1. Bhatt P, Patel A, Kumar V, Lekshminarayanan A, Patel V, Alapati S, Billimoria ZC. {{Impact of hospital volume on outcomes of percutaneous ASD/PFO closure in pediatric patients}}. {World journal of pediatrics : WJP}. 2018.
BACKGROUND: We investigated the effect of hospital volume on percutaneous closure of atrial septal defect/patent foramen ovale (ASD) among pediatric patients. METHODS: We identified patients undergoing percutaneous closure of ASD with device using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) procedure code 35.52 from the National Inpatient Sample, years 2002-2011. Patients with age Lien vers le texte intégral (Open Access ou abonnement)
2. Bolton TAW, Jochaut D, Giraud AL, Van De Ville D. {{Brain dynamics in ASD during movie-watching show idiosyncratic functional integration and segregation}}. {Hum Brain Mapp}. 2018.
To refine our understanding of autism spectrum disorders (ASD), studies of the brain in dynamic, multimodal and ecological experimental settings are required. One way to achieve this is to compare the neural responses of ASD and typically developing (TD) individuals when viewing a naturalistic movie, but the temporal complexity of the stimulus hampers this task, and the presence of intrinsic functional connectivity (FC) may overshadow movie-driven fluctuations. Here, we detected inter-subject functional correlation (ISFC) transients to disentangle movie-induced functional changes from underlying resting-state activity while probing FC dynamically. When considering the number of significant ISFC excursions triggered by the movie across the brain, connections between remote functional modules were more heterogeneously engaged in the ASD population. Dynamically tracking the temporal profiles of those ISFC changes and tying them to specific movie subparts, this idiosyncrasy in ASD responses was then shown to involve functional integration and segregation mechanisms such as response inhibition, background suppression, or multisensory integration, while low-level visual processing was spared. Through the application of a new framework for the study of dynamic experimental paradigms, our results reveal a temporally localized idiosyncrasy in ASD responses, specific to short-lived episodes of long-range functional interplays.
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3. Braam W, Ehrhart F, Maas A, Smits MG, Curfs L. {{Low maternal melatonin level increases autism spectrum disorder risk in children}}. {Res Dev Disabil}. 2018.
BACKGROUND: It is assumed that autism spectrum disorder (ASD) is caused by a combination of de novo inherited variation and common variation as well as environmental factors. It often co-occurs with intellectual disability (ID). Almost eight hundred potential causative genetic variations have been found in ASD patients. However, not one of them is responsible for more than 1% of ASD cases. Low melatonin levels are a frequent finding in ASD patients. Melatonin levels are negatively correlated with severity of autistic impairments, it is important for normal neurodevelopment and is highly effective in protecting DNA from oxidative damage. Melatonin deficiency could be a major factor, and well a common heritable variation, that increases the susceptibility to environmental risk factors for ASD. ASD is already present at birth. As the fetus does not produce melatonin, low maternal melatonin levels may be involved. METHODS: We measured 6-sulfatoxymelatonin in urine of 60 mothers of a child with ASD and controls. RESULTS: 6-sulfatoxymelatonin levels were significantly lower in mothers with an ASD child than in controls (p=0.012). CONCLUSIONS: Low parental melatonin levels could be one of the contributors to ASD and possibly ID etiology. Our findings need to be duplicated on a larger scale. If our hypothesis is correct, this could lead to policies to detect future parents who are at risk and to treatment strategies to ASD and intellectual disability risk.
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4. Cai Y, Tang X, Chen X, Li X, Wang Y, Bao X, Wang L, Sun D, Zhao J, Xing Y, Warner M, Xu H, Gustafsson JA, Fan X. {{Liver X receptor beta regulates the development of the dentate gyrus and autistic-like behavior in the mouse}}. {Proceedings of the National Academy of Sciences of the United States of America}. 2018.
The dentate gyrus (DG) of the hippocampus is a laminated brain region in which neurogenesis begins during early embryonic development and continues until adulthood. Recent studies have implicated that defects in the neurogenesis of the DG seem to be involved in the genesis of autism spectrum disorders (ASD)-like behaviors. Liver X receptor beta (LXRbeta) has recently emerged as an important transcription factor involved in the development of laminated CNS structures, but little is known about its role in the development of the DG. Here, we show that deletion of the LXRbeta in mice causes hypoplasia in the DG, including abnormalities in the formation of progenitor cells and granule cell differentiation. We also found that expression of Notch1, a central mediator of progenitor cell self-renewal, is reduced in LXRbeta-null mice. In addition, LXRbeta deletion in mice results in autistic-like behaviors, including abnormal social interaction and repetitive behavior. These data reveal a central role for LXRbeta in orchestrating the timely differentiation of neural progenitor cells within the DG, thereby providing a likely explanation for its association with the genesis of autism-related behaviors in LXRbeta-deficient mice.
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5. Ferri SL, Abel T, Brodkin ES. {{Sex Differences in Autism Spectrum Disorder: a Review}}. {Curr Psychiatry Rep}. 2018; 20(2): 9.
PURPOSE OF REVIEW: Neurodevelopmental disorders disproportionately affect males. The mechanisms underlying male vulnerability or female protection are not known and remain understudied. Determining the processes involved is crucial to understanding the etiology and advancing treatment of neurodevelopmental disorders. Here, we review current findings and theories that contribute to male preponderance of neurodevelopmental disorders, with a focus on autism. RECENT FINDINGS: Recent work on the biological basis of the male preponderance of autism and other neurodevelopmental disorders includes discussion of a higher genetic burden in females and sex-specific gene mutations or epigenetic changes that differentially confer risk to males or protection to females. Other mechanisms discussed are sex chromosome and sex hormone involvement. Specifically, fetal testosterone is involved in many aspects of development and may interact with neurotransmitter, neuropeptide, or immune pathways to contribute to male vulnerability. Finally, the possibilities of female underdiagnosis and a multi-hit hypothesis are discussed. This review highlights current theories of male bias in developmental disorders. Topics include environmental, genetic, and epigenetic mechanisms; theories of sex chromosomes, hormones, neuroendocrine, and immune function; underdiagnosis of females; and a multi-hit hypothesis.
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6. Lashewicz B. {{Our Ultimate Fellow Travelers: A Pilot Exploration of Sibling Support for Adults with Developmental Disabilities}}. {Issues in mental health nursing}. 2018: 1-7.
People with developmental disabilities often experience needs for support that extend beyond the caregiving capacity of their aging parents and their siblings tend to be looked to as next-generation support providers. Yet, sibling support relationships are distinct for their simultaneously obligatory and voluntary nature. This pilot exploration, using in-depth focus group data from five siblings of people with developmental disabilities, is aimed at enriching understandings of the nature of, and expectations surrounding, sibling support for brothers and sisters with developmental disabilities. Findings reflect how sibling support evolves over time and can manifest in siblings assuming roles of: 1-companion and protector, 2-follower, 3-caregiver, and 4-within family protector. Siblings are a vital resource, yet not one that can be assumed as automatically forthcoming.
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7. Liu Y, Cao Y, Li Y, Lei D, Li L, Hou ZL, Han S, Meng M, Shi J, Zhang Y, Wang Y, Niu Z, Xie Y, Xiao B, Wang Y, Li X, Yang L, Wang W, Jiang L. {{Novel Genetic Variants of Sporadic Atrial Septal Defect (ASD) in a Chinese Population Identified by Whole-Exome Sequencing (WES)}}. {Medical science monitor : international medical journal of experimental and clinical research}. 2018; 24: 1340-58.
BACKGROUND Recently, mutations in several genes have been described to be associated with sporadic ASD, but some genetic variants remain to be identified. The aim of this study was to use whole-exome sequencing (WES) combined with bioinformatics analysis to identify novel genetic variants in cases of sporadic congenital ASD, followed by validation by Sanger sequencing. MATERIAL AND METHODS Five Han patients with secundum ASD were recruited, and their tissue samples were analyzed by WES, followed by verification by Sanger sequencing of tissue and blood samples. Further evaluation using blood samples included 452 additional patients with sporadic secundum ASD (212 male and 240 female patients) and 519 healthy subjects (252 male and 267 female subjects) for further verification by a multiplexed MassARRAY system. Bioinformatic analyses were performed to identify novel genetic variants associated with sporadic ASD. RESULTS From five patients with sporadic ASD, a total of 181,762 genomic variants in 33 exon loci, validated by Sanger sequencing, were selected and underwent MassARRAY analysis in 452 patients with ASD and 519 healthy subjects. Three loci with high mutation frequencies, the 138665410 FOXL2 gene variant, the 23862952 MYH6 gene variant, and the 71098693 HYDIN gene variant were found to be significantly associated with sporadic ASD (P<0.05); variants in FOXL2 and MYH6 were found in patients with isolated, sporadic ASD (P<5x10^-4). CONCLUSIONS This was the first study that demonstrated variants in FOXL2 and HYDIN associated with sporadic ASD, and supported the use of WES and bioinformatics analysis to identify disease-associated mutations. Lien vers Pubmed
8. Medina MA, Andrade VM, Caracci MO, Avila ME, Verdugo DA, Vargas MF, Ugarte GD, Reyes AE, Opazo C, De Ferrari GV. {{Wnt/beta-catenin signaling stimulates the expression and synaptic clustering of the autism-associated Neuroligin 3 gene}}. {Translational psychiatry}. 2018; 8(1): 45.
Synaptic abnormalities have been described in individuals with autism spectrum disorders (ASD). The cell-adhesion molecule Neuroligin-3 (Nlgn3) has an essential role in the function and maturation of synapses and NLGN3 ASD-associated mutations disrupt hippocampal and cortical function. Here we show that Wnt/beta-catenin signaling increases Nlgn3 mRNA and protein levels in HT22 mouse hippocampal cells and primary cultures of rat hippocampal neurons. We characterized the activity of mouse and rat Nlgn3 promoter constructs containing conserved putative T-cell factor/lymphoid enhancing factor (TCF/LEF)-binding elements (TBE) and found that their activity is significantly augmented in Wnt/beta-catenin cell reporter assays. Chromatin immunoprecipitation (ChIP) assays and site-directed mutagenesis experiments revealed that endogenous beta-catenin binds to novel TBE consensus sequences in the Nlgn3 promoter. Moreover, activation of the signaling cascade increased Nlgn3 clustering and co- localization with the scaffold PSD-95 protein in dendritic processes of primary neurons. Our results directly link Wnt/beta-catenin signaling to the transcription of the Nlgn3 gene and support a functional role for the signaling pathway in the dysregulation of excitatory/inhibitory neuronal activity, as is observed in animal models of ASD.
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9. Nordahl-Hansen A, Hart L, Oien RA. {{The Scientific Study of Parents and Caregivers of Children with ASD: A Flourishing Field but Still Work to be Done}}. {J Autism Dev Disord}. 2018.
There is a long history of research on parents and caregivers of individuals within autism. Parents and other primary caregivers typically play the most important part in the lives of persons with ASD although the need for support as the child becomes of age varies widely. This special issue includes 30 articles on central areas related to parenting and caregiving for people with ASD. Some of the key themes include intervention and training, mental health issues related to parent and family stress, measurement and assessment, and parent-child transactional processes. Other articles in this issue consider different but equally important topics such as sibling as potential future caregivers and parent support of preschool peer relationships.
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10. Romero V, Fitzpatrick P, Roulier S, Duncan A, Richardson MJ, Schmidt RC. {{Evidence of embodied social competence during conversation in high functioning children with autism spectrum disorder}}. {PLoS One}. 2018; 13(3): e0193906.
Even high functioning children with Autism Spectrum Disorder (ASD) exhibit impairments that affect their ability to carry out and maintain effective social interactions in multiple contexts. One aspect of subtle nonverbal communication that might play a role in this impairment is the whole-body motor coordination that naturally arises between people during conversation. The current study aimed to measure the time-dependent, coordinated whole-body movements between children with ASD and a clinician during a conversational exchange using tools of nonlinear dynamics. Given the influence that subtle interpersonal coordination has on social interaction feelings, we expected there to be important associations between the dynamic motor movement measures introduced in the current study and the measures used traditionally to categorize ASD impairment (ADOS-2, joint attention and theory of mind). The study found that children with ASD coordinated their bodily movements with a clinician, that these movements were complex and that the complexity of the children’s movements matched that of the clinician’s movements. Importantly, the degree of this bodily coordination was related to higher social cognitive ability. This suggests children with ASD are embodying some degree of social competence during conversations. This study demonstrates the importance of further investigating the subtle but important bodily movement coordination that occurs during social interaction in children with ASD.
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11. Rutherford M, Forsyth K, McKenzie K, McClure I, Murray A, McCartney D, Irvine L, O’Hare A. {{Implementation of a Practice Development Model to Reduce the Wait for Autism Spectrum Diagnosis in Adults}}. {J Autism Dev Disord}. 2018.
This study examined waiting times for diagnostic assessment of Autism Spectrum Disorder in 11 adult services, prior to and following the implementation of a 12 month change program. Methods to support change are reported and a multi-level modelling approach determined the effect of the change program on overall wait times. Results were statistically significant (b = – 0.25, t(136) = – 2.88, p = 0.005). The average time individuals waited for diagnosis across all services reduced from 149.4 days prior to the change program and 119.5 days after it, with an average reduction of 29.9 days overall. This innovative intervention provides a promising framework for service improvement to reduce the wait for diagnostic assessment of ASD in adults across the range of spectrum presentations.
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12. Saikusa T, Hara M, Iwama K, Yuge K, Ohba C, Okada JI, Hisano T, Yamashita Y, Okamoto N, Saitsu H, Matsumoto N, Matsuishi T. {{De novo HDAC8 mutation causes Rett-related disorder with distinctive facial features and multiple congenital anomalies}}. {Brain Dev}. 2018.
We present a unique 11-year-old girl showing clinical features of Rett-related disorder with distinctive facial features and multiple congenital anomalies including ocular hypertelorism, arched eyebrows, a broad nose, dental anomalies, congenital heart disease, truncal obesity, and epilepsy. A novel de novo mutation in histone deacetylase 8 (HDAC8) (c.652G>T, p.Gly218Cys) was confirmed by whole exome sequencing and Sanger sequencing. X-chromosome inactivation analysis on DNA isolated from peripheral blood lymphocytes revealed a completely skewed pattern associated with an inactive maternal allele. Late clinical loss of acquired purposeful hand movements and psychomotor deterioration may be a feature of Rett-related disorder, while distinctive facial features and multiple congenital anomalies are reminiscent of Cornelia de Lange syndrome.
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13. Talebizadeh Z, Shah A. {{Building a Bridge Between Genetics and Outcomes Research: Application in Autism (The AutGO Study)}}. {The patient}. 2018.
BACKGROUND: Concerns over the need to improve translational aspects of genetics research studies and engaging community members in the research process have been noted in the literature and raised by patient advocates. In addition to the work done by patient advocacy groups, organizations such as the Patient-Centered Outcomes Research Institute advocate for a change in the culture of research from being researcher-driven to becoming more patient-driven. OBJECTIVE: Our project, Autism Genetics and Outcomes (AutGO), consists of two phases. The goal for phase I was to initiate a general discussion around the main topic (i.e., linking genetics and outcomes research). We used the Patient-Centered Outcomes Research Institute engagement approach to: (aim 1) develop a partnership with a wide range of stakeholders to assess their perspective on developing projects that use both genetics and outcomes research data/principles; (aim 2) identify barriers, facilitators, and needs to promote engagement in patient-centered genetics research; and (aim 3) distill and describe actions that may facilitate utilization of patient/parent perspectives in designing genetics research studies. METHODS: In phase I, we formed a community advisory board composed of 33 participants, including outcomes and genetics researchers, clinicians, healthcare providers, patients/family members, and community/industry representatives, and convened six sessions over the 12-month period. We structured the sessions as a combination of online PowerPoint presentations, surveys, and in-person group discussions. During the sessions, we discussed topics pertaining to linking genetics and outcomes research and reviewed relevant materials, including patient stories, research projects, and existing resources. RESULTS: Two sets of surveys, project evaluations (k = 2) and session evaluations (k = 6), were distributed among participants. Feedback was analyzed using content analysis strategies to identify the themes and subthemes. Herein, we describe: the established partnership (aim 1), the identified barriers, facilitators, and needs (aim 2), as well as the lessons learned and suggested recommendations for the research community (aim 3). Following phase I participants’ recommendation, in phase II, we will focus on a specific disease (i.e., autism); this projected plan is briefly outlined to highlight the overarching goal of the project and its potential significance. We also discuss the study limitations, challenges for conducting this type of multidisciplinary work, as well as potential ways to address them. CONCLUSIONS: The AutGO project has created a unique collaborative forum to facilitate the much needed dialogue between genetics and outcomes researchers, which may contribute to finding ways to improve the translational aspects of genetics research studies.
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14. Tanaka A, Furubayashi T, Arai M, Inoue D, Kimura S, Kiriyama A, Kusamori K, Katsumi H, Yutani R, Sakane T, Yamamoto A. {{Delivery of Oxytocin to the Brain for the Treatment of Autism Spectrum Disorder by Nasal Application}}. {Molecular pharmaceutics}. 2018; 15(3): 1105-11.
Oxytocin (OXT) is a cyclic nonapeptide, two amino acids of which are cysteine, forming an intramolecular disulfide bond. OXT is produced in the hypothalamus and is secreted into the bloodstream from the posterior pituitary. As recent studies have suggested that OXT is a neurotransmitter exhibiting central effects important for social deficits, it has drawn much attention as a drug candidate for the treatment of autism. Although human-stage clinical trials of the nasal spray of OXT for the treatment of autism have already begun, few studies have examined the pharmacokinetics and brain distribution of OXT after nasal application. The aim of this study is to evaluate the disposition, nasal absorption, and therapeutic potential of OXT after nasal administration. The pharmacokinetics of OXT after intravenous bolus injection to rats followed a two-compartment model, with a rapid initial half-life of 3 min. The nasal bioavailability of OXT was approximately 2%. The brain concentration of OXT after nasal application was much higher than that after intravenous application, despite much lower concentrations in the plasma. More than 95% of OXT in the brain was directly transported from the nasal cavity. The in vivo stress-relief effect by OXT was observed only after intranasal administration. These results indicate that pharmacologically active OXT was effectively delivered to the brain after intranasal administration. In conclusion, the nasal cavity is a promising route for the efficient delivery of OXT to the brain.
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15. Tuffrey-Wijne I, Curfs L, Finlay I, Hollins S. {{Euthanasia and assisted suicide for people with an intellectual disability and/or autism spectrum disorder: an examination of nine relevant euthanasia cases in the Netherlands (2012-2016)}}. {BMC medical ethics}. 2018; 19(1): 17.
BACKGROUND: Euthanasia and assisted suicide (EAS) have been legally possible in the Netherlands since 2001, provided that statutory due care criteria are met, including: (a) voluntary and well-considered request; (b) unbearable suffering without prospect of improvement; (c) informing the patient; (d) lack of a reasonable alternative; (e) independent second physician’s opinion. ‘Unbearable suffering’ must have a medical basis, either somatic or psychiatric, but there is no requirement of limited life expectancy. All EAS cases must be reported and are scrutinised by regional review committees (RTE). The purpose of this study was to investigate whether any particular difficulties arise when the EAS due care criteria are applied to patients with an intellectual disability and/or autism spectrum disorder. METHODS: The 416 case summaries available on the RTE website (2012-2016) were searched for intellectual disability (6) and autism spectrum disorder (3). Direct content analysis was used on these nine cases. RESULTS: Assessment of decisional capacity was mentioned in eight cases, but few details given; in two cases, there had been uncertainty or disagreement about capacity. Two patients had progressive somatic conditions. For most, suffering was due to an inability to cope with changing circumstances or increasing dependency; in several cases, suffering was described in terms of characteristics of living with an autism spectrum disorder, rather than an acquired medical condition. Some physicians struggled to understand the patient’s perspective. Treatment refusal was a common theme, leading physicians to conclude that EAS was the only remaining option. There was a lack of detail on social circumstances and how patients were informed about their prognosis. CONCLUSIONS: Autonomy and decisional capacity are highly complex for patients with intellectual disabilities and difficult to assess; capacity tests in these cases did not appear sufficiently stringent. Assessment of suffering is particularly difficult for patients who have experienced life-long disability. The sometimes brief time frames and limited number of physician-patient meetings may not be sufficient to make a decision as serious as EAS. The Dutch EAS due care criteria are not easily applied to people with intellectual disabilities and/or autism spectrum disorder, and do not appear to act as adequate safeguards.
