1. {{Developmental disabilities among children younger than 5 years in 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016}}. {Lancet Glob Health};2018 (Aug 29)
BACKGROUND: The Sustainable Development Goals (SDGs) mandate systematic monitoring of the health and wellbeing of all children to achieve optimal early childhood development. However, global epidemiological data on children with developmental disabilities are scarce. The Global Burden of Diseases, Injuries, and Risk Factors Study 2016 provides a comprehensive assessment of prevalence and years lived with disability (YLDs) for development disabilities among children younger than 5 years in 195 countries and territories from 1990 to 2016. METHODS: We estimated prevalence and YLDs for epilepsy, intellectual disability, hearing loss, vision loss, autism spectrum disorder, and attention deficit hyperactivity disorder. YLDs were estimated as the product of the prevalence estimate and the disability weight for each mutually exclusive disorder, corrected for comorbidity. We used DisMod-MR 2.1, a Bayesian meta-regression tool, on a pool of primary data derived from systematic reviews of the literature, health surveys, hospital and claims databases, cohort studies, and disease-specific registries. FINDINGS: Globally, 52.9 million (95% uncertainty interval [UI] 48.7-57.3; or 8.4% [7.7-9.1]) children younger than 5 years (54% males) had developmental disabilities in 2016 compared with 53.0 million (49.0-57.1; or 8.9% [8.2-9.5]) in 1990. About 95% of these children lived in low-income and middle-income countries. YLDs among these children increased from 3.8 million (95% UI 2.8-4.9) in 1990 to 3.9 million (2.9-5.2) in 2016. These disabilities accounted for 13.3% of the 29.3 million YLDs for all health conditions among children younger than 5 years in 2016. Vision loss was the most prevalent disability, followed by hearing loss, intellectual disability, and autism spectrum disorder. However, intellectual disability was the largest contributor to YLDs in both 1990 and 2016. Although the prevalence of developmental disabilities among children younger than 5 years decreased in all countries (except for North America) between 1990 and 2016, the number of children with developmental disabilities increased significantly in sub-Saharan Africa (71.3%) and in North Africa and the Middle East (7.6%). South Asia had the highest prevalence of children with developmental disabilities in 2016 and North America had the lowest. INTERPRETATION: The global burden of developmental disabilities has not significantly improved since 1990, suggesting inadequate global attention on the developmental potential of children who survived childhood as a result of child survival programmes, particularly in sub-Saharan Africa and south Asia. The SDGs provide a framework for policy and action to address the needs of children with or at risk of developmental disabilities, particularly in resource-poor countries. FUNDING: The Bill & Melinda Gates Foundation.
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2. Alvares GA, Dawson PA, Dissanayake C, Eapen V, Gratten J, Grove R, Henders A, Heussler H, Lawson L, Masi A, Raymond E, Rose F, Wallace L, Wray NR, Whitehouse AJO. {{Study protocol for the Australian autism biobank: an international resource to advance autism discovery research}}. {BMC Pediatr};2018 (Aug 27);18(1):284.
BACKGROUND: The phenotypic and genetic heterogeneity of autism spectrum disorder (ASD) presents considerable challenges in understanding etiological pathways, selecting effective therapies, providing genetic counselling, and predicting clinical outcomes. With advances in genetic and biological research alongside rapid-pace technological innovations, there is an increasing imperative to access large, representative, and diverse cohorts to advance knowledge of ASD. To date, there has not been any single collective effort towards a similar resource in Australia, which has its own unique ethnic and cultural diversity. The Australian Autism Biobank was initiated by the Cooperative Research Centre for Living with Autism (Autism CRC) to establish a large-scale repository of biological samples and detailed clinical information about children diagnosed with ASD to facilitate future discovery research. METHODS: The primary group of participants were children with a confirmed diagnosis of ASD, aged between 2 and 17 years, recruited through four sites in Australia. No exclusion criteria regarding language level, cognitive ability, or comorbid conditions were applied to ensure a representative cohort was recruited. Both biological parents and siblings were invited to participate, along with children without a diagnosis of ASD, and children who had been queried for an ASD diagnosis but did not meet diagnostic criteria. All children completed cognitive assessments, with probands and parents completing additional assessments measuring ASD symptomatology. Parents completed questionnaires about their child’s medical history and early development. Physical measurements and biological samples (blood, stool, urine, and hair) were collected from children, and physical measurements and blood samples were collected from parents. Samples were sent to a central processing site and placed into long-term storage. DISCUSSION: The establishment of this biobank is a valuable international resource incorporating detailed clinical and biological information that will help accelerate the pace of ASD discovery research. Recruitment into this study has also supported the feasibility of large-scale biological sample collection in children diagnosed with ASD with comprehensive phenotyping across a wide range of ages, intellectual abilities, and levels of adaptive functioning. This biological and clinical resource will be open to data access requests from national and international researchers to support future discovery research that will benefit the autistic community.
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3. Black MM, Lawn JE. {{Early childhood developmental disabilities-data still needed}}. {Lancet Glob Health};2018 (Aug 29)
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4. Brewe AM, Reisinger DL, Adlof SM, Roberts JE. {{Initiating joint attention use in infants at high-risk for autism spectrum disorder}}. {J Intellect Disabil Res};2018 (Aug 29)
BACKGROUND: Impairment in initiating joint attention (IJA) is associated with autism spectrum disorder (ASD) in children, although it is unclear when impairments arise. Due to the early development of IJA use and late diagnosis of ASD, groups at high-risk of ASD, such as infants with an older sibling with ASD (ASIBs) and infants with fragile X syndrome (FXS), provide opportunities to study early IJA behaviours for children who are later diagnosed with ASD. This study analysed these two groups to determine if IJA use differed compared with typically developing (TD) peers at 12 months and whether IJA was associated with later ASD outcomes. METHOD: An experimental attention task was used to analyse IJA gaze shifts and gestures in the high-risk groups. Clinical best estimate diagnoses were given to each participant to compare IJA behaviours to ASD severity. RESULTS: No differences in the frequency of IJA gaze shifts and gestures were found between 12-month-old ASIBs and TD controls, but infants with FXS demonstrated a significantly reduced range of IJA gaze shifts relative to TD controls. Additionally, ASD outcomes at 24 months were related to IJA use for infants with FXS at 12 months, but not infant ASIBs, although these findings were explained by differences in nonverbal cognitive development. CONCLUSIONS: Although previous studies have reported delays in IJA use in children with FXS and ASIBs at ages 21 and 14 months, respectively, our results suggest IJA behaviours for these high-risk groups are not distinct from TD children at 12 months. When differences were found at 12 months, they were explained by nonverbal cognitive development, particularly for infants with FXS. Differences in IJA use at 12 months in this study were too small to serve as a potential indicator of later ASD.
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5. Dalrymple KA, Wall N, Spezio M, Hazlett HC, Piven J, Elison JT. {{Rapid face orienting in infants and school-age children with and without autism: Exploring measurement invariance in eye-tracking}}. {PLoS One};2018;13(8):e0202875.
Questions concerning the ontogenetic stability of autism have recently received increased attention as long-term longitudinal studies have appeared in the literature. Most experimental measures are designed for specific ages and functioning levels, yet developing experimental tasks appropriate for a wide range of ages and functioning levels is critical for future long-term longitudinal studies, and treatment studies implemented at different ages. Accordingly, we designed an eye-tracking task to measure preferential orienting to facial features and implemented it with groups of participants with varying levels of functioning: infants, and school-age children with and without autism. All groups fixated eyes first, revealing an early and stable orienting bias. This indicates common bias towards the eyes across participants regardless of age or diagnosis. We also demonstrate that this eye-tracking task can be used with diverse populations who range in age and cognitive functioning. Our developmental approach has conceptual implications for future work focused on task development and particularly new experimental measures that offer measurement equivalence across broad age ranges, intellectual functioning and verbal abilities.
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6. Deckmann I, Schwingel GB, Fontes-Dutra M, Bambini-Junior V, Gottfried C. {{Neuroimmune Alterations in Autism: A Translational Analysis Focusing on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid}}. {Neuroimmunomodulation};2018 (Aug 29):1-15.
Autism spectrum disorder (ASD) is a highly prevalent developmental disorder characterized by deficits in communication and social interaction and in stereotyped or repetitive behaviors. Besides the classical behavioral dyad, several comorbidities are frequently present in patients with ASD, such as anxiety, epilepsy, sleep disturbances, and gastrointestinal tract dysfunction. Although the etiology of ASD remains unclear, there is supporting evidence for the involvement of both genetic and environmental factors. Valproic acid (VPA) is an anticonvulsant and mood stabilizer that, when used during the gestational period, increases the risk of ASD in the offspring. The animal model of autism induced by prenatal exposure to VPA demonstrates important structural and behavioral features that can be observed in individuals with autism; it is thus an excellent tool for testing new drug targets and developing novel behavioral and drug therapies. In addition, immunological alterations during pregnancy could affect the developing embryo because immune molecules can pass through the placental barrier. In fact, exposure to pathogens during the pregnancy is a known risk factor for ASD, and maternal immune activation can lead to autistic-like features in animals. Interestingly, neuroimmune alterations are common in both autistic individuals and in animal models of ASD. We summarize here the important alterations in inflammatory markers, such as cytokines and chemokines, in patients with ASD and in the VPA animal model.
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7. Edey R, Brewer R, Bird G, Press C. {{Brief Report: Typical Auditory-Motor and Enhanced Visual-Motor Temporal Synchronization in Adults with Autism Spectrum Disorder}}. {J Autism Dev Disord};2018 (Aug 29)
The perception of subsecond durations in adults with autism spectrum disorder (hereafter ‘autism’; n = 25 Experiment 1, n = 21 Experiment 2) and matched typical adults (n = 24 Experiment 1, n = 22 Experiment 2) was examined by requiring participants to perform an action in time with auditory (Experiment 1) or visual (Experiment 2) events. Individuals with autism performed comparably to typical participants in the auditory task and exhibited less temporal error relative to their typical counterparts in the visual task. These findings suggest that perception of subsecond intervals is intact in autism, if not enhanced. Results support recent Bayesian theories of enhanced visual-perceptual precision in people with autism, and extend empirical support into the precision of subsecond temporal estimates.
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8. Eskow KG, Summers JA. {{Family perceptions of the impacts of a home and community based services autism waiver: Making family life possible}}. {J Appl Res Intellect Disabil};2018 (Aug 27)
BACKGROUND: An important mechanism that provides support and services for families with a child/youth with autism spectrum disorder is the home- and community-based services (HCBS) Waiver authorized by Section 1915(c) of the Social Security Act or Medicaid. METHODS: This study used qualitative research methods to explore parent perspectives about the impact of HCBS Waiver services on the child/youth with autism and their family. In-depth interviews focused on aspects of the programme they valued, identification of barriers and general issues they experienced. RESULTS: Results of the qualitative study indicated that improved outcomes could be explained by providers of services who were well-trained, flexible and allowed parents’ opportunities for choice regarding provision of services to meet child/youth and family needs. CONCLUSION: The findings of this study provide guideposts for further research about factors that contribute to satisfaction of families receiving waiver services for quality of life and child progress.
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9. Esnafoglu E. {{Levels of peripheral Neuregulin 1 are increased in non-medicated autism spectrum disorder patients}}. {J Clin Neurosci};2018 (Aug 24)
Though schizophrenia and autism spectrum disorders (ASD) are separate diseases, they have some common clinical manifestations and common pathogenic mechanisms. Numerous genes are associated with these conditions. Among these genes, Neuregulin-1 forms a risk for schizophrenia and some studies have shown polymorphism of this gene accompanies schizophrenia. NRG1 has a wide variety of functions, including neuronal migration, axon guidance, synaptic transmission, oligodendroglial maturation, and neurite outgrowth. To date, NRG1 levels have not been researched in ASD patients and considering the neurodevelopmental effects of NRG1, this study aimed to research the peripheral NRG1 levels in ASD patients. The study compared 32 ASD patients and 32 healthy controls. Serum NRG-1 levels were measured with ELISA. In ASD patients (mean+/-SD, 10.80+/-4.78ng/ml), the NRG1 levels were found to be statistically significantly high compared to the health control group (mean+/-SD, 6.92+/-4.91ng/ml) (p=0.004). According to the results we obtained, NRG1 was shown to play a possible role in ASD pathogenesis. There is a need for advanced studies on the possible role of NRG1 in ASD patients. This study is significant as it is the first study to measure peripheral NRG1 in ASD patients.
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10. Harlalka V, Bapi RS, Vinod PK, Roy D. {{Age, Disease, and Their Interaction Effects on Intrinsic Connectivity of Children and Adolescents in Autism Spectrum Disorder Using Functional Connectomics}}. {Brain Connect};2018 (Aug 29)
Brain connectivity analysis has provided crucial insights to pinpoint the differences between autistic and typically developing (TD) children during development. The aim of this study is to investigate the functional connectomics of autism spectrum disorder (ASD) versus TD and underpin the effects of development, disease, and their interactions on the observed atypical brain connectivity patterns. Resting-state functional magnetic resonance imaging (rs-fMRI) from the Autism Brain Imaging Data Exchange (ABIDE) data set, which is stratified into two cohorts: children (9-12 years) and adolescents (13-16 years), is used for the analysis. Differences in various graph theoretical network measures are calculated between ASD and TD in each group. Furthermore, two-factor analysis of variance test is used to study the effect of age, disease, and their interaction on the network measures and the network edges. Furthermore, the differences in connection strength between TD and ASD subjects are assessed using network-based statistics. The results showed that ASD exhibits increased functional integration at the expense of decreased functional segregation. In ASD adolescents, there is a significant decrease in modularity suggesting a less robust modular organization, and an increase in participation coefficient suggesting more random integration and widely distributed connection edges. Furthermore, there is significant hypoconnectivity observed in the adolescent group especially in the default mode network, while the children group shows both hyper- and hypoconnectivity. This study lends support to a model of global atypical connections and further identifies functional networks and areas that are independently affected by age, disease, and their interaction.
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11. Knuppel A, Telleus GK, Jakobsen H, Lauritsen MB. {{Characteristics of Young Adults with Autism Spectrum Disorder Performing Different Daytime Activities}}. {J Autism Dev Disord};2018 (Aug 27)
Daytime activity, in terms of engagement in an occupation or education, is highly important for individuals with autism spectrum disorder (ASD), regardless of their level of functioning. In this nationwide survey, the parents of young adults diagnosed with ASD in childhood (n = 1266) provided information about the current daytime activity of their child, as well as behavioral characteristics, comorbidity, history of schooling during primary and secondary school, and availability of support. The young adults without a regular daytime activity constituted approximately one-fifth of the sample and had more behavioral difficulties and comorbidities than young adults with a daytime activity. Intellectual disability, part-time job, history of schooling, including type of school, and availability of support were found to be associated with daytime activity.
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12. Krieger B, Piskur B, Schulze C, Jakobs U, Beurskens A, Moser A. {{Supporting and hindering environments for participation of adolescents diagnosed with autism spectrum disorder: A scoping review}}. {PLoS One};2018;13(8):e0202071.
The influence of a person’s environment and its modifying potential on participation is well recognized for most childhood disabilities, but scarcely studied for adolescents with autism spectrum disorder (ASD). A scoping review was conducted, the aim of which was to map the existing literature about supporting and hindering environments for the participation of adolescents with ASD. Sources of scientific evidence were searched for in four databases. Inclusion criteria were the perspectives of adolescents between 12 and 21, families, peers, or significant others; ecologic validity; and a clear connection between environment and participation. The publication dates ranged from 2001 to 2014 and partly up to 2018. The International Classification of Functioning, Disability and Health (ICF) served as the guiding framework for inclusion/exclusion during the selection process. Thematic analysis was performed by five independent reviewers. Results were additionally validated by stakeholders. This scoping review identified 5528 articles, and finally included 31 studies. Two main themes were found: « providing security » indicates how the environment, and specifically the parental, physical, and informational environments, have a securing or intimidating effect. The second theme, « helping to connect », indicates which environments support or hinder social relationships or social activities, and hence participation. An additional third main theme, « tension in participation », relates to ambiguities that seem essential to understand participation or isolation of adolescents with ASD. Results show that participation is a value-laden concept. This research widens the field of dealing with adolescents with ASD, as it directs attention towards the responsibility of the environment regarding participation.
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13. Kyriakopoulos P, McNiven V, Carter MT, Humphreys P, Dyment D, Fantaneanu TA. {{Atypical Rett Syndrome and Intractable Epilepsy With Novel GRIN2B Mutation}}. {Child Neurol Open};2018;5:2329048×18787946.
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14. Moreno-Rius J. {{Is there an « antisocial » cerebellum? Evidence from disorders other than autism characterized by abnormal social behaviours}}. {Prog Neuropsychopharmacol Biol Psychiatry};2018 (Aug 25);89:1-8.
The cerebellum is a hindbrain structure which involvement in functions not related to motor control and planning is being increasingly recognized in the last decades. Studies on Autism Spectrum Disorders (ASD) have reported cerebellar involvement on these conditions characterized by social deficits and repetitive motor behavior patterns. Although such an involvement hints at a possible cerebellar participation in the social domain, the fact that ASD patients present both social and motor deficits impedes drawing any firm conclusion regarding cerebellar involvement in pathological social behaviours, probably influenced by the classical view of the cerebellum as a purely « motor » brain structure. Here, we suggest the cerebellum can be a key node for the production and control of normal and particularly aberrant social behaviours, as indicated by its involvement in other neuropsychiatric disorders which main symptom is deregulated social behaviour. Therefore, in this work, we briefly review cerebellar involvement in social behavior in rodent models, followed by discussing the findings linking the cerebellum to those other psychiatric conditions characterized by defective social behaviours. Finally, possible commonalities between the studies and putative underlying impaired functions will be discussed and experimental approaches both in patients and experimental animals will also be proposed, aimed at stimulating research on the role of the cerebellum in social behaviours and disorders characterized by social impairments, which, if successful, will definitely help reinforcing the proposed cerebellar involvement in the social domain.
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15. Mori Y, Downs J, Wong K, Leonard H. {{Longitudinal effects of caregiving on parental well-being: the example of Rett syndrome, a severe neurological disorder}}. {Eur Child Adolesc Psychiatry};2018 (Aug 27)
Little longitudinal research has examined parental well-being in those with a child with specific genetic developmental disorder although the associated severe neurological impairments and multiple physical comorbidities likely place substantial burden of caregiving on the parent. We aimed to examine longitudinally the well-being of parents of individuals included in the Australian Rett Syndrome Database over the period from 2002 to 2011 using the Short Form 12 Health Survey. Residential remoteness, the child being a teenager at baseline, having frequent sleep disturbances or behavioural problems, and the type of MECP2 gene mutation were each associated with later poorer parental physical well-being scores. Being a single parent or on a low income was also associated with later poorer physical well-being, while the child having enteral feeding was associated with later poorer emotional well-being. Both the physical and emotional well-being of the parent improved if the child was living in out-of-home care. Our findings suggest that some opportunities do exist for clinicians to help optimise parental well-being. Being alert to the possibility and need for management of a child’s sleep or emotional disturbance is important as is awareness of the additional likely parental burden as the child moves through adolescence into early adulthood and their need for additional support at that time. However, the findings also highlight the complex nature of parental well-being over time in parents of children with a severe neurological disorder and how they may be affected by a range of inter-related family and child factors.
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16. Okuno M, Uehara T. {{Early childhood behavioral features that discriminate autism from other developmental problems in Japan}}. {J Child Adolesc Psychiatr Nurs};2018 (Aug 29)
PROBLEM: The criteria for early detection of autism spectrum disorder (ASD) and its discrimination from other developmental problems (ODP) are not clear. The Social Attention and Communication Study, which identified methods for early identification of ASD in community settings, was modified to the Japanese situation, and we examined its discriminant validity. METHODS: This study followed a cohort of newborns in one town for 4 years. Structured behavioral assessments were added to the standardized health examination and performed five times during toddlerhood. Of the 264 children included in the statistical analysis, four were diagnosed with ASD, and four were diagnosed with ODP. FINDINGS: A canonical discrimination analysis indicated two significant functions. Canonical 1, which involved disturbances of « eye contact » at 27 months and « concept comprehension » at 38 months, characterized both ASD and ODP. Canonical 2, which involved disturbances of « response name call » at 15 months, « showing » at 27 months, and negative loading of vocabulary development at 20 months, discriminated between ASD and ODP. The canonical plot showed good separation, but a few cases were misclassified. CONCLUSIONS: Evaluations of early behavioral signs by public health nurses during general toddler examinations could be useful and convenient.
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17. Oztan O, Garner JP, Partap S, Sherr EH, Hardan AY, Farmer C, Thurm A, Swedo SE, Parker KJ. {{Cerebrospinal fluid vasopressin and symptom severity in children with autism}}. {Ann Neurol};2018 (Aug 28)
Autism is a brain disorder characterized by social impairments. Progress in understanding autism has been hindered by difficulty in obtaining brain-relevant tissues [e.g., cerebrospinal fluid (CSF)] by which to identify markers of disease and targets for treatment. Here we overcome this barrier by providing evidence that mean CSF concentration of the « social » neuropeptide arginine vasopressin (AVP) is lower in children with autism versus controls. CSF AVP concentration also significantly differentiates individual cases from controls and is associated with greater social symptom severity in children with autism. These findings indicate that AVP may be a promising CSF marker of autism’s social deficits. This article is protected by copyright. All rights reserved.
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18. Patzlaff NE, Shen M, Zhao X. {{Regulation of Adult Neurogenesis by the Fragile X Family of RNA Binding Proteins}}. {Brain Plast};2018 (Aug 10);3(2):205-223.
The fragile X mental retardation protein (FMRP) has an important role in neural development. Functional loss of FMRP in humans leads to fragile X syndrome, and it is the most common monogenetic contributor to intellectual disability and autism. FMRP is part of a larger family of RNA-binding proteins known as FXRs, which also includes fragile X related protein 1 (FXR1P) and fragile X related protein 2 (FXR2P). Despite the similarities of the family members, the functions of FXR1P and FXR2P in human diseases remain unclear. Although most studies focus on FMRP’s role in mature neurons, all three FXRs regulate adult neurogenesis. Extensive studies have demonstrated important roles of adult neurogenesis in neuroplasticity, learning, and cognition. Impaired adult neurogenesis is implicated in neuropsychiatric disorders, neurodegenerative diseases, and neurodevelopmental disorders. Interventions aimed at regulating adult neurogenesis are thus being evaluated as potential therapeutic strategies. Here, we review and discuss the functions of FXRs in adult neurogenesis and their known similarities and differences. Understanding the overlapping regulatory functions of FXRs in adult neurogenesis can give us insights into the adult brain and fragile X syndrome.
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19. Poisson A, Chatron N, Labalme A, Till M, Broussolle E, Sanlaville D, Demily C, Lesca G. {{Regressive Autism Spectrum Disorder Expands the Phenotype of BSCL2/Seipin-Associated Neurodegeneration}}. {Biol Psychiatry};2018 (Aug 24)
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20. Poleg S, Golubchik P, Offen D, Weizman A. {{Cannabidiol as a suggested candidate for treatment of autism spectrum disorder}}. {Prog Neuropsychopharmacol Biol Psychiatry};2018 (Aug 29)
Autism Spectrum Disorder (ASD) is characterized by persistent deficits in social communication, restricted and repetitive patterns of behavior, interests, or activities and often intellectual disabilities. ASD has a number of prevalent co-morbidities, such as sleep disorders, attention deficit/hyperactivity disorder and epilepsy. No effective treatment for the core symptoms of ASD is currently available. There is increasing interest in cannabinoids, especially cannabidiol (CBD), as monotherapy or add-on treatment for the core symptoms and co-morbidities of ASD. In this review we summarize the available pre-clinical and clinical data regarding the safety and effectiveness of medical cannabis, including CBD, in young ASD patients. Cannabidiol seems to be a candidate for the treatment of ASD. At present, however, there are no convincing pre-clinical or clinical data showing efficacy and safety of cannabinoid treatment in ASD patients.
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21. Rodgers JD, Lodi-Smith J, Donnelly JP, Lopata C, McDonald CA, Thomeer ML, Lipinski AM, Nasca BC, Booth AJ. {{Brief Report: Examination of Sex-Based Differences in ASD Symptom Severity Among High-Functioning Children with ASD Using the SRS-2}}. {J Autism Dev Disord};2018 (Aug 27)
Prior studies of sex-based differences in autism spectrum disorder (ASD) have yielded mixed findings. This study examined ASD symptom severity and functional correlates in a sample of 34 high-functioning females with ASD (HFASD; M age = 8.93; M IQ = 104.64) compared to 34 matched males (M age = 8.96; M IQ = 104.44) using the Social Responsiveness Scale-Second Edition (SRS-2). Results identified non-significant and minimal differences (negligible-to-small) on the SRS-2 total, DSM-5 symptom subscale, and treatment subscale scores. Significant negative (moderate) correlations were found between the SRS-2 Social Cognition subscale and IQ and language scores and between the SRS-2 Social Motivation subscale and receptive language scores for females only; no significant correlations were found for males.
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22. Shuffrey LC, Levinson L, Becerra A, Pak G, Moya Sepulveda D, Montgomery AK, Green HL, Froud K. {{Visually Evoked Response Differences to Contrast and Motion in Children with Autism Spectrum Disorder}}. {Brain Sci};2018 (Aug 24);8(9)
High-density electroencephalography (EEG) was used to examine the utility of the P1 event-related potential (ERP) as a marker of visual motion sensitivity to luminance defined low-spatial frequency drifting gratings in 16 children with autism and 16 neurotypical children. Children with autism displayed enhanced sensitivity to large, high-contrast low-spatial frequency stimuli as indexed by significantly shorter P1 response latencies to large vs. small gratings. The current study also found that children with autism had larger amplitude responses to large gratings irrespective of contrast. A linear regression established that P1 adaptive mean amplitude for large, high-contrast sinusoidal gratings significantly predicted hyperresponsiveness item mean scores on the Sensory Experiences Questionnaire for children with autism, but not for neurotypical children. We conclude that children with autism have differences in the mechanisms that underlie low-level visual processing potentially related to altered visual spatial suppression or contrast gain control.
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23. Stankiewicz E, Ouellette-Kuntz H, McIsaac M, Shooshtari S, Balogh R. {{Patterns of mortality among adults with intellectual and developmental disabilities in Ontario}}. {Can J Public Health};2018 (Aug 27)
OBJECTIVES: To determine recent mortality rates among Ontarian adults with intellectual and developmental disabilities (IDDs) and investigate changes over time in contrast to the general population. To determine the most commonly reported underlying causes of death and explore related coding practices. METHODS: Using linked health administrative data, four cohorts of adults with IDD aged 25-99 living in Ontario were followed for 1 year (one cohort for each year between 2011 and 2014). Deaths (2011 to 2014) and causes of death (2011 to 2013) were identified, and age-standardized mortality rates were calculated annually. For 2013, overall and sex-specific standardized mortality ratios (SMRs) were calculated. Mortality ratios were also examined across 5-year age groups. Commonly reported causes of death were tabulated by ICD-10 chapter, differences by sex examined, and cause-specific SMRs calculated. All deaths with IDD diagnostic codes reported as underlying cause of death were identified. RESULTS: Mortality rates among individuals with IDD have been decreasing over time; in 2014, the mortality rate was 22.6 deaths per 1000 person-years. Disparities in mortality rates relative to the general population decreased with increasing age. Men with IDD had higher mortality rates than women with IDD. The most common causes of death among individuals with IDD were cardiovascular disease, neoplasms, and diseases of the respiratory system. An IDD diagnostic code was reported as cause of death in 3.8% of cases. CONCLUSIONS: The ongoing excess mortality among Ontarians with IDD should be closely monitored by policy makers and service providers. Attention to cause of death reporting should be considered so that cause of death can be thoroughly examined.
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24. Thal LB, Tomlinson ID, Quinlan MA, Kovtun O, Blakely RD, Rosenthal SJ. {{Single quantum dot imaging reveals PKCbeta-dependent alterations in membrane diffusion and clustering of an ADHD/autism/bipolar disorder-associated dopamine transporter variant}}. {ACS Chem Neurosci};2018 (Aug 28)
The dopamine transporter (DAT) is a transmembrane protein that terminates dopamine signaling in the brain by driving rapid dopamine reuptake into presynaptic nerve terminals. Several lines of evidence indicate that DAT dysfunction is linked to neuropsychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BPD), and autism spectrum disorder (ASD). Indeed, individuals with these disorders have been found to express the rare, functional DAT coding variant Val559 which confers anomalous dopamine efflux (ADE) in vitro and in vivo. To elucidate the impact of the DAT Val559 variant on membrane diffusion dynamics, we implemented our antagonist-conjugated quantum dot (QD) labeling approach to monitor the lateral mobility of single particle-labeled transporters in transfected HEK-293 and SK-N-MC cells. Our results demonstrate significantly higher diffusion coefficients of DAT Val559 compared to DAT Ala559, effects likely determined by elevated N-terminal transporter phosphorylation. We also provide pharmacological evidence that PKCbeta-mediated signaling supports enhanced DAT Val559 membrane diffusion rates. Our results are complimented with diffusion rates of phosphomimicked and phosphorylation-occluded DAT variants. Furthermore, we show DAT Val559 has a lower propensity for membrane clustering which may be caused by a mutation-derived shift out of membrane microdomains leading to faster lateral membrane diffusion rates. These findings further demonstrate a functional impact of DAT Val559 and suggest that changes in transporter localization and lateral mobility may sustain ADE and contribute to alterations in dopamine signaling underlying multiple neuropsychiatric disorders.
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25. Tsilioni I, Theoharides TC. {{Extracellular vesicles are increased in the serum of children with autism spectrum disorder, contain mitochondrial DNA, and stimulate human microglia to secrete IL-1beta}}. {J Neuroinflammation};2018 (Aug 27);15(1):239.
BACKGROUND: Autism spectrum disorder (ASD) has been associated with brain inflammation as indicated by the activation of microglia, but the triggers are not known. Extracellular vesicles (EVs) are secreted from many cells in the blood and other biological fluids and carry molecules that could influence the function of target cells. EVs have been recently implicated in several diseases, but their presence or function in ASD has not been studied. METHODS: EVs were isolated from the serum of children with ASD (n = 20, 16 males and 4 females, 4-12 years old) and unrelated age and sex-matched normotypic controls (n = 8, 6 males and 2 females, 4-12 years old) using the exoEasy Qiagen kit. EVs were characterized by determining the CD9 and CD81 membrane-associated markers with Western blot analysis, while their morphology and size were assessed by transmission electron microscopy (TEM). Human microglia SV40 were cultured for 24 h and then stimulated with EVs (1 or 5 mug/mL), quantitated as total EV-associated protein, for 24 or 48 h. IL-1beta secretion was measured by ELISA. The results were analyzed using the Mann-Whitney U non-parametric test, and all statistical analyses were performed using Graph Pad Prism 5. RESULTS: EVs were isolated and shown to be spherical structures (about 100 nm) surrounded by a membrane. Total EV-associated protein was found to be significantly increased (p = 0.02) in patients as compared to normotypic controls. EVs (5 mug/mL) isolated from the serum of patients with ASD stimulated cultured human microglia to secrete significantly more of the pro-inflammatory cytokine interleukin IL-1beta (163.5 +/- 13.34 pg/mL) as compared to the control (117.7 +/- 3.96 pg/mL, p < 0.0001). The amount of mitochondrial DNA (mtDNA7S) contained in EVs from children with ASD was found to be increased (p = 0.046) compared to the normotypic controls. CONCLUSIONS: These findings provide novel information that may help explain what triggers inflammation in the brain of children with ASD and could lead to novel effective treatments. Lien vers le texte intégral (Open Access ou abonnement)
26. Wang X, Guo J, Song Y, Wang Q, Hu S, Gou L, Gao Y. {{Decreased Number and Expression of nNOS-Positive Interneurons in Basolateral Amygdala in Two Mouse Models of Autism}}. {Front Cell Neurosci};2018;12:251.
The basolateral amygdala (BLA) controls socio-emotional behaviors and is involved in the etiology of autism. We have recently shown that virtually every neuronal nitric oxide synthase (nNOS) positive cell is a GABAergic inhibitory interneuron in the mouse BLA. Here, stereology was used to quantify the number of nNOS-expressing interneurons in valproic acid (VPA)-exposed C57BL/6J (B6) and BTBR T(+)Itpr3(tf)/J (BTBR) mice models of autism. Additionally, the protein and mRNA levels of nNOS in the BLA were quantitatively assessed by western blot and qRT-PCR analysis, respectively. Our results showed the decreased number of nNOS interneurons in the BLA of animal models relative to autism. Consistently, nNOS was significantly reduced in the VPA-exposed and BTBR mice at both protein and mRNA levels. Together, these preliminary findings suggest that down-regulation of nNOS may be an attractive target for the pharmacological intervention in autism.
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27. Ye D, Tester DJ, Zhou W, Papagiannis J, Ackerman MJ. {{A Pore-Localizing CACNA1C-E1115K Missense Mutation, Identified in a Patient with Idiopathic QT Prolongation, Bradycardia, and Autism Spectrum Disorder, Converts the L-type Calcium Channel into a Hybrid Non-Selective Monovalent Cation Channel}}. {Heart Rhythm};2018 (Aug 29)
BACKGROUND: Gain-of-function variants in the CACNA1C-encoded L-type calcium channel (LTCC, Cav1.2) cause type 8 long QT syndrome (LQT8). The pore region contains highly conserved glutamic acid (E) residues that collectively form the LTCC’s selectivity filter. Here, we identified and characterized a pore-localizing missense variant, E1115K, that yielded a novel perturbation in the LTCC. OBJECTIVE: To determine whether CACNA1C-E1115K alters LTCC selectivity and is the substrate for the patient’s LQTS. METHODS: The proband was a 14-year-old male with idiopathic QT prolongation and bradycardia. Genetic testing revealed a missense variant, CACNA1C-E1115K. Whole-cell patch clamp technique was used to measure CACNA1C-WT and -E1115K currents when heterologously expressed in TSA201 cells. RESULTS: The CACNA1C-E1115K channel exhibited no inward calcium current. Instead, robust Ito-like outward currents which were blocked significantly by nifedipine were measured when extracellular/intracellular 2 mM/0.1 mM CaCl2 or 4 mM/141 mM KCl were applied. Further, when 140 mM extracellular NaCl was applied, the CACNA1C-E1115K channel revealed both robust inward persistent Na(+) current with slower inactivation and outward current which were also nifedipine sensitive. In contrast, CACNA1C-WT only revealed a small inward persistent Na(+) current without robust outward current. CONCLUSIONS: This CACNA1C-E1115K variant destroyed the LTCC’s calcium selectivity and instead converted the mutant channel into a channel with a marked increase in sodium-mediated inward current and potassium -mediated outward currents. Despite the anticipated 50% reduction in LTCC, the creation of a new population of channels with accentuated inward and outward currents represents the likely pathogenic substrates for the patient’s LQTS and arrhythmia phenotype.
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28. Zappulo E, Riccio MP, Binda S, Pellegrinelli L, Pregliasco F, Buonomo AR, Pinchera B, D’Urso G, Bravaccio C, Borgia G, Gentile I. {{Prevalence of HSV1/2 Congenital Infection Assessed Through Genome Detection on Dried Blood Spot in Individuals with Autism Spectrum Disorders}}. {In Vivo};2018 (Sep-Oct);32(5):1255-1258.
BACKGROUND/AIM: Etiopathogenesis of autism spectrum disorders (ASD) remains to be elucidated. Congenital infections, particularly viral infections, have repeatedly been associated with the onset of such disorders. Our study aimed at assessing the prevalence of herpes simplex type 1 and 2 (HSV1/2) congenital infections in patients with ASD. MATERIALS AND METHODS: In our case-control study, a total of 38 children with ASD were compared to 44 age- and sex-matched controls regarding the presence of HSV1/2 infection though viral DNA polymerase chain reaction performed on dried blood spots collected at birth. RESULTS: No HSV congenital infection was detected in either group. CONCLUSION: Our negative finding is in agreement with other studies that failed to demonstrate a definitive role of HSV on the onset of ASD. Further investigation of congenital HSV prevalence in larger and more powerful studies is needed to undeniably discard a role of such virus in the etiopathogenesis of ASD.
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29. Zhang L, Liu L, Wen Y, Ma M, Cheng S, Yang J, Li P, Cheng B, Du Y, Liang X, Zhao Y, Ding M, Guo X, Zhang F. {{Genome-Wide Association Study and Identification of Chromosomal Enhancer Maps in Multiple Brain Regions Related to Autism Spectrum Disorder}}. {Autism Res};2018 (Aug 29)
Autism spectrum disorder (ASD) is a complex developmental disorder with strong genetic components involved. Recent studies have demonstrated the importance of non-coding regulatory variants for complex diseases. To explore the roles of chromosomal enhancer regions in the pathogenesis of ASD, we conducted an integrative analysis of genome-wide association study (GWAS) and brain region related enhancer-gene networks for ASD. The GWAS data of ASD were driven from a published study, involving 7,387 ASD cases and 8,567 controls. The enhancer-gene networks of eight brain regions were used here. The GWAS of ASD was first merged respectively with the enhancer datasets of eight brain regions. Pathway enrichment analysis was then performed to detect ASD associated pathways based on the enhancer-related single nucleotide polymorphism (SNPs) of each brain region. We detected multiple genes with brain region specific or common association signals, such as PGM3 (P value = 1.93 x 10(-5) ) and RWDD2A (P value = 1.93 x 10(-5) ) for hippocampus middle, and ENPP4 (all P values <0.05), and ENPP5 (all P values <0.05) for seven brain regions. By comparing the pathway enrichment analysis results of various brain regions, several cross brain regions pathways were detected for ASD, such as REACTOME_POTASSIUM_CHANNELS (all P values <0.05) for six brain regions and KEGG_CELL_ADHESION_MOLECULES_CAMS (all P values <0.05) for seven brain regions. In addition, several pathways were also identified for specific brain regions, such as REACTOME_CD28_DEPENDENT_PI3K_AKT_SIGNALING (P value = 4.00 x 10(-3) ) for angular gyrus, REACTOME_SIGNALING_BY_CONSTITUTIVELY_ACTIVE_EGFR (P value = 2.22 x 10(-3) ) for anterior caudate, and KEGG_PRION_DISEASES (P value = 1.00 x 10(-4) ) for germinal matrix. Our results provide novel clues for understanding the genetic basis of ASD. LAY SUMMARY: ASD is a complex developmental disorder with strong genetic components, but the pathogenesis of ASD is still unclear. Using the latest GWAS data and enhancer map, we explored the brain region related biological pathways associated with ASD. Our results provide novel clues for revealing the functional relevance of enhancer variants with ASD and understanding the genetic basis of ASD. Lien vers le texte intégral (Open Access ou abonnement)
