1. Altunel A, Sever A, Altunel EO. {{ACTH has beneficial effects on stuttering in ADHD and ASD patients with ESES: A retrospective study}}. {Brain Dev};2016 (Sep 16)
INTRODUCTION: Etiology of stuttering remains unknown and no pharmacologic intervention has been approved for treatment. We aimed to evaluate EEG parameters and the effect of adrenocorticotropic hormone (ACTH) therapy in stuttering. METHODS: In this retrospective study, 25 patients with attention deficit and hyperactivity (ADHD) or autism spectrum disorder (ASD), and comorbid stuttering were followed and treated with ACTH for electrical status epilepticus in sleep (ESES). Sleep EEGs were recorded at referral and follow-up visits and short courses of ACTH were administered when spike-wave index (SWI) was 15%. The assessment of treatment effectiveness was based on reduction in SWI, and the clinician-reported improvement in stuttering, and ADHD or ASD. Statistical analyses were conducted in order to investigate the relationship between the clinical and EEG parameters. RESULTS: Following treatment with ACTH, a reduction in SWI in all the patients was accompanied by a 72% improvement in ADHD or ASD, and 83.8% improvement in stuttering. Twelve of the 25 patients with stuttering showed complete treatment response. Linear regressions established that SWI at final visit significantly predicted improvement in ADHD or ASD, and in stuttering. If symptoms had recurred, improvement was once again achieved with repeated ACTH therapies. Stuttering always improved prior to, and recurred following ADHD or ASD. CONCLUSION: The underlying etiology leading to ESES may play a significant role in the pathophysiology of stuttering and connect stuttering to other developmental disorders. ACTH therapy has beneficial effects on stuttering and improves EEG parameters.
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2. Alvares GA, Quintana DS, Whitehouse AJ. {{Beyond the hype and hope: Critical considerations for intranasal oxytocin research in autism spectrum disorder}}. {Autism Res};2016 (Sep 21)
Extensive research efforts in the last decade have been expended into understanding whether intranasal oxytocin may be an effective therapeutic in treating social communication impairments in individuals with autism spectrum disorder (ASD). After much hyped early findings, subsequent clinical trials of longer-term administration have yielded more conservative and mixed evidence. However, it is still unclear at this stage whether these more disappointing findings reflect a true null effect or are mitigated by methodological differences masking true effects. In this review, we comprehensively evaluate the rationale for oxytocin as a therapeutic, evaluating evidence from randomized controlled trials, case reports, and open-label studies of oxytocin administration in individuals with ASD. The evidence to date, including reviews of preregistered trials, suggests a number of critical considerations for the design and interpretation of research in this area. These include considering the choice of ASD outcome measures, dosing and nasal spray device issues, and participant selection. Despite these limitations in the field to date, there remains significant potential for oxytocin to ameliorate aspects of the persistent and debilitating social impairments in individuals with ASD. Given the considerable media hype around new treatments for ASD, as well as the needs of eager families, there is an urgent need for researchers to prioritise considering such factors when conducting well-designed and controlled studies to further advance this field. Autism Res 2016,. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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3. Desai A, Sequeira JM, Quadros EV. {{Prevention of behavioral deficits in rats exposed to folate receptor antibodies: implication in autism}}. {Mol Psychiatry};2016 (Sep 20)
Folate receptor alpha (FRalpha) autoantibodies have been associated with fetal abnormalities and cerebral folate deficiency-related developmental disorders. Over 70% of the children with autism spectrum disorders (ASD) are positive for these autoantibodies and high-dose folinic acid is beneficial in treating these children. Here we show that antibodies (Abs) to the rat FRalpha administered during gestation produce communication, learning and cognitive deficits in a rat model that can be prevented by folinic acid and dexamethasone. FRalpha Ab can trigger inflammation as well as block folate transport to the fetus and to the developing brain to produce the functional deficits. In humans, exposure to FRalpha autoantibodies during fetal development and infancy could contribute to brain dysfunction such as that seen in ASD and other developmental disorders. Identifying women positive for the autoantibody and treating them with high-dose folinic acid along with other interventions to lower the autoantibody titer are effective strategies that may be considered to reduce the risk of having a child with developmental deficits.Molecular Psychiatry advance online publication, 20 September 2016; doi:10.1038/mp.2016.153.
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4. Funakoshi Y, Harada M, Otsuka H, Mori K, Ito H, Iwanaga T. {{Default mode network abnormalities in children with autism spectrum disorder detected by resting-state functional magnetic resonance imaging}}. {J Med Invest};2016;63(3-4):204-208.
PURPOSE: The purpose of this study was to investigate changes in the functional connectivity of the default mode network (DMN) in normal aging and in children with autistic spectrum disorder (ASD) by using resting-state functional magnetic resonance imaging (rsfMRI) and independent component analysis. METHODS: Thirty-one healthy controls (HC) in four age groups (1-3, 4-8, 20-29, and 50-59 years) and 14 childhood ASD cases (1-8 years of age) were examined by rsfMRI echo-planar imaging on a clinical 3-T MRI scanner. Imaging of all children (1-8 years) was conducted under sedation, while adults were scanned in the awake state with eyes closed. RESULTS: The regions of DMN functional connectivity in the bilateral inferior parietal lobule and posterior cingulate cortex were smaller in HC children than in HC adults, and smaller in the ASD group than in the HC children. CONCLUSION: It is possible to observe developmental and pathological changes in the DMN by rsfMRI. Reduced DMN functional connectivity in children may be a useful biomarker for ASD diagnosis. J. Med. Invest. 63: 204-208, August, 2016.
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5. Hwang YT, Dudding T, Aliaga SM, Arpone M, Francis D, Li X, Slater HR, Rogers C, Bretherton L, du Sart D, Heard R, Godler DE. {{Molecular Inconsistencies in a Fragile X Male with Early Onset Ataxia}}. {Genes (Basel)};2016;7(9)
Mosaicism for FMR1 premutation (PM: 55-199 CGG)/full mutation (FM: >200 CGG) alleles or the presence of unmethylated FM (UFM) have been associated with a less severe fragile X syndrome (FXS) phenotype and fragile X associated tremor/ataxia syndrome (FXTAS)-a late onset neurodegenerative disorder. We describe a 38 year old male carrying a 100% methylated FM detected with Southern blot (SB), which is consistent with complete silencing of FMR1 and a diagnosis of fragile X syndrome. However, his formal cognitive scores were not at the most severe end of the FXS phenotype and he displayed tremor and ataxic gait. With the association of UFM with FXTAS, we speculated that his ataxia might be related to an undetected proportion of UFM alleles. Such UFM alleles were confirmed by more sensitive PCR based methylation testing showing FM methylation between 60% and 70% in blood, buccal, and saliva samples and real-time PCR analysis showing incomplete silencing of FMR1. While he did not meet diagnostic criteria for FXTAS based on MRI findings, the underlying cause of his ataxia may be related to UFM alleles not detected by SB, and follow-up clinical and molecular assessment are justified if his symptoms worsen.
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6. Iovene MR, Bombace F, Maresca R, Sapone A, Iardino P, Picardi A, Marotta R, Schiraldi C, Siniscalco D, Serra N, de Magistris L, Bravaccio C. {{Intestinal Dysbiosis and Yeast Isolation in Stool of Subjects with Autism Spectrum Disorders}}. {Mycopathologia};2016 (Sep 21)
High frequency of gastrointestinal yeast presence in ASD subjects was shown through a simple cultural approach (Candida spp. in 57.5 % of ASDs and no controls); the identification of aggressive form (pseudo-hyphae presenting) of Candida spp. at light microscope means that adhesion to intestinal mucosa is facilitated. Dysbiosis appears sustained by lowered Lactobacillus spp. and decreased number of Clostridium spp. Absence of C. difficilis and its toxins in both ASDs and controls is also shown. Low-mild gut inflammation and augmented intestinal permeability were demonstrated together with the presence of GI symptoms. Significant linear correlation was found between disease severity (CARs score) and calprotectin and Clostridium spp. presence. Also GI symptoms, such as constipation and alternating bowel, did correlate (multivariate analyses) with the increased permeability to lactulose. The present data provide rationale basis to a possible specific therapeutic intervention in restoring gut homeostasis in ASDs.
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7. Johnson CM, Zhong W, Cui N, Wu Y, Xing H, Zhang S, Jiang C. {{Defects in brainstem neurons associated with breathing and motor function in the Mecp2R168X/Y mouse model of Rett syndrome}}. {Am J Physiol Cell Physiol};2016 (Sep 21):ajpcell 00132 02016.
Rett Syndrome (RTT) is an X-linked neurodevelopmental disorder caused mostly by disruption of the MECP2 gene. Among several RTT-like mouse models, one of them is a strain of mice that carries an R168X point mutation in Mecp2, and resembles one of the most common RTT-causing mutations in humans. Although several behavioral defects have previously been found in Mecp2R168X/Y mice, alterations in nerve cells remain unknown. Here we compare several behavioral and cellular outcomes between this Mecp2R168X/Y model and a widely used Mecp2Bird/Y mouse model. With lower body weight and shorter lifespan than their wild-type littermates, the Mecp2R168X/Y mice showed impairments of breathing and motor function. Thus we studied brainstem CO2 chemosensitive neurons and propriosensory cells that are associated with these two functions, respectively. Neurons in the locus coeruleus (LC) of both mutant strains showed defects in their intrinsic membrane properties, including changes in action potential morphology and excessive firing activity. Neurons in the mesencephalic trigeminal nucleus (Me5) of both strains displayed a higher firing response to depolarization than their WT littermates, likely due to a lower firing threshold. Because the increased excitability in LC and Me5 neurons tends to impact the excitation-inhibition balances in brainstem neuronal networks as well as their associated functions, it is likely that the defects in the intrinsic membrane properties of these brainstem neurons contribute to the breathing abnormalities and motor dysfunction. Furthermore, our results showing comparable phenotypical outcomes of Mecp2R168X/Y mice with Mecp2Bird/Y mice suggest that both strains are valid animal models for RTT research.
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8. Kirk HE, Gray K, Riby DM, Taffe J, Cornish KM. {{Visual attention and academic performance in children with developmental disabilities and behavioural attention deficits}}. {Dev Sci};2016 (Sep 21)
Despite well-documented attention deficits in children with intellectual and developmental disabilities (IDD), distinctions across types of attention problems and their association with academic attainment has not been fully explored. This study examines visual attention capacities and inattentive/hyperactive behaviours in 77 children aged 4 to 11 years with IDD and elevated behavioural attention difficulties. Children with autism spectrum disorder (ASD; n = 23), Down syndrome (DS; n = 22), and non-specific intellectual disability (NSID; n = 32) completed computerized visual search and vigilance paradigms. In addition, parents and teachers completed rating scales of inattention and hyperactivity. Concurrent associations between attention abilities and early literacy and numeracy skills were also examined. Children completed measures of receptive vocabulary, phonological abilities and cardinality skills. As expected, the results indicated that all groups had relatively comparable levels of inattentive/hyperactive behaviours as rated by parents and teachers. However, the extent of visual attention deficits varied as a result of group; namely children with DS had poorer visual search and vigilance abilities than children with ASD and NSID. Further, significant associations between visual attention difficulties and poorer literacy and numeracy skills were observed, regardless of group. Collectively the findings demonstrate that in children with IDD who present with homogenous behavioural attention difficulties, at the cognitive level, subtle profiles of attentional problems can be delineated.
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9. Lam J, Sutton P, Kalkbrenner A, Windham G, Halladay A, Koustas E, Lawler C, Davidson L, Daniels N, Newschaffer C, Woodruff T. {{A Systematic Review and Meta-Analysis of Multiple Airborne Pollutants and Autism Spectrum Disorder}}. {PLoS One};2016;11(9):e0161851.
BACKGROUND: Exposure to ambient air pollution is widespread and may be detrimental to human brain development and a potential risk factor for Autism Spectrum Disorder (ASD). We conducted a systematic review of the human evidence on the relationship between ASD and exposure to all airborne pollutants, including particulate matter air pollutants and others (e.g. pesticides and metals). OBJECTIVE: To answer the question: « is developmental exposure to air pollution associated with ASD? » METHODS: We conducted a comprehensive search of the literature, identified relevant studies using inclusion/exclusion criteria pre-specified in our protocol (registered in PROSPERO, CRD # 42015017890), evaluated the potential risk of bias for each included study and identified an appropriate subset of studies to combine in a meta-analysis. We then rated the overall quality and strength of the evidence collectively across all air pollutants. RESULTS: Of 1,158 total references identified, 23 human studies met our inclusion criteria (17 case-control, 4 ecological, 2 cohort). Risk of bias was generally low across studies for most domains; study limitations were related to potential confounding and accuracy of exposure assessment methods. We rated the quality of the body of evidence across all air pollutants as « moderate. » From our meta-analysis, we found statistically significant summary odds ratios (ORs) of 1.07 (95% CI: 1.06, 1.08) per 10-mug/m3 increase in PM10 exposure (n = 6 studies) and 2.32 (95% CI: 2.15, 2.51) per 10-mug/m3 increase in PM2.5 exposure (n = 3 studies). For pollutants not included in a meta-analysis, we collectively evaluated evidence from each study in rating the strength and quality of overall evidence considering factors such as inconsistency, imprecision, and evidence of dose-response. All included studies generally showed increased risk of ASD with increasing exposure to air pollution, although not consistently across all chemical components. CONCLUSION: After considering strengths and limitations of the body of research, we concluded that there is « limited evidence of toxicity » for the association between early life exposure to air pollution as a whole and diagnosis of ASD. The strongest evidence was between prenatal exposure to particulate matter and ASD. However, the small number of studies in the meta-analysis and unexplained statistical heterogeneity across the individual study estimates means that the effect could be larger or smaller (including not significant) than these studies estimate. Our research supports the need for health protective public policy to reduce exposures to harmful airborne contaminants among pregnant women and children and suggests opportunities for optimizing future research.
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10. McAuliffe D, Pillai AS, Tiedemann A, Mostofsky SH, Ewen JB. {{Dyspraxia in ASD: Impaired coordination of movement elements}}. {Autism Res};2016 (Sep 21)
Children with autism spectrum disorders (ASD) have long been known to have deficits in the performance of praxis gestures; these motor deficits also correlate with social and communicative deficits. To date, the precise nature of the errors involved in praxis has not been clearly mapped out. Based on observations of individuals with ASD performing gestures, we hypothesized that the simultaneous execution of multiple movement elements is especially impaired in affected children. We examined 25 school-aged participants with ASD and 25 age-matched controls performing seven simultaneous gestures that required the concurrent performance of movement elements and nine serial gestures, in which all elements were performed serially. There was indeed a group x gesture-type interaction (P < 0.001). Whereas both groups had greater difficulty performing simultaneous than serial gestures, children with ASD had a 2.6-times greater performance decrement with simultaneous (vs. serial) gestures than controls. These results point to a potential deficit in the simultaneous processing of multiple inputs and outputs in ASD. Such deficits could relate to models of social interaction that highlight the parallel-processing nature of social communication. Autism Res 2016,. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. Lien vers le texte intégral (Open Access ou abonnement)
11. Meltzer A, Van de Water J. {{The Role of the Immune System in Autism Spectrum Disorder}}. {Neuropsychopharmacology};2016 (Sep 21)
Autism is a neurodevelopmental disorder characterized by deficits in communication and social skills as well as repetitive and stereotypical behaviors. While much effort has focused on the identification of genes associated with autism, research emerging within the past two decades suggests that immune dysfunction is a viable risk factor contributing to the neurodevelopmental deficits observed in autism spectrum disorders (ASD). Further, it is the heterogeneity within this disorder that has brought to light much of the current thinking regarding the subphenotypes within ASD and how the immune system is associated with these distinctions. This review will focus on the two main axes of immune involvement in ASD, namely dysfunction in the prenatal and postnatal periods. During gestation, prenatal insults including maternal infection and subsequent immunological activation may increase the risk of autism in the child. Similarly, the presence of maternally derived anti-brain autoantibodies found in ~20% of mothers whose children are at risk for developing autism has defined an additional subphenotype of ASD. The postnatal environment, on the other hand, is characterized by related but distinct profiles of immune dysregulation, inflammation, and endogenous autoantibodies that all persist within the affected individual. Further definition of the role of immune dysregulation in ASD thus necessitates a deeper understanding of the interaction between both maternal and child immune systems, and the role they have in diagnosis and treatment.Neuropsychopharmacology advance online publication, 21 September 2016; doi:10.1038/npp.2016.158.
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12. Moghaddam K, Zadeh Mohammadi A, Sharifi Daramadi P, Afrooz G. {{Effect of the Family-based Art Therapy Program on the Social Interactions, Verbal Skills and Stereotypic Behaviors of Children with Autism Spectrum Disorders (ASD)}}. {Iran J Public Health};2016 (Jun);45(6):830-832.
13. Moradi E, Khundrakpam B, Lewis JD, Evans AC, Tohka J. {{Predicting symptom severity in autism spectrum disorder based on cortical thickness measures in agglomerative data}}. {Neuroimage};2016 (Sep 21)
Machine learning approaches have been widely used for the identification of neuropathology from neuroimaging data. However, these approaches require large samples and suffer from the challenges associated with multi-site, multi-protocol data. We propose a novel approach to address these challenges, and demonstrate its usefulness with the Autism Brain Imaging Data Exchange (ABIDE) database. We predict symptom severity based on cortical thickness measurements from 156 individuals with autism spectrum disorder (ASD) from four different sites. The proposed approach consists of two main stages: a domain adaptation stage using partial least squares regression to maximize the consistency of imaging data across sites; and a learning stage combining support vector regression for regional prediction of severity with elastic-net penalized linear regression for integrating regional predictions into a whole-brain severity prediction. The proposed method performed markedly better than simpler alternatives, better with multi-site than single-site data, and resulted in a considerably higher cross-validated correlation score than has previously been reported in the literature for multi-site data. This demonstration of the utility of the proposed approach for detecting structural brain abnormalities in ASD from the multi-site, multi-protocol ABIDE dataset indicates the potential of designing machine learning methods to meet the challenges of agglomerative data.
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14. Preckel K, Kanske P, Singer T, Paulus FM, Krach S. {{Clinical trial of modulatory effects of oxytocin treatment on higher-order social cognition in autism spectrum disorder: a randomized, placebo-controlled, double-blind and crossover trial}}. {BMC Psychiatry};2016;16(1):329.
BACKGROUND: Autism spectrum disorders are neurodevelopmental conditions with severe impairments in social communication and interaction. Pioneering research suggests that oxytocin can improve motivation, cognition and attention to social cues in patients with autism spectrum disorder. The aim of this clinical trial is to characterize basic mechanisms of action of acute oxytocin treatment on neural levels and to relate these to changes in different levels of socio-affective and -cognitive functioning. METHODS: This clinical study is a randomized, double-blind, cross-over, placebo-controlled, multicenter functional magnetic resonance imaging study with two arms. A sample of 102 male autism spectrum disorder patients, diagnosed with Infantile Autistic Disorder (F84.0 according to ICD-10), Asperger Syndrome (F84.5 according to ICD-10), or Atypical Autism (F84.1 according to ICD-10) will be recruited and will receive oxytocin and placebo nasal spray on two different days. Autism spectrum disorder patients will be randomized to determine who receives oxytocin on the first and who on the second visit. Healthy control participants will be recruited and case-control matched to the autism spectrum disorder patients. The primary outcome will be neural network activity, measured with functional magnetic resonance imaging while participants perform socio-affective and -cognitive tasks. Behavioral markers such as theory of mind accuracy ratings and response times will be assessed as secondary outcomes in addition to physiological measures such as skin conductance. Trait measures for alexithymia, interpersonal reactivity, and social anxiety will also be evaluated. Additionally, we will analyze the effect of oxytocin receptor gene variants and how these potentially influence the primary and secondary outcome measures. Functional magnetic resonance imaging assessments will take place at two time points which will be scheduled at least two weeks apart to ensure a sufficient wash-out time after oxytocin treatment. The study has been approved by an ethical review board and the competent authority. DISCUSSION: Revealing the mechanisms of acute oxytocin administration, especially on the socio-affective and -cognitive domains at hand, will be a further step towards novel therapeutic interventions regarding autism. TRIAL REGISTRATION: German Clinical Trial Register DRKS00010053 . The trial was registered on the 8th of April 2016.
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15. Rayan A, Ahmad M. {{Psychological Distress in Jordanian Parents of Children With Autism Spectrum Disorder: The Role of Trait Mindfulness}}. {Perspect Psychiatr Care};2016 (Sep 20)
AIM: This study examines the role of mindfulness in predicting psychological distress in Arab parents of children with autism spectrum disorder (ASD). METHOD: In this descriptive study, parents of 104 children with ASD completed measures of psychological distress and mindfulness. The severity of autism in children was measured using the DSM-V criteria. RESULTS: After controlling for parental age and gender and the severity level of ASD, mindfulness was significantly associated with the levels of anxiety, stress, and depression in parents (anxiety: beta = 0.49, p < .001; stress: beta = 0.55, p < .001; depression: beta = 0.53, p < .001). CONCLUSION: Mindfulness-based intervention may help to reduce psychological distress in Arab parents of children with ASD. Lien vers le texte intégral (Open Access ou abonnement)
16. Sah WH, Torng PC. {{Production of mental state terms in narratives of Mandarin-speaking children with autism spectrum disorder}}. {Clin Linguist Phon};2016 (Sep 19):1-18.
This study investigates the ability of Mandarin-speaking children with autism spectrum disorder (ASD) to use mental state terms in narratives. The narrative data are from 16 children with ASD and 16 typically developing children, matched on language and cognitive abilities. The narratives were elicited using Frog, where are you? Participants’ use of lexical expressions referring to emotion, cognition, desire and perception was examined. The ‘deer episode’ of the story was chosen to analyse children’s ability to talk about misrepresentation. The results reveal that the two groups of children performed comparably in basic narrative measures, overall use of mental state terms and references to the misrepresentation. The outcomes underscore the importance of examining different types of mental state terms separately. These findings are discussed in relation to linguistic and cognitive factors in mental-state attribution.
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17. Seritan AL, Kim K, Benjamin I, Seritan I, Hagerman RJ. {{Risk Factors for Cognitive Impairment in Fragile X-Associated Tremor/Ataxia Syndrome}}. {J Geriatr Psychiatry Neurol};2016 (Sep 19)
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disease with motor, psychiatric, and cognitive manifestations that occurs in carriers of the fragile X mental retardation 1 (FMR1) gene premutations. This was a retrospective chart review of 196 individuals (127 men and 69 women) with FXTAS. Forty-six (23%) participants were cognitively impaired, of whom 19 (10%) had dementia. Risk factors for dementia were examined (CGG repeat size; alcohol, benzodiazepine, and opioid use; diabetes; hyperlipidemia; hypertension; hypothyroidism; obesity; sleep apnea; surgeries with general anesthesia; depression; family history of dementia). Thirteen individuals with FXTAS and dementia were then compared to 13 cognitively intact individuals matched on age, gender, and FXTAS stage. CGG repeat size was significantly higher (mean = 98.5, standard deviation [SD] = 22.2) in the dementia group, compared to the cognitively intact group (mean = 81.6, SD = 11.5; P = .0256). These results show that CGG repeat size is a risk factor for FXTAS dementia.
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18. Toft AK, Lundbye CJ, Banke TG. {{Dysregulated NMDA-Receptor Signaling Inhibits Long-Term Depression in a Mouse Model of Fragile X Syndrome}}. {J Neurosci};2016 (Sep 21);36(38):9817-9827.
Fragile X syndrome (FXS) is a neurodevelopmental disease. It is one of the leading monogenic causes of intellectual disability among boys with most also displaying autism spectrum disorder traits. Here we investigated the role of NMDA receptors on mGluR-dependent long-term depression (mGluR-LTD), a key biomarker in the disease, at four different developmental stages. First, we applied the mGluR agonist 3,5-dihydroxyphenylglycine in the absence or presence of the NMDAR blocker, APV, hereby unmasking the NMDAR component in this process. As expected, in the presence of APV, we found more LTD in the mouse KO than in WT. This, however, was only observed in the p30-60 age group. At all other age groups tested, mGluR-LTD was almost identical between KO and WT. Interestingly, at p60, in the absence of APV, no or very little LTD was found in KO that was completely restored by application of APV. This suggests that the underlying cause of the enhanced mGluR-LTD in KO (at p30) is caused by dysregulated NMDAR signaling. To investigate this further, we next used NMDAR-subunit-specific antagonists. Inhibition of GluN2B, but not GluN2A, blocked mGluR-LTD only in WT. This was in contrast in the KO where blocking GluN2B rescued mGluR-LTD, suggesting GluN2B-containing NMDARs in the KO are hyperactive. Thus, these findings suggest strong involvement of GluN2B-containing-NMDARs in the pathophysiology of FXS and highlight a potential path for treatment for the disease. SIGNIFICANCE STATEMENT: There is currently no cure for fragile X, although medications targeting specific FXS symptoms do exist. The FXS animal model, the Fmr1 knock-out mouse, has demonstrated an increased mGluR5-mediated long-term depression (LTD) leading to several clinical trials of mGluR5 inhibitors/modulators, yet all have failed. In addition, surprisingly little information exists about the possible role of other ion channels/receptors, including NMDA receptors (NMDAR), in mGluR-LTD. Here we focus on NMDARs and their regulation of mGluR-mediated LTD at different developmental stages using several different NMDAR blockers/antagonists. Our findings suggest dysregulated NMDARs in the pathophysiology of FXS leading to altered mGluR-mediated LTD. Together, these data will help to develop new drug candidates that could lead to reversal of the FXS phenotype.
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19. Vaivre-Douret L, Boschi A, Cuny ML, Clouard C, Mosser A, Golse B, Philippe A, Bourgeois M, Boddaert N, Puget S. {{[Left temporal arachnoid cyst and specific learning disorders associated with Pervasive Developmental Disorders – Not Otherwise Specified (PDD-NOS): contributions of an integrative neuropsychomotor, neuropsychological, psychopathological and neurosurgical approach about a case report in a child (Francois)]}}. {Encephale};2016 (Sep 16)
Left temporal arachnoid cyst and specific learning disorders associated with pervasive developmental disorders – not otherwise specified (PDD-NOS): contributions of an integrative neuro-psychomotor, neuropsychological, psychopathological and neurosurgical approach about a case report in a child (Francois). With DSM-IV and DSM-IV-TR, the terminology of pervasive developmental disorders (PDD) covers two main categories of infantile disorders: disorders of « strictly » autistic nature and pervasive developmental disorders – not otherwise specified (PDD-NOS). Under the terminology of multiple complex developmental disorder (MCDD), it is proposed to classify children presenting symptoms approaching the psychotic disharmonies and usually diagnosed as PDD-NOS. Such a category of developmental disorders is now included without nosographic distinction in the autistic spectrum in the Diagnostic and Statistical Manual of mental disorders (DSM-V). CASE REPORT: We are reporting a case report of a 6-year-old boy which shows a PDD-NoS/MCDD complex symptomatology type. This child presents multiple disorders: minor neurological signs (soft signs), neuro-psychomotor disorders, developmental coordination disorder (DCD), communication, thought, and regulation of emotions disorders, attention deficit disorders (ADD); in the presence of a high verbal intellectual potential, which makes it difficult to establish a clear diagnosis. A cerebral magnetic resonance imaging (MRI) was carried out due to the presence of minor neurological signs (soft signs) and of neurodevelopmental multiple disorders. The MRI revealed a voluminous arachnoid temporo-polar left cyst with a marked mass effect on the left temporal lobe. DISCUSSION: A neurosurgical intervention allowed to observe the gradual disappearance of the specific symptomatology (in particular soft signs, neuro-psychomotor functions and autistic symptoms) secondary to the interference of the cyst’s pressure with intracranial areas involving neurological and psychopathological abnormalities, underlying at the same time the reversibility of the disorders after decompression as demonstrated in some studies. There are always, with a quantitative and qualitative decrease, an emotional dysregulation, a DCD, an ADD as well as impairments in the executive functions. CONCLUSION: This clinical case underlines the necessity of an evaluation in a transdisciplinary way and to follow the developmental evolution of the child in order to focus adapted therapeutics. Furthermore, with neurodevelopmental disorders not specified, it is important to examine the presence of soft signs with standardized neuro-psychomotor assessment, and then, to propose an MRI investigation. To our knowledge, this is the first report in the literature with a school age child of an unusual association between a temporal arachnoid cyst associated with PDD-NOS/MCDD.
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20. van der Weiden RM, Helmerhorst FM, Eriksson T. {{Gonadotropin-releasing hormone agonist against severe aggression in autism}}. {BMJ Case Rep};2016;2016
Aggression in patients with autism spectrum disorder (ASD) presents an important therapeutic challenge. Conventional treatment appears to be inadequate in a number of cases. The occurrence of severe aggressive symptoms since the inception of adolescence in a male patient with ASD suggested a hormonal influence by androgens. Conventional treatment with antipsychotic and antiepileptic drugs and benzodiazepines was ineffective. A subcutaneous long-acting gonadotropin-releasing hormone agonist (GnRH agonist) injection was given on a monthly basis resulting in a substantial improvement in his aggressive behaviour and renewed socialisation.
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21. Visootsak J, Kidd SA, Anderson T, Bassell JL, Sherman SL, Berry-Kravis EM. {{Importance of a specialty clinic for individuals with fragile X syndrome}}. {Am J Med Genet A};2016 (Sep 20)
Advances in human genetics have identified a significant number of genetic disorders associated with intellectual disability. As a result, appropriate clinical management of these affected individuals and their family members have become critical in addressing medical needs to improve quality of life. We examine the importance of a Fragile X Clinic for individuals with fragile X syndrome (FXS) and their family members by conducting a retrospective chart review of 123 new patients with FXS evaluated at the Fragile X Clinic at Emory University. After the initial diagnosis of a proband with FXS with cascade testing, there were 345 family members identified with a mutation (70% with premutations; 30% with full mutations). In terms of the impact of the clinic visit, males had a substantial number of new diagnoses in all behavioral disorders (P < 0.001), with anxiety (62%) being the most common. For female probands, the most frequent diagnosis was also anxiety (87%). Prior to the clinic visit, very few patients were prescribed psychotropic medications. After the clinic visit, the most frequently prescribed psychotropic medications for males were stimulants (41%; P < 0.001) and SSRIs (40%; P < 0.001). For females, only stimulants (33%; P = 0.03) and SSRIs (44%; P = 0.008) were statistically significantly prescribed. Our results revealed that there is a gap in care to address the co-morbid behavioral issues, psychopharmacologic medication management, and genetic counseling needs regarding FXS. A multidisciplinary setting and approach, such as that offered by a Fragile X Clinic, is one method of treating the complex needs of patients with FXS. (c) 2016 Wiley Periodicals, Inc. Lien vers le texte intégral (Open Access ou abonnement)
22. Wieckowski AT, White SW. {{Eye-Gaze Analysis of Facial Emotion Recognition and Expression in Adolescents with ASD}}. {J Clin Child Adolesc Psychol};2016 (Sep 21):1-15.
Impaired emotion recognition and expression in individuals with autism spectrum disorder (ASD) may contribute to observed social impairment. The aim of this study was to examine the role of visual attention directed toward nonsocial aspects of a scene as a possible mechanism underlying recognition and expressive ability deficiency in ASD. One recognition and two expression tasks were administered. Recognition was assessed in force-choice paradigm, and expression was assessed during scripted and free-choice response (in response to emotional stimuli) tasks in youth with ASD (n = 20) and an age-matched sample of typically developing youth (n = 20). During stimulus presentation prior to response in each task, participants’ eye gaze was tracked. Youth with ASD were less accurate at identifying disgust and sadness in the recognition task. They fixated less to the eye region of stimuli showing surprise. A group difference was found during the free-choice response task, such that those with ASD expressed emotion less clearly but not during the scripted task. Results suggest altered eye gaze to the mouth region but not the eye region as a candidate mechanism for decreased ability to recognize or express emotion. Findings inform our understanding of the association between social attention and emotion recognition and expression deficits.
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23. Zhao XN, Usdin K. {{Ups and Downs: Mechanisms of Repeat Instability in the Fragile X-Related Disorders}}. {Genes (Basel)};2016;7(9)
The Fragile X-related disorders (FXDs) are a group of clinical conditions resulting from the expansion of a CGG/CCG-repeat tract in exon 1 of the Fragile X mental retardation 1 (FMR1) gene. While expansions of the repeat tract predominate, contractions are also seen with the net result being that individuals can show extensive repeat length heterogeneity in different tissues. The mechanisms responsible for expansion and contraction are still not well understood. This review will discuss what is known about these processes and current evidence that supports a model in which expansion arises from the interaction of components of the base excision repair, mismatch repair and transcription coupled repair pathways.
