6): e845.
Up to 40% of youth with autism spectrum disorder (ASD) also suffer from anxiety, and this comorbidity is linked with significant functional impairment. However, the mechanisms of this overlap are poorly understood. We investigated the interplay between ASD traits and anxiety during reward processing, known to be affected in ASD, in a community sample of 1472 adolescents (mean age=14.4 years) who performed a modified monetary incentive delay task as part of the Imagen project. Blood-oxygen-level dependent (BOLD) responses to reward anticipation and feedback were compared using a 2×2 analysis of variance test (ASD traits: low/high; anxiety symptoms: low/high), controlling for plausible covariates. In addition, we used a longitudinal design to assess whether neural responses during reward processing predicted anxiety at 2-year follow-up. High ASD traits were associated with reduced BOLD responses in dorsal prefrontal regions during reward anticipation and negative feedback. Participants with high anxiety symptoms showed increased lateral prefrontal responses during anticipation, but decreased responses following feedback. Interaction effects revealed that youth with combined ASD traits and anxiety, relative to other youth, showed high right insula activation when anticipating reward, and low right-sided caudate, putamen, medial and lateral prefrontal activations during negative feedback (all clusters PFWE<0.05). BOLD activation patterns in the right dorsal cingulate and right medial frontal gyrus predicted new-onset anxiety in participants with high but not low ASD traits. Our results reveal both quantitatively enhanced and qualitatively distinct neural correlates underlying the comorbidity between ASD traits and anxiety. Specific neural responses during reward processing may represent a risk factor for developing anxiety in ASD youth. Lien vers le texte intégral (Open Access ou abonnement)
20. Miller NA, Merryman MB, Eskow KG, Chasson GS. {{State Design and Use of Medicaid 1915(c) Waivers and Related Benefits to Provide Services to Children and Youth With Autism Spectrum Disorder}}. {Am J Intellect Dev Disabil}. 2016; 121(4): 295-311.
Medicaid is the most significant source of funding for medical services for individuals with autism spectrum disorder (ASD). We surveyed state Medicaid directors or their designees regarding their use of autism specific 1915(c) waivers and other Medicaid benefits to provide services to children and youth with ASD, with a response rate of 84%. Ten states used autism-specific waivers to provide services. These waivers varied in the number of children served, eligibility criteria and services provided, among other characteristics. Issues related to the number of children to serve and the specific services to provide were perceived to be the most difficult waiver design issues, while provider geographic distribution, capacity and expertise were perceived to be the most difficult implementation concerns. States used a variety of additional Medicaid state plan services (e.g., the optional rehabilitation benefit) and 1915(c) waivers (e.g., a more general waiver serving individuals with intellectual and developmental disabilities) to provide services to children and youth with ASD. Thus, continuing to examine the adequacy and effectiveness of state use of a range of Medicaid benefits, including autism-specific 1915(c) waivers is critical. Expanding the evidence base for intervention effectiveness is important as well.
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21. Morisada N, Tsuneishi S, Taguchi K, Yagi R, Nishiyama M, Toyoshima D, Nakagawa T, Takeshima Y, Takada S, Iijima K. {{[A woman with beta-propeller protein-associated neurodegeneration identified by the WDR45 mutation presenting as Rett-like syndrome in childhood]}}. {No To Hattatsu}. 2016; 48(3): 209-12.
Beta-propeller protein-associated neurodegeneration (BPAN) is one of the neurodegenerative disorders characterized by iron deposition in the brain and is the only known disease in humans to be caused by an aberration in autophagocytosis. Here, we present the case of a 42-year-old woman with BPAN identified by the WDR45 mutation. From early childhood, she was recognized as having global developmental delay, and she frequently sucked her hand, which was considered to be a stereotypical movement. She had a febrile convulsion at 6 months of age but there was no history of epilepsy. The delay in language development was more severe than the delay in motor development; she was able to dress herself, walk unaided, and follow simple instructions until adolescence. After the age of 20, her movement ability rapidly declined. By the time she was 42 years old, she was bedridden and unable to communicate. Brain magnetic resonance imaging (MRI) at 21 years revealed no abnormality except non-specific cerebral atrophy. However, MRI at 39 years revealed abnormalities in the globus pallidus and substantia nigra, with neurodegeneration and iron accumulation in the brain. Genetic analysis for WDR45 revealed that she had a splice site mutation (NM_007075.3: c.830 + 2 T > C) which was previously reported, and a diagnosis of BPAN was confirmed. For specific therapies to be developed for BPAN in the future, it is necessary to establish early diagnosis, including genetic analysis.
22. Santa Maria L, Aliaga S, Faundes V, Morales P, Pugin A, Curotto B, Soto P, Pena MI, Salas I, Alliende MA. {{FMR1 gene mutations in patients with fragile X syndrome and obligate carriers: 30 years of experience in Chile}}. {Genet Res (Camb)}. 2016; 98: e11.
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID) and co-morbid autism. It is caused by an amplification of the CGG repeat (>200), which is known as the full mutation, within the 5’UTR of the FMR1 gene. Expansions between 55-200 CGG repeats are termed premutation and are associated with a greater risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated premature ovarian insufficiency. Intermediate alleles, also called the grey zone, include approximately 45-54 repeats and are considered borderline. Individuals with less than 45 repeats have a normal FMR1 gene. We report the occurrence of CGG expansions of the FMR1 gene in Chile among patients with ID and families with a known history of FXS. Here, we present a retrospective review conducted on 2321 cases (2202 probands and 119 relatives) referred for FXS diagnosis and cascade screening at the Institute of Nutrition and Food Technology (INTA), University of Chile. Samples were analysed using traditional cytogenetic methods and/or PCR. Southern blot was used to confirm the diagnosis. Overall frequency of FMR1 expansions observed among probands was 194 (8.8%), the average age of diagnosis was 8.8 +/- 5.4 years. Of 119 family members studied, 72 (60%) were diagnosed with a CGG expansion. Our results indicated that the prevalence of CGG expansions of the FMR1 gene among probands is relatively higher than other populations. The average age of diagnosis is also higher than reference values. PCR and Southern blot represent a reliable molecular technique in the diagnosis of FXS.
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23. Schneider A, Johnston C, Tassone F, Sansone S, Hagerman RJ, Ferrer E, Rivera SM, Hessl D. {{Broad autism spectrum and obsessive-compulsive symptoms in adults with the fragile X premutation}}. {Clin Neuropsychol}. 2016: 1-15.
OBJECTIVE: Clinical observations and a limited number of research studies provide evidence that the fragile X premutation may confer risk for autism, executive dysfunction, and psychopathology. The link to autism spectrum symptoms and social cognition deficits with the premutation remains uncertain, and thus was the focus of the present investigation. METHOD: Our sample included 131 individuals, 42 men/22 women with the FMR1 premutation (mean age = 31.83 +/- 8.59 years) with a normal neurological exam, and 48 men/19 women healthy age-matched controls (mean age = 29.48 +/- 7.29 years). Individuals completed a comprehensive neuropsychological battery with additional assessments for social cognition, broad autism spectrum, and obsessive-compulsive (OC) symptoms. RESULTS: Premutation carriers self-reported higher rates of autism-related symptoms (Autism Quotient; p = .001). Among males only, premutation carriers showed more atypical social interaction (p < .001) and stereotyped behavior (p = .014) during standardized clinical examination on the Autism Diagnostic Observation Schedule (ADOS) relative to controls. Female premutation carriers reported significantly higher rates of OC symptoms compared to control females (p = .012). Molecular measures defining the expanded premutation (FMR1 CGG repeat length and/or mRNA) were significantly associated with a measure of theory of mind (Reading the Mind in the Eyes Task). CONCLUSIONS: The results of this study indicate a higher rate of broad autism spectrum symptoms in some males with the premutation and provide evidence for an obsessive-compulsive subtype in female premutation carriers. Lien vers le texte intégral (Open Access ou abonnement)
24. Schulte-Ruther M, Otte E, Adiguzel K, Firk C, Herpertz-Dahlmann B, Koch I, Konrad K. {{Intact mirror mechanisms for automatic facial emotions in children and adolescents with autism spectrum disorder}}. {Autism Res}. 2016.
It has been suggested that an early deficit in the human mirror neuron system (MNS) is an important feature of autism. Recent findings related to simple hand and finger movements do not support a general dysfunction of the MNS in autism. Studies investigating facial actions (e.g., emotional expressions) have been more consistent, however, mostly relied on passive observation tasks. We used a new variant of a compatibility task for the assessment of automatic facial mimicry responses that allowed for simultaneous control of attention to facial stimuli. We used facial electromyography in 18 children and adolescents with Autism spectrum disorder (ASD) and 18 typically developing controls (TDCs). We observed a robust compatibility effect in ASD, that is, the execution of a facial expression was facilitated if a congruent facial expression was observed. Time course analysis of RT distributions and comparison to a classic compatibility task (symbolic Simon task) revealed that the facial compatibility effect appeared early and increased with time, suggesting fast and sustained activation of motor codes during observation of facial expressions. We observed a negative correlation of the compatibility effect with age across participants and in ASD, and a positive correlation between self-rated empathy and congruency for smiling faces in TDC but not in ASD. This pattern of results suggests that basic motor mimicry is intact in ASD, but is not associated with complex social cognitive abilities such as emotion understanding and empathy. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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25. Takahashi K, Miyatake N, Kurato R, Takahashi N. {{Prevalence of attention deficit hyperactivity disorder and/or autism spectrum disorder and its relation to lifestyle in female college students}}. {Environ Health Prev Med}. 2016.
OBJECTIVE: The aim of this study was to explore the prevalence of attention deficit hyperactivity disorder (ADHD) and/or autism spectrum disorder (ASD) and its relation to lifestyle in female college students. SUBJECTS AND METHODS: A total of 375 female college students (19.2 +/- 1.3 years) among 439 students were enrolled in this cross-sectional study. Using a self-reported questionnaire, we measured the prevalence of ADHD using the ADHD Self-Report Scale-v1.1 (ASRS) and the prevalence of ASD using the Autism-Spectrum Quotient (AQ). In addition, lifestyle choices such as medications, physical activity, cigarette smoking, alcohol drinking and sleeping habits were also evaluated. RESULTS: The suspected prevalence of ADHD was 102 students (27.2 %) and the suspected prevalence of ASD was 4 students (1.1 %). Only one student (0.3 %) was thought to have both ADHD and ASD. Subjects with suspected ADHD had higher AQ scores compared with those without suspected ADHD. There were no unhealthy lifestyle choices in subjects with suspected ADHD and/or ASD. CONCLUSION: The prevalence of suspected ADHD and/or ASD may be relatively high even among female college students in Japan.
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26. Theoharides TC, Tsilioni I, Patel AB, Doyle R. {{Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders}}. {Transl Psychiatry}. 2016; 6(6): e844.
Autism spectrum disorders (ASDs) affect as many as 1 in 45 children and are characterized by deficits in sociability and communication, as well as stereotypic movements. Many children also show severe anxiety. The lack of distinct pathogenesis and reliable biomarkers hampers the development of effective treatments. As a result, most children with ASD are prescribed psychopharmacologic agents that do not address the core symptoms of ASD. Autoantibodies against brain epitopes in mothers of children with ASD and many such children strongly correlate with allergic symptoms and indicate an aberrant immune response, as well as disruption of the blood-brain barrier (BBB). Recent epidemiological studies have shown a strong statistical correlation between risk for ASD and either maternal or infantile atopic diseases, such as asthma, eczema, food allergies and food intolerance, all of which involve activation of mast cells (MCs). These unique tissue immune cells are located perivascularly in all tissues, including the thalamus and hypothalamus, which regulate emotions. MC-derived inflammatory and vasoactive mediators increase BBB permeability. Expression of the inflammatory molecules interleukin (IL-1beta), IL-6, 1 L-17 and tumor necrosis factor (TNF) is increased in the brain, cerebrospinal fluid and serum of some patients with ASD, while NF-kB is activated in brain samples and stimulated peripheral blood immune cells of other patients; however, these molecules are not specific. Instead the peptide neurotensin is uniquely elevated in the serum of children with ASD, as is corticotropin-releasing hormone, secreted from the hypothalamus under stress. Both peptides trigger MC to release IL-6 and TNF, which in turn, stimulate microglia proliferation and activation, leading to disruption of neuronal connectivity. MC-derived IL-6 and TGFbeta induce maturation of Th17 cells and MCs also secrete IL-17, which is increased in ASD. Serum IL-6 and TNF may define an ASD subgroup that benefits most from treatment with the natural flavonoid luteolin. Atopic diseases may create a phenotype susceptible to ASD and formulations targeting focal inflammation of the brain could have great promise in the treatment of ASD.
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27. Yang Y, Kucukkal TG, Li J, Alexov E, Cao W. {{Binding Analysis of Methyl-CpG Binding Domain of MeCP2 and Rett Syndrome Mutations}}. {ACS Chem Biol}. 2016.
Methyl-CpG binding protein 2 (MeCP2) binds to methylated cytosine in CpG island through its methyl-CpG binding domain (MBD). Here, the effects of the Rett syndrome-causing missense mutations on binding affinity of MBD to cytosine (C), methylcytosine (mC), hydroxymethylcytosine (hmC), formylcytosine (fC) and carboxylcytosine (caC) in CpG dinucleotide are investigated. MeCP2-MBD binds to mC-containing variants of double stranded CpG stronger than any other cytosine modified CpG with strongest affinity to mC/mC. Thirteen MBD missense mutations show reduced binding affinity for mC/mC ranging with 2-fold decrease for T158M to 88-fold for R111G. The binding affinities of these mutants to C/C are also reduced to various degrees except for T158M. Consistent with free energy perturbation analysis, correlation of binding affinity with protein unfolding allows for grouping mutations into three clusters. Correlation of the first cluster includes mutations that have a higher tendency to unfold and have lesser affinity to mC/mC and C/C. Mutations in the second cluster have similar structural stability but various affinity to mC/mC and C/C. R111G and A140V belong to the third cluster in which the loss of protein flexibility may underlie their reduction in binding affinity to mC/mC and C/C. Most notably, R111 emerges as the key structural element that modulates the specific contacts with mCpG. Implications of the results for the mCpG binding mechanism of MeCP2-MBD are discussed. These analyses provide new insights on the structure and function relationships in MeCP2-MBD and offer new clues to their roles in the pathology of Rett syndrome.
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28. Yoo MH, Kim TY, Yoon YH, Koh JY. {{Autism phenotypes in ZnT3 null mice: Involvement of zinc dyshomeostasis, MMP-9 activation and BDNF upregulation}}. {Sci Rep}. 2016; 6: 28548.
To investigate the role of synaptic zinc in the ASD pathogenesis, we examined zinc transporter 3 (ZnT3) null mice. At 4-5 weeks of age, male but not female ZnT3 null mice exhibited autistic-like behaviors. Cortical volume and neurite density were significantly greater in male ZnT3 null mice than in WT mice. In male ZnT3 null mice, consistent with enhanced neurotrophic stimuli, the level of BDNF as well as activity of MMP-9 was increased. Consistent with known roles for MMPs in BDNF upregulation, 2.5-week treatment with minocycline, an MMP inhibitor, significantly attenuated BDNF levels as well as megalencephaly and autistic-like behaviors. Although the ZnT3 null state removed synaptic zinc, it rather increased free zinc in the cytosol of brain cells, which appeared to increase MMP-9 activity and BDNF levels. The present results suggest that zinc dyshomeostasis during the critical period of brain development may be a possible contributing mechanism for ASD.
