1. Berry-Kravis EM, Lindemann L, Jonch AE, Apostol G, Bear MF, Carpenter RL, Crawley JN, Curie A, Des Portes V, Hossain F, Gasparini F, Gomez-Mancilla B, Hessl D, Loth E, Scharf SH, Wang PP, Von Raison F, Hagerman R, Spooren W, Jacquemont S. {{Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome}}. {Nat Rev Drug Discov};2017 (Dec 8)
Neurodevelopmental disorders such as fragile X syndrome (FXS) result in lifelong cognitive and behavioural deficits and represent a major public health burden. FXS is the most frequent monogenic form of intellectual disability and autism, and the underlying pathophysiology linked to its causal gene, FMR1, has been the focus of intense research. Key alterations in synaptic function thought to underlie this neurodevelopmental disorder have been characterized and rescued in animal models of FXS using genetic and pharmacological approaches. These robust preclinical findings have led to the implementation of the most comprehensive drug development programme undertaken thus far for a genetically defined neurodevelopmental disorder, including phase IIb trials of metabotropic glutamate receptor 5 (mGluR5) antagonists and a phase III trial of a GABAB receptor agonist. However, none of the trials has been able to unambiguously demonstrate efficacy, and they have also highlighted the extent of the knowledge gaps in drug development for FXS and other neurodevelopmental disorders. In this Review, we examine potential issues in the previous studies and future directions for preclinical and clinical trials. FXS is at the forefront of efforts to develop drugs for neurodevelopmental disorders, and lessons learned in the process will also be important for such disorders.
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2. Carter Leno V, Chandler S, White P, Pickles A, Baird G, Hobson C, Smith AB, Charman T, Rubia K, Simonoff E. {{Testing the specificity of executive functioning impairments in adolescents with ADHD, ODD/CD and ASD}}. {Eur Child Adolesc Psychiatry};2017 (Dec 9)
Current diagnostic systems conceptualise attention deficit hyperactivity disorder (ADHD), oppositional defiant/conduct disorder (ODD/CD) and autism spectrum disorder (ASD) as separate diagnoses. However, all three demonstrate executive functioning (EF) impairments. Whether these impairments are trans-diagnostic or disorder-specific remains relatively unexplored. Four groups of 10-16 year-olds [typically developing (TD; N = 43), individuals clinically diagnosed with ADHD (N = 21), ODD/CD (N = 26) and ASD (N = 41)] completed Go/NoGo and Switch tasks. Group differences were tested using analysis of co-variance (ANCOVA) including age, IQ, sex, conduct problems and ADHD symptoms as co-variates. Results indicated some disorder-specificity as only the ASD group demonstrated decreased probability of inhibition in the Go/NoGo task compared to all other groups. However, shared impairments were also found; all three diagnostic groups demonstrated increased reaction time variability (RTV) compared to the TD group, and both the ODD/CD and the ASD group demonstrated increased premature responses. When controlling for ADHD symptoms and conduct problems, group differences in RTV were no longer significant; however, the ASD group continued to demonstrate increased premature responses. No group differences were found in cognitive flexibility in the Switch task. A more varied response style was present across all clinical groups, although this appeared to be accounted for by sub-threshold ODD/CD and ADHD symptoms. Only the ASD group was impaired in response inhibition and premature responsiveness relative to TD adolescents. The findings suggest that some EF impairments typically associated with ADHD may also be found in individuals with ASD.
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3. Chukoskie L, Westerfield M, Townsend J. {{A novel approach to training attention and gaze in ASD: A feasibility and efficacy pilot study}}. {Dev Neurobiol};2017 (Dec 8)
In addition to the social, communicative and behavioral symptoms that define the disorder, individuals with ASD have difficulty re-orienting attention quickly and accurately. Similarly, fast re-orienting saccadic eye movements are also inaccurate and more variable in both endpoint and timing. Atypical gaze and attention are among the earliest symptoms observed in ASD. Disruption of these foundation skills critically affects the development of higher level cognitive and social behavior. We propose that interventions aimed at these early deficits that support social and cognitive skills will be broadly effective. We conducted a pilot clinical trial designed to demonstrate the feasibility and preliminary efficacy of using gaze-contingent video games for low-cost in-home training of attention and eye movement. Eight adolescents with ASD participated in an 8-week training, with pre-, mid- and post-testing of eye movement and attention control. Six of the eight adolescents completed the 8 weeks of training and all six showed improvement in attention (orienting, disengagement) and eye movement control or both. All game systems remained intact for the duration of training and all participants could use the system independently. We delivered a robust, low-cost, gaze-contingent game system for home use that, in our pilot training sample, improved the attention orienting and eye movement performance of adolescent participants in 8 weeks of training. We are currently conducting a clinical trial to replicate these results and to examine what, if any, aspects of training transfer to more real-world tasks. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol, 2017.
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4. Gabis LV, Hochberg O, Leon Attia O, Banet-Levi Y, Topf D, Shefer S. {{Prolonged Time Lag to Final Diagnosis of Fragile X Syndrome}}. {J Pediatr};2017 (Dec 5)
OBJECTIVE: To evaluate the diagnostic process in children ultimately diagnosed with fragile X syndrome (FXS), with an emphasis on the time lag between initial presentation and on diagnosis in female vs male children. STUDY DESIGN: Interviews were conducted with 89 families of children with a final diagnosis of FXS and assessment of time intervals between initial presentation and confirmed molecular diagnosis. RESULTS: Screening of 117 patients (25 female patients) from the 89 families revealed that less than 20% of patients obtained a diagnosis within the first year of seeking medical attention. Mean age at the time of initial presentation was 12.3 months in male patients and 23 months in female patients, while definitive diagnosis of FXS was made at a mean of 4 and 9 years, respectively. Presenting symptoms of developmental delays were recognized by 72% of parents, and 84% had another child with FXS before the index case diagnosis. Average age of diagnosis for children with FXS born since 2007 was significantly lower at 31.9 months, compared with 69.5 months for children born before 2007. CONCLUSIONS: Although FXS is a significant and prevalent cause of disability in children, it is underdiagnosed and diagnosed late, especially in female patients. In every male and female patient presenting with developmental delay or autism, FXS should be considered. Dysmorphic physical features may not be present in infancy, and the absence of those features cannot exclude a diagnosis of FXS.
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5. Guan J, Li G. {{Characteristics of unintentional drowning deaths in children with autism spectrum disorder}}. {Inj Epidemiol};2017 (Dec 8);4(1):32.
BACKGROUND: The reported prevalence of autism spectrum disorder (ASD) has increased markedly in the past two decades. Recent research indicates that children with ASD are at a substantially increased risk of injury mortality, particularly from unintentional drowning. The purpose of this study was to explore the circumstances of fatal unintentional drowning incidents involving children with ASD under 15 years of age. FINDINGS: During January 2000 through May 2017, US newspapers reported a total of 23 fatal drowning incidents involving 18 boys and 5 girls with ASD. Age of victims ranged from 3 to 14 years (mean = 7.7 +/- 2.9 years). These drowning incidents most commonly occurred in ponds (52.2%), followed by rivers (13.0%), and lakes (13.0%). For 11 incidents with location data available, the distance between victim residence and the water body where drowning occurred averaged 290.7 m (+/- 231.5 m). About three-quarters (73.3%) of the drowning incidents occurred in the afternoon hours from 12:00 to 18:59. Wandering was the most commonly reported activity that led to drowning, accounting for 73.9% of the incidents. CONCLUSIONS: Fatal drowning in children with ASD typically occur in water bodies near the victims’ homes in the afternoon hours precipitated by wandering. Multifaceted intervention programs are urgently needed to reduce the excess risk of drowning in children with ASD.
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6. Gupta A, Sun MW, Paskov KM, Stockham NT, Jung JY, Wall DP. {{Coalitional game theory as a promising approach to identify candidate autism genes}}. {Pac Symp Biocomput};2018;23:436-447.
Despite mounting evidence for the strong role of genetics in the phenotypic manifestation of Autism Spectrum Disorder (ASD), the specific genes responsible for the variable forms of ASD remain undefined. ASD may be best explained by a combinatorial genetic model with varying epistatic interactions across many small effect mutations. Coalitional or cooperative game theory is a technique that studies the combined effects of groups of players, known as coalitions, seeking to identify players who tend to improve the performance–the relationship to a specific disease phenotype–of any coalition they join. This method has been previously shown to boost biologically informative signal in gene expression data but to-date has not been applied to the search for cooperative mutations among putative ASD genes. We describe our approach to highlight genes relevant to ASD using coalitional game theory on alteration data of 1,965 fully sequenced genomes from 756 multiplex families. Alterations were encoded into binary matrices for ASD (case) and unaffected (control) samples, indicating likely gene-disrupting, inherited mutations in altered genes. To determine individual gene contributions given an ASD phenotype, a « player » metric, referred to as the Shapley value, was calculated for each gene in the case and control cohorts. Sixty seven genes were found to have significantly elevated player scores and likely represent significant contributors to the genetic coordination underlying ASD. Using network and cross-study analysis, we found that these genes are involved in biological pathways known to be affected in the autism cases and that a subset directly interact with several genes known to have strong associations to autism. These findings suggest that coalitional game theory can be applied to large-scale genomic data to identify hidden yet influential players in complex polygenic disorders such as autism.
7. Haq SS, Machalicek W, Garbacz SA, Drew C. {{Employing a Fixed-Lean Multiple Schedule in the Treatment of Challenging Behavior for Children With Autism Spectrum Disorder}}. {Behav Modif};2017 (Dec 1):145445517743206.
Despite its utility, there is limited applied research on employing fixed-lean (FL) schedules of reinforcement in treatment packages to address challenging behavior. One potential reason is that abrupt shifts to terminal schedules of reinforcement have been associated with immediate increases in challenging behavior before subsiding to clinically acceptable levels. The purpose of the present study was to (a) provide evidence demonstrating the utility of a FL multiple schedule (MS) in the treatment of challenging behavior in applied settings, (b) examine the potential effects of alternative stimuli on challenging behavior during a FL MS, and (c) assess the social validity of this treatment package with participants and caregivers. The results of this study showed low levels of challenging behavior and discriminated mands during the FL MS, but no evidence to support the inclusion of alternative stimuli. In addition, caregivers of both participants reported high levels of satisfaction with the treatment package. Implications for research and clinical practice are discussed.
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8. Janus M, Mauti E, Horner M, Duku E, Siddiqua A, Davies S. {{Behavior profiles of children with autism spectrum disorder in kindergarten: Comparison with other developmental disabilities and typically developing children}}. {Autism Res};2017 (Dec 8)
Monitoring behavior patterns that may be specific to autism spectrum disorder (ASD) at a population level has the potential to improve the allocation of intervention strategies and reduction of the burden of the disease. In Ontario, Canada, developmental data are regularly collected for all kindergarten children with the Early Development Instrument (EDI), a teacher-completed questionnaire that provides information on children’s status in five domains: physical, social, emotional, language/cognitive, and communication/general knowledge. Our main research questions are: (a) are there differences in kindergarten EDI domain scores between children who are diagnosed with ASD by Grade 3 and those who develop typically or have other disabilities?; (b) do these differences show a different pattern in relation to an early (by kindergarten) or late (by Grade 3) diagnosis?; and (c) are there specific subdomains on the EDI that demonstrate a consistent pattern of differences? EDI domain and subdomain scores were compared among groups using multivariate analysis of variance controlling for age, gender, EDI year, and EDI year by age interaction. Children with ASD, regardless of timing of identification, had significantly lower scores on all domains of the EDI than typically developing children. Children with later ASD diagnosis had higher scores in kindergarten in cognitive areas but lower scores in social-emotional areas than children with other disabilities. These findings support the potential of the EDI to monitor ASD-like behaviors at the population level. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Identifying behavior patterns among kindergarten children that may be specific to autism spectrum disorder (ASD) at a population level has the potential to improve intervention strategies and thus reduce the burden of the disease. In Ontario, Canada, developmental data are regularly collected with the Early Development Instrument (EDI) for all kindergarten children. The behavior in kindergarten of a sub-population of children diagnosed with developmental disabilities by age 9 is investigated here for patterns that may distinguish children with ASD from those with other disorders. Children with later ASD diagnosis had higher scores in kindergarten in cognitive areas but lower scores in social-emotional areas than children with other disabilities, indicating meaningful differences between those groups even before diagnosis. These results support the potential of using the EDI to monitor ASD-like behaviors at the population level.
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9. Kalkman HO, Feuerbach D. {{Microglia M2A Polarization as Potential Link between Food Allergy and Autism Spectrum Disorders}}. {Pharmaceuticals (Basel)};2017 (Dec 9);10(4)
Atopic diseases are frequently co-morbid with autism spectrum disorders (ASD). Allergic responses are associated with an activation of mast cells, innate lymphoid cells, and Th2 cells. These cells produce type-2 cytokines (IL4 and IL13), which stimulate microglia and macrophages to adopt a phenotype referred to as ‘alternative activation’ or ‘M2A’. M2A-polarized macrophages and microglia play a physiological role in tissue repair by secreting growth factors such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1. In ASD there is evidence for increased type-2 cytokines, microglia activation, M2A polarization, and increased levels of growth factors. In neurons, these growth factors drive a signal transduction pathway that leads to activation of the enzyme mammalian Target of Rapamycin (mTOR), and thereby to the inhibition of autophagy. Activation of mTOR is an effect that is also common to several of the genetic forms of autism. In the central nervous system, redundant synapses are removed via an autophagic process. Activation of mTOR would diminish the pruning of redundant synapses, which in the context of ASD is likely to be undesired. Based on this line of reasoning, atopic diseases like food allergy, eczema or asthma would represent risk factors for autism spectrum disorders.
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10. Mo W, Liu J, Zhang Z, Yu H, Yang A, Qu F, Hu P, Liu Z, Hu F. {{A study of single nucleotide polymorphisms in CD157, AIM2 and JARID2 genes in Han Chinese children with autism spectrum disorder}}. {Nord J Psychiatry};2017 (Dec 7):1-5.
PURPOSE: Autism spectrum disorder (ASD) is a group of developmental brain disorders caused by genetic and environmental factors. The objective of this study was to investigate whether single nucleotide polymorphisms (SNPs) in genes related to immune function were associated with ASD in Chinese Han children. MATERIALS AND METHODS: A total of 201 children with ASD and 200 age- and gender-matched healthy controls were recruited from September 2012 to June 2106. A TaqMan probe-based approach was used to genotype SNPs corresponding to rs28532698 and rs4301112 in CD157, rs855867 in AIM2, and rs2237126 in JARID2. Case-control and case-only studies were performed to determine the contribution of SNPs to the predisposition of disease and its severity, respectively. RESULTS: Our results revealed that the genotypes and allele frequencies of these SNPs were not significantly associated with childhood ASD and its severity in this population. CONCLUSIONS: Results of our study suggest that these SNPs are not predictors of childhood ASD in the Chinese Han population. The discrepant results suggest the predictor roles of SNPs have to be determined in different ethnic populations due to genetic heterogeneity of ASD.
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11. Steinmetz AB, Stern SA, Kohtz AS, Descalzi G, Alberini CM. {{Insulin-like Growth Factor II Targets the mTOR Pathway to Reverse Autism-like Phenotypes in Mice}}. {J Neurosci};2017 (Dec 7)
Autism spectrum disorder (ASD) is a developmental disability characterized by impairments in social interaction and repetitive behavior, and is also associated with cognitive deficits. There is no current treatment that can ameliorate most of the ASD symptomatology; thus, identifying novel therapies is urgently needed. We used male BTBR T(+)Itpr3(tf) /J (BTBR) mice, a model that reproduces most of the core behavioral phenotypes of ASD, to test the effects of systemic administration of insulin like growth factor II (IGF-II), a polypeptide that crosses the blood brain barrier and acts as a cognitive enhancer. We show that systemic IGF-II treatments reverse the typical defects in social interaction, cognitive/executive functions, and repetitive behaviors reflective of ASD-like phenotypes. In BTBR mice, IGF-II, via IGF-II- receptor, but not via IGF-I- receptor, reverses the abnormal levels of the AMPK-mTOR-S6K pathway and of active translation at synapses. Thus, IGF-II may represent a novel potential therapy for ASD.SIGNIFICANCE STATEMENTCurrently, there is no effective treatment for autism spectrum disorder (ASD), a developmental disability affecting a high number of children. Using a mouse model that expresses most of the key core as well as associated behavioral deficits of ASD, that are, social, cognitive, and repetitive behaviors, we report that a systemic administration of the polypeptide insulin like growth factor II (IGF-II) reverses all these deficits. The effects of IGF-II occur via IGF-II receptors, and not IGF-I receptors, and target both basal and learning-dependent molecular abnormalities found in several ASD mice models, including those of identified genetic mutations. We suggest that IGF-II represents a potential novel therapeutic target for ASD.
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12. Tan CD. {{« I’m a normal autistic person, not an abnormal neurotypical »: Autism Spectrum Disorder diagnosis as biographical illumination}}. {Soc Sci Med};2017 (Dec 9);197:161-167.
Building on Michael Bury’s « biographical disruption » and Kathy Charmaz’s « loss of self, » which describe the deteriorative impacts of chronic illness on perceptions of selfhood, I propose « biographical illumination »-a transformed conceptualization of self and identity that is facilitated by but extends beyond medical meaning, enriching personal biography and social relationships. The concept is perhaps most applicable to experiences with neurological and neurodevelopmental conditions in which brain difference and personhood are perceived to be closely intertwined. In this study, biographical illumination is used to describe the experiences of autistic adults who learned of their Autism Spectrum Disorder (ASD) diagnosis during teen years or adulthood. Through an ASD lens, participants found explanation for their atypicality and developed a more valued self-concept. Learning of the condition did not disrupt their biography; rather, it became integral to and constitutive of it. With a new self-concept, participants re-gauged personal expectations for normalization and accessed communities of alike others, forging relationships that affirmed identity.
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13. Walsh E, Holloway J, Lydon H. {{An Evaluation of a Social Skills Intervention for Adults with Autism Spectrum Disorder and Intellectual Disabilities preparing for Employment in Ireland: A Pilot Study}}. {J Autism Dev Disord};2017 (Dec 9)
Individuals with autism spectrum disorder (ASD) are faced with significant barriers relating to employment opportunities and workplace participation. This study evaluated the effectiveness of the Walker social skills curriculum: the ACCESS program and video modeling to increase social communication skills necessary for workplace inclusion. Participants attended two sessions (i.e., 3 h) per week across a period of 20 weeks. A multiple-probe design was used to demonstrate social skills outcomes across three broad curricular areas (i.e., peer-related, adult-related, and self-related social skills). Pre-and post-intervention standardized assessments were also taken. Results showed significant increases in target social skills and a significant decrease in problem behaviors following intervention. Evidence of maintenance and generalization were also demonstrated. Implications for practice and research are discussed.
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14. Wu H, Zhang Q, Gao J, Sun C, Wang J, Xia W, Cao Y, Hao Y, Wu L. {{Modulation of sphingosine 1-phosphate (S1P) attenuates spatial learning and memory impairments in the valproic acid rat model of autism}}. {Psychopharmacology (Berl)};2017 (Dec 7)
RATIONALE: Autism spectrum disorders (ASD) are a set of pervasive neurodevelopmental disorders that manifest in early childhood, and it is growing up to be a major cause of disability in children. However, the etiology and treatment of ASD are not well understood. In our previous study, we found that serum levels of sphingosine 1-phosphate (S1P) were increased significantly in children with autism, indicating that S1P levels may be involved in ASD. OBJECTIVE: The objective of this study was to identify a link between increased levels of S1P and neurobehavioral changes in autism. METHODS: We utilized a valproic acid (VPA) -induced rat model of autism to evaluate the levels of S1P and the expression of sphingosine kinase (SphK), a key enzyme for S1P production, in serum and hippocampal tissue. Furthermore, we assessed cognitive functional changes and histopathological and neurochemical alterations in VPA-exposed rats after SphK blockade to explore the possible link between increased levels of S1P and neurobehavioral changes in autism. RESULTS: We found that SphK2 and S1P are upregulated in hippocampal tissue from VPA-exposed rats, while pharmacological inhibition of SphK reduced S1P levels, attenuated spatial learning and memory impairments, increased the expression of phosphorylated CaMKII and CREB and autophagy-related proteins, inhibited cytochrome c release, decreased the expression of apoptosis related proteins, and protected against neuronal loss in the hippocampus. CONCLUSION: We have demonstrated that an increased level of SphK2/S1P is involved in the spatial learning and memory impairments of autism, and this signaling pathway represents a novel therapeutic target and direction for future studies.
