1. Avraham S, Almog B, Reches A, Zakar L, Malcov M, Sokolov A, Alpern S, Azem F. {{The ovarian response in fragile X patients and premutation carriers undergoing IVF-PGD: reappraisal}}. {Hum Reprod};2017 (May 03):1-4.
STUDY QUESTION: What is the association between the ovarian response and the number of CGG repeats among full mutation and premutation carriers of fragile X (FMR1), undergoing controlled ovarian hyperstimulation (COH) for PGD? SUMMARY ANSWER: Ovarian response was normal in full mutation patients but decreased in premutation carriers, although the number of repeats was not statistically significantly associated with the number of oocytes retrieved. WHAT IS KNOWN ALREADY: There is inconsistent data in the literature regarding ovarian response in FMR1 carriers. Studies exploring the ovarian response of full mutation patients are lacking. STUDY DESIGN, SIZE, DURATION: Retrospective study, a university affiliated tertiary hospital, IVF unit, PGD referral center. PARTICIPANTS/MATERIALS, SETTING, METHODS: We examined the medical records of all women undergoing fresh IVF-PGD cycles due to fragile X. Data recorded included demography, duration of stimulation, amount of gonadotropins administered, number of dominant follicles, maximal E2 levels and number of oocytes retrieved. Data were analyzed using univariate and multivariate mixed models. P-values <0.05 were considered significant. Data were collected from the medical records of 21 patients with a full mutation on the FMR1 gene and 51 premutation carriers. Overall 309 fresh cycles were analyzed. MAIN RESULTS AND THE ROLE OF CHANCE: Premutation carriers displayed reduced ovarian response, as demonstrated by fewer oocytes retrieved. In contrast, full mutation patients had a normal response. Comparison of premutation carriers and full mutation patients showed: mean oocytes retrieved per cycle (8.4 +/- 1.1 versus 14.1 +/- 1.7, P = 0.005), lower levels of estradiol (E2; 1756 +/- 177, versus 2928 +/- 263, P = 0.0004), respectively. There was no significant difference between premutation carriers and full mutation patients in regard to fertilization rate, cleavage rate or biopsy rate. No correlation was found between the number of repeats in the premutation carriers and the number of oocytes retrieved or E2 levels. Age and the type of protocol were the only factors found to be in correlation with the number of the oocyte retrieved (P = 0.037, and P = 0.003, respectively) among the premutation carriers. Similarly, no association was found between the number of repeats and the fertilization rate, cleavage rate or biopsy rate among premutation carriers. LIMITATIONS, REASONS FOR CAUTION: We had a relatively low number of premutation carriers with >100 repeats, which made it challenging to draw a firm conclusions from this group. WIDER IMPLICATIONS OF THE FINDINGS: Physicians must address the increased risk for reduced ovarian response and primary ovarian insufficiency (POI) among carriers and consider surveillance of ovarian reserve markers. The last, might expedite family plans completion or fertility preservation. STUDY FUNDING/COMPETING INTEREST(S): None.
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2. Ben-Ari Y. {{Progress in autism research and postgenomic studies}}. {Lancet Neurol};2016 (Feb);15(2):136.
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3. Berg AT, Dobyns WB. {{Progress in autism research and postgenomic studies – Authors’ reply}}. {Lancet Neurol};2016 (Feb);15(2):136-137.
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4. Cheak-Zamora NC, Teti M, Maurer-Batjer A, Koegler E. {{Exploration and Comparison of Adolescents With Autism Spectrum Disorder and Their Caregiver’s Perspectives on Transitioning to Adult Health Care and Adulthood}}. {J Pediatr Psychol};2017 (May 04)
Background : Adolescents with autism spectrum disorder (ASD) experience challenges achieving independence. Few studies assess both adolescents and caregivers’ needs as adolescents transition to adult health care. This study explored and compared the health-related independence experiences of 27 adolescents with ASD and their caregivers. Caregivers participated in focus groups and adolescents participated in semi-structured interviews. Thematic analysis of dyads’ responses highlighted three common themes: (a) efforts toward independence, (b) low self-efficacy for adolescents’ independence, and (c) desire for independence. Nuances in responses indicated that although members of dyads shared many experiences, they were not communicating these experiences with each other. Results suggest both groups understand the importance of health-related independence and are motivated to achieve independence but lack skills and supports. Improved communication about experiences and goals between caregivers, adolescents, and the care team are needed. These findings can inform future interventions to better support adolescents’ transition to adult health care.
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5. De Jaco A, Mango D, De Angelis F, Favaloro FL, Andolina D, Nistico R, Fiori E, Colamartino M, Pascucci T. {{Unbalance between Excitation and Inhibition in Phenylketonuria, a Genetic Metabolic Disease Associated with Autism}}. {Int J Mol Sci};2017 (Apr 29);18(5)
Phenylketonuria (PKU) is the most common genetic metabolic disease with a well-documented association with autism spectrum disorders. It is characterized by the deficiency of the phenylalanine hydroxylase activity, causing plasmatic hyperphenylalaninemia and variable neurological and cognitive impairments. Among the potential pathophysiological mechanisms implicated in autism spectrum disorders is the excitation/inhibition (E/I) imbalance which might result from alterations in excitatory/inhibitory synapse development, synaptic transmission and plasticity, downstream signalling pathways, and intrinsic neuronal excitability. Here, we investigated functional and molecular alterations in the prefrontal cortex (pFC) of BTBR-Pahenu2 (ENU2) mice, the animal model of PKU. Our data show higher frequency of inhibitory transmissions and significant reduced frequency of excitatory transmissions in the PKU-affected mice in comparison to wild type. Moreover, in the pFC of ENU2 mice, we reported higher levels of the post-synaptic cell-adhesion proteins neuroligin1 and 2. Altogether, our data point toward an imbalance in the E/I neurotransmission favouring inhibition in the pFC of ENU2 mice, along with alterations of the molecular components involved in the organization of cortical synapse. In addition to being the first evidence of E/I imbalance within cortical areas of a mouse model of PKU, our study provides further evidence of E/I imbalance in animal models of pathology associated with autism spectrum disorders.
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6. Durrleman S, Burnel M, Reboul A. {{Theory of mind in SLI revisited: links with syntax, comparisons with ASD}}. {Int J Lang Commun Disord};2017 (May 04)
BACKGROUND: According to the linguistic determinism approach, knowledge of sentential complements such as: John says that the earth is flat plays a crucial role in theory of mind (ToM) development by providing a means to represent explicitly people’s mental attitudes and beliefs. This approach predicts that mastery of complements determines successful belief reasoning across explicit ToM tasks, even low-verbal ones, and across populations. AIMS: (1) To investigate the link between a low-verbal ToM-task and complements in Specific Language Impairment (SLI), (2) To determine whether this population shows similar ToM performance to that of children with Autism Spectrum Disorder (ASD) or those with Typical Development (TD) once these groups are matched on competency for complements, (3) To explore whether complements conveying a falsehood without jeopardizing the veracity of the entire sentence, such as complements of verbs of communication, are more crucial for belief attribution than complements which do not have this property, namely complements of verbs of perception, (?John sees that the earth is flat). METHODS & PROCEDURES: Children with SLI (n = 20), with ASD (n = 34) and TD (n = 30) completed sentence-picture-matching tasks assessing complementation with communication and perception verbs, as well as a picture-sequencing task assessing ToM. Children were furthermore evaluated for general grammatical and lexical abilities and non-verbal IQ. OUTCOMES & RESULTS: Results reveal that competency on complements relates to ToM performance with a low-verbal task in SLI, and that SLI, ASD and TD groups of equivalent performance on complements also perform similarly for ToM. Results further suggest that complements with an independent truth-value are the only ones to show a significant relation to ToM performance after teasing out the impact of non-verbal reasoning. CONCLUSIONS & IMPLICATIONS: This study suggests that clinical groups of different aetiologies as well as TD children perform comparably for ToM once they have similar complementation skills. Findings further highlight that specific types of complements, namely those with an independent truth value, relate in a special way to mentalizing. Future work should determine whether these specific structures could be effective in ToM remediation programmes.
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7. Ferrarelli LK. {{Finding drugs for fragile X syndrome}}. {Science};2017 (May 05);356(6337):497-498.
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8. Flor J, Bellando J, Lopez M, Shui A. {{Developmental functioning and medical Co-morbidity profile of children with complex and essential autism}}. {Autism Res};2017 (May 05)
Children with Autism Spectrum Disorders (ASD) may be characterized as « complex » (those with microcephaly and/or dysmorphology) or « essential » (those with neither of these two). Previous studies found subjects in the complex group exhibited lower IQ scores, poorer response to behavioral intervention, more seizures and more abnormal EEGs and brain MRIs compared to the essential group. The objective of this study was to determine if there are differences in complex versus essential subjects based on several developmental/psychological measures as well as certain medical comorbidities. This study utilized data from 1,347 individuals (2-17 years old) well-characterized subjects enrolled in Autism Treatment Network (ATN) Registry. Head circumference measurement and the Autism Dysmorphology Measure (ADM) were used by trained physicians to classify subjects as complex or essential. Significantly lower scores were seen for complex subjects in cognitive level, adaptive behavior and quality of life. Complex subjects showed significantly increased physician-documented GI symptoms and were on a higher number of medications. No significant differences in autism severity scores, behavioral ratings and parent-reported sleep problems were found. After adjusting for multiple comparisons made, adaptive scores remained significantly lower for the complex group, and the complex group used a significantly higher number of medications and had increased GI symptoms. Complex and essential autism subtypes may have distinct developmental and medical correlates and thus underlines the importance of looking for microcephaly and dysmorphology, when evaluating a child with autism. Determining this distinction in autism may have implications in prognosis, identifying medical co-morbidities, directing diagnostic evaluations and treatment interventions. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc.
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9. Gladfelter A, Goffman L. {{Semantic richness and word learning in children with autism spectrum disorder}}. {Dev Sci};2017 (May 04)
Semantically rich learning contexts facilitate semantic, phonological, and articulatory aspects of word learning in children with typical development (TD). However, because children with autism spectrum disorder (ASD) show differences at each of these processing levels, it is unclear whether they will benefit from semantic cues in the same manner as their typical peers. The goal of this study was to track how the inclusion of rich, sparse, or no semantic cues influences semantic, phonological, and articulatory aspects of word learning in children with ASD and TD over time. Twenty-four school-aged children (12 in each group), matched on expressive vocabulary, participated in an extended word learning paradigm. Performance on five measures of learning (referent identification, confrontation naming, defining, phonetic accuracy, and speech motor stability) were tracked across three sessions approximately one week apart to assess the influence of semantic richness on extended learning. Results indicate that children with ASD benefit from semantically rich learning contexts similarly to their peers with TD; however, one key difference between the two groups emerged – the children with ASD showed heightened shifts in speech motor stability. These findings offer insights into common learning mechanisms in children with ASD and TD, as well as pointing to a potentially distinct speech motor learning trajectory in children with ASD, providing a window into the emergence of stereotypic vocalizations in these children.
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10. Hadad BS, Goldstein EK, Russo NN. {{Atypical perception in autism: A Failure of Perceptual Specialization?}}. {Autism Res};2017 (May 05)
We examined whether reduced perceptual specialization underlies atypical perception in autism spectrum disorder (ASD) testing classifications of stimuli that differ either along integral dimensions (prototypical integral dimensions of value and chroma), or along separable dimensions (prototypical separable dimensions of value and size). Current models of the perception of individuals with an ASD would suggest that on these tasks, individuals with ASD would be as, or more, likely to process dimensions as separable, regardless of whether they represented separable or integrated dimensions. In contrast, reduced specialization would propose that individuals with ASD would respond in a more integral manner to stimuli that differ along separable dimensions, and at the same time, respond in a more separable manner to stimuli that differ along integral dimensions. A group of nineteen adults diagnosed with high functioning ASD and seventeen typically developing participants of similar age and IQ, were tested on speeded and restricted classifications tasks. Consistent with the reduced specialization account, results show that individuals with ASD do not always respond more analytically than typically developed (TD) observers: Dimensions identified as integral for TD individuals evoke less integral responding in individuals with ASD, while those identified as separable evoke less analytic responding. These results suggest that perceptual representations are more broadly tuned and more flexibly represented in ASD. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc.
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11. Haigh SM. {{Variable Sensory Perception in Autism}}. {Eur J Neurosci};2017 (May 05)
Autism is associated with sensory and cognitive abnormalities. Individuals with autism generally show normal or superior early sensory processing abilities compared to healthy controls, but deficits in complex sensory processing. In the current opinion paper, it will be argued that sensory abnormalities impact cognition by limiting the amount of signal that can be used to interpret and interact with environment. There is a growing body of literature showing that individuals with autism exhibit greater trial-to-trial variability in behavioural and cortical sensory responses. If multiple sensory signals that are highly variable are added together to process more complex sensory stimuli, then this might destabilize later perception and impair cognition. Methods to improve sensory processing have shown improvements in more general cognition. Studies that specifically investigate differences in sensory trial-to-trial variability in autism, and the potential changes in variability before and after treatment, could ascertain if trial-to-trial variability is a good mechanism to target for treatment in autism. This article is protected by copyright. All rights reserved.
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12. Hanley M, Khairat M, Taylor K, Wilson R, Cole-Fletcher R, Riby DM. {{Classroom Displays-Attraction or Distraction? Evidence of Impact on Attention and Learning From Children With and Without Autism}}. {Dev Psychol};2017 (May 04)
Paying attention is a critical first step toward learning. For children in primary school classrooms there can be many things to attend to other than the focus of a lesson, such as visual displays on classroom walls. The aim of this study was to use eye-tracking techniques to explore the impact of visual displays on attention and learning for children. Critically, we explored these issues for children developing typically and for children with autism spectrum disorder (ASD). Both groups of children watched videos of a teacher delivering classroom activities-2 of « story-time » and 2 mini lessons. Half of the videos each child saw contained high levels of classroom visual displays in the background (high visual display [HVD]) and half had none (no visual display [NVD]). Children completed worksheets after the mini lessons to measure learning. During viewing of all videos children’s eye movements were recorded. The presence of visual displays had a significant impact on attention for all children, but to a greater extent for children with ASD. Visual displays also had an impact on learning from the mini lessons, whereby children had poorer learning scores in the HVD compared with the NVD lesson. Individual differences in age, verbal, nonverbal, and attention abilities were important predictors of learning, but time spent attending the visual displays in HVD was the most important predictor. This novel and timely investigation has implications for the use of classroom visual displays for all children, but particularly for children with ASD. (PsycINFO Database Record
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13. Higuchi T, Ishizaki Y, Noritake A, Yanagimoto Y, Kobayashi H, Nakamura K, Kaneko K. {{Spatiotemporal characteristics of gaze of children with autism spectrum disorders while looking at classroom scenes}}. {PLoS One};2017;12(5):e0175912.
Children with autism spectrum disorders (ASD) who have neurodevelopmental impairments in social communication often refuse to go to school because of difficulties in learning in class. The exact cause of maladaptation to school in such children is unknown. We hypothesized that these children have difficulty in paying attention to objects at which teachers are pointing. We performed gaze behavior analysis of children with ASD to understand their difficulties in the classroom. The subjects were 26 children with ASD (19 boys and 7 girls; mean age, 8.6 years) and 27 age-matched children with typical development (TD) (14 boys and 13 girls; mean age, 8.2 years). We measured eye movements of the children while they performed free viewing of two movies depicting actual classes: a Japanese class in which a teacher pointed at cartoon characters and an arithmetic class in which the teacher pointed at geometric figures. In the analysis, we defined the regions of interest (ROIs) as the teacher’s face and finger, the cartoon characters and geometric figures at which the teacher pointed, and the classroom wall that contained no objects. We then compared total gaze time for each ROI between the children with ASD and TD by two-way ANOVA. Children with ASD spent less gaze time on the cartoon characters pointed at by the teacher; they spent more gaze time on the wall in both classroom scenes. We could differentiate children with ASD from those with TD almost perfectly by the proportion of total gaze time that children with ASD spent looking at the wall. These results suggest that children with ASD do not follow the teacher’s instructions in class and persist in gazing at inappropriate visual areas such as walls. Thus, they may have difficulties in understanding content in class, leading to maladaptation to school.
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14. Kim SJ, Shonka S, French WP, Strickland J, Miller L, Stein MA. {{Dose-Response Effects of Long-Acting Liquid Methylphenidate in Children with Attention Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD): A Pilot Study}}. {J Autism Dev Disord};2017 (May 05)
Attention deficit/hyperactivity disorder (ADHD) symptoms are common in youth with autism spectrum disorders (ASD) and are frequently treated with stimulant medications. Twenty-seven children were randomized to different dose titration schedules, and ADHD symptoms, tolerability, and aberrant behaviors were assessed weekly during a 6-week trial with long-acting liquid methylphenidate (MPH). MPH at low to moderate doses was effective in reducing ADHD symptoms and was well tolerated in young children with ASD and ADHD. Future studies are needed to assess generalization and maintenance of efficacy.
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15. Kuo YC. {{Women’s Experiences Caring for Their Husbands’ Siblings With Developmental Disabilities}}. {Glob Qual Nurs Res};2015 (Jan-Dec);2:2333393615604169.
A phenomenological method was used in this study to examine the experiences of women caring for the husband’s sibling with developmental disabilities (DDs) with the aim of establishing how and why they came to care and continued to care for them. Three themes emerged after drawing on stories shared by seven women: for the sake of my husband, powerlessness, and trade-off between cost and rewards. The findings of this study show that Taiwanese women accept the cultural norms, thus accepting the caregiving responsibility. Reciprocity did not help determine whether women started caring for the husband’s sibling with DD. However, when an imbalance in reciprocity is present, women experience negative emotions that often result in tension within the family. Positive factors contributed by the husband and parents-in-law can facilitate the work of caregivers by ameliorating physical pain and psychological distress that can occur during the caregiving process.
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16. Martinez-Cerdeno V, Lechpammer M, Noctor S, Ariza J, Hagerman P, Hagerman R. {{FMR1 premutation with Prader-Willi phenotype and fragile X-associated tremor/ataxia syndrome}}. {Clin Case Rep};2017 (May);5(5):625-629.
This is a report of FMR1 premutation with Prader-Willi phenotype (PWP) and FXTAS. Although the PWP is common in fragile X syndrome (FXS), it has never been described in someone with the premutation. The patient presented intranuclear inclusions, severe obesity, hyperphagia, and ADHD symptoms, typical of the PWP in FXS. In addition, the autopsy revealed multiple architectural cortical abnormalities.
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17. Meguid NA, Ghozlan SAS, Mohamed MF, Ibrahim MK, Dawood RM, Din N, Abdelhafez TH, Hemimi M, Awady MKE. {{Expression of Reactive Oxygen Species-Related Transcripts in Egyptian Children With Autism}}. {Biomark Insights};2017;12:1177271917691035.
The molecular basis of the pathophysiological role of oxidative stress in autism is understudied. Herein, we used polymerase chain reaction (PCR) array to analyze transcriptional pattern of 84 oxidative stress genes in peripheral blood mononuclear cell pools isolated from 32 autistic patients (16 mild/moderate and 16 severe) and 16 healthy subjects (each sample is a pool from 4 autistic patients or 4 controls). The PCR array data were further validated by quantitative real-time PCR in 80 autistic children (55 mild/moderate and 25 severe) and 60 healthy subjects. Our data revealed downregulation in GCLM, SOD2, NCF2, PRNP, and PTGS2 transcripts (1.5, 3.8, 1.2, 1.7, and 2.2, respectively; P < .05 for all) in autistic group compared with controls. In addition, TXN and FTH1 exhibited 1.4- and 1.7-fold downregulation, respectively, in severe autistic patients when compared with mild/moderate group (P = .005 and .0008, respectively). This study helps in a better understanding of the underlying biology and related genetic factors of autism, and most importantly, it presents suggested candidate biomarkers for diagnosis and prognosis purposes as well as targets for therapeutic intervention. Lien vers le texte intégral (Open Access ou abonnement)
18. Mozhgan A, Sakineh S, Mohammad Reza K, Maryam H. {{Measurement of Serum Superoxide Dismutase and Its Relevance to Disease Intensity Autistic Children}}. {Maedica (Buchar)};2015 (Sep);10(4):315-318.
BACKGROUND: Autism is a pervasive disorder and its prevalence increased in recent surveys. An estimated 1 out of every 88 children is affected by autism. Autism disorder symptoms appear before the age of three. It is believed that serum levels of superoxide dismutase may play a role in etiology of autism. MATERIALS AND METHODS: Between October and November 2014, 27 Iranian children from Mashhad city were selected in this study. Given these assumptions, the amount of SOD serum in autistic patients and healthy individuals and correlation between the amount of SOD and autism severity were examined. Blood samples of 30 autistic children and 18 age-matched healthy children were collected between 9 to 11 am. Serum level of SOD in both groups was measured by ELISA method. RESULTS: The mean SOD level in the treatment group (1.04 +/-1.33 ng/ml) was significantly lower than the control group (p = 0.001). However, SOD level was not significantly associated with the autism severity (p = 0.667). Conclusions: Decreased serum levels of superoxide dismutase in the early diagnosis of autistic children can be considered as a diagnostic biomarker.
19. Munshi K, Pawlowski K, Gonzalez-Heydrich J, Picker JD. {{Review of Salient Investigational Drugs for the Treatment of Fragile X Syndrome}}. {J Child Adolesc Psychopharmacol};2017 (May 05)
OBJECTIVES: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability, in addition to being the commonest diagnosable cause of autism. The identification of the biochemical mechanism underlying this disorder has provided amenable targets for therapy. This review aims to provide an overview of investigational drug therapies for FXS. METHODS: The authors carried out a search of clinical and preclinical trials for FXS in PubMed and on the U.S. National Institutes of Health index of clinical trials ( www.clinicaltrials.gov ). We limited our review to Phase II trials or more preliminary and reviewed the associated publications for these studies, complemented by a review of the literature on PubMed. RESULTS: The review of the preclinical, Phase I, and Phase II trials of agents with therapeutic potential in FXS revolves around an understanding of the putative pathways in the pathogenesis of FXS. While there is significant overlap between some of these pathways, the agents can be categorized as modulators of the metabotropic glutamate receptor system, GABAergic agents, and miscellaneous modulators affecting other pathways. CONCLUSION: As trials involving agents targeting different aspects of the molecular biology proceed, common themes have emerged. With the great hope came great disappointment as the initial trials failed to demonstrate sufficient significance. In particular, the differences in outcome between the animal models and humans have highlighted the unique challenges of carrying out trials in these cognitively and behaviorally challenged individuals, as well as a dearth of clinically relevant outcome measures for use in medication trials. However, in reviewing and reframing the studies of the last decade, many important lessons have been learned, which will ultimately have a greater impact on therapeutic research in the field of developmental delay as a whole.
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20. Nicolini C, Fahnestock M. {{The valproic acid-induced rodent model of autism}}. {Exp Neurol};2017 (May 01)
Autism is a lifelong neurodevelopmental disorder characterized by impairments in social communication and interaction and by repetitive patterns of behavior, interests and activities. While autism has a strong genetic component, environmental factors including toxins, pesticides, infection and drugs are known to confer autism susceptibility, likely by inducing epigenetic changes. In particular, exposure to valproic acid (VPA) during pregnancy has been demonstrated to increase the risk of autism in children. Furthermore, rodents prenatally exposed to this drug display behavioral phenotypes characteristics of the human condition. Indeed, animal studies have shown that in utero exposure to VPA of rodents represents a robust model of autism exhibiting face, construct and predictive validity. This model might better represent the many cases of idiopathic autism which are of environmental/epigenetic origins than do transgenic models carrying mutations in single autism-associated genes. The VPA model provides a valuable tool to investigate the neurobiology underlying autistic behavior and to screen for novel therapeutics. Here we review the VPA-induced rodent model of autism, highlighting its importance and reliability as an environmentally-induced animal model of autism.
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21. Nuntamool N, Ngamsamut N, Vanwong N, Puangpetch A, Chamnanphon M, Hongkaew Y, Limsila P, Suthisisang C, Wilffert B, Sukasem C. {{Pharmacogenomics and Efficacy of Risperidone Long-Term Treatment in Thai Autistic Children and Adolescents}}. {Basic Clin Pharmacol Toxicol};2017 (May 04)
The purpose of this study was to evaluate the association of pharmacogenomic factors and clinical outcomes in autistic children and adolescents who were treated with risperidone for long periods. Eighty-two autistic subjects diagnosed with DSM-IV and who were treated with risperidone for more than 1 year were recruited. Pharmacogenomics and clinical outcome (CGI-I, aggressive, over-activity and repetitive score) were evaluated. Almost all patients showed stable symptoms on aggressive behaviour (89.02%), over-activity (71.95%), repetitive (70.89%) behavior and all clinical symptoms (81.71%). Only 4.48% of patients showed minimally worse CGI-I score. Patients in the non-stable symptom group had DRD2 Taq1A non-wildtype (TT and CT) frequencies higher than the clinically stable group (P = 0.04), whereas other gene polymorphisms showed no significant association. Haplotype ACCTCAT (rs6311, rs1045642, rs1128503, rs1800497, rs4436578, rs1799978, rs6280) showed a significant association with non-stable clinical outcome (chi2 = 6.642, p = 0.010). Risperidone levels showed no association with any clinical outcomes. On the other hand, risperidone dose, 9-OH Risperidone levels and prolactin levels were significantly higher in the non-stable compared to the stable symptom group (P = 0.013, P = 0.044, P = 0.030). Increased appetite was the most common adverse drug reaction and associated with higher body weight, whereas it was not significantly associated with genetic variations and non-genetic information. In conclusion, risperidone showed efficacy to control autism, especially aggressive symptoms in long-term treatment. However, Taq1A T – carrier of dopamine2 receptor gene is associated with non-stable response in risperidone-treated patients. This study supports pharmacogenomics testing for personalized therapy with risperidone in autistic children and adolescents. This article is protected by copyright. All rights reserved.
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22. Pinggera A, Mackenroth L, Rump A, Schallner J, Beleggia F, Wollnik B, Striessnig J. {{New gain-of-function mutation shows CACNA1D as recurrently mutated gene in autism spectrum disorders and epilepsy}}. {Hum Mol Genet};2017 (May 04)
CACNA1D encodes the pore-forming alpha1-subunit of Cav1.3, an L-type voltage-gated Ca2+-channel. Despite the recent discovery of two de novo missense gain-of-function mutations in Cav1.3 in two individuals with autism spectrum disorder (ASD) and intellectual disability CACNA1D has not been considered a prominent ASD-risk gene in large scale genetic analyses, since such studies primarly focus on likely-disruptive genetic variants. Here we report the discovery and characterization of a third de novo missense mutation in CACNA1D (V401L) in a patient with ASD and epilepsy.For the functional characterization we introduced mutation V401L into two major C-terminal long and short Cav1.3 splice variants, expressed wild-type or mutant channel complexes in tsA-201 cells and performed whole-cell patch-clamp recordings.Mutation V401L, localized within the channel’s activation gate, significantly enhanced current densities, shifted voltage dependence of activation and inactivation to more negative voltages and reduced channel inactivation in both Cav1.3 splice variants. Altogether these gating changes are expected to result in enhanced Ca2+-influx through the channel, thus representing a strong gain-of-function phenotype. Additionally, we also found that mutant channels retained full sensitivity towards the clinically available Ca2+ -channel blocker isradipine.Our findings strengthen the evidence for CACNA1D as a novel candidate autism risk gene and encourage experimental therapy with available channel-blockers for this mutation. The additional presence of seizures and neurological abnormalities in our patient define a novel phenotype partially overlapping with symptoms in two individuals with PASNA (congential primary aldosteronism, seizures and neurological abnormalities) caused by similar Cav1.3 gain-of-function mutations.
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23. Shelton AL, Cornish KM, Godler D, Bui QM, Kolbe S, Fielding J. {{White matter microstructure, cognition, and molecular markers in fragile X premutation females}}. {Neurology};2017 (May 05)
OBJECTIVE: To examine the interrelationships between fragile X mental retardation 1 (FMR1) mRNA and the FMR1 exon 1/intron 1 boundary methylation, white matter microstructure, and executive function, in women with a FMR1 premutation expansion (PM; 55-199 CGG repeats) and controls (CGG < 44). METHODS: Twenty women with PM without fragile X-associated tremor/ataxia syndrome (FXTAS) and 20 control women between 22 and 54 years of age completed this study. FMR1 mRNA and methylation levels for 9 CpG sites within the FMR1 exon 1/intron 1 boundary from peripheral blood samples were analyzed. To measure white matter microstructure, diffusion-weighted imaging was used, from which fractional anisotropy (FA) and mean diffusivity (MD) values from anatomic regions within the corpus callosum and cerebellar peduncles were extracted. Executive function was assessed across a range of tasks. RESULTS: No differences were revealed in white matter microstructure between women with PM and controls. However, we reveal that for women with PM (but not controls), higher FMR1 mRNA correlated with lower MD values within the middle cerebellar peduncle and Paced Auditory Serial Addition Test scores, higher methylation of the FMR1 exon 1/intron 1 boundary correlated with lower MD within the inferior and middle cerebellar peduncles and longer prosaccade latencies, and higher FA values within the corpus callosum and cerebellar peduncle regions corresponded to superior executive function. CONCLUSIONS: We provide evidence linking white matter microstructure to executive dysfunction and elevated FMR1 mRNA and FMR1 exon 1/intron 1 boundary methylation in women with PM without FXTAS. This suggests that the FXTAS phenotype may not be distinct but may form part of a spectrum of PM involvement. Lien vers le texte intégral (Open Access ou abonnement)
24. Tint A, Weiss JA, Lunsky Y. {{Identifying the clinical needs and patterns of health service use of adolescent girls and women with autism spectrum disorder}}. {Autism Res};2017 (May 05)
Girls and women in the general population present with a distinct profile of clinical needs and use more associated health services compared to boys and men; however, research focused on health service use patterns among girls and women with Autism Spectrum Disorder (ASD) is limited. In the current study, caregivers of 61 adolescent girls and women with ASD and 223 boys and men with ASD completed an online survey. Descriptive analyses were conducted to better understand the clinical needs and associated service use patterns of girls and women with ASD. Sex/gender comparisons were made of individuals’ clinical needs and service use. Adolescent girls and women with ASD had prevalent co-occurring mental and physical conditions and parents reported elevated levels of caregiver strain. Multiple service use was common across age groups, particularly among adolescent girls and women with intellectual disability. Overall, few sex/gender differences emerged, although a significantly greater proportion of girls and women accessed psychiatry and emergency department services as compared to boys and men. Though the current study is limited by its use of parent report and small sample size, it suggests that girls and women with ASD may share many of the same high clinical needs and patterns of services use as boys and men with ASD. Areas for future research are discussed to help ensure appropriate support is provided to this understudied population. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc.
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25. Tsiplova K, Zur RM, Marshall CR, Stavropoulos DJ, Pereira SL, Merico D, Young EJ, Sung WWL, Scherer SW, Ungar WJ. {{A microcosting and cost-consequence analysis of clinical genomic testing strategies in autism spectrum disorder}}. {Genet Med};2017 (May 04)
PurposeWhole-exome (WES) and whole-genome sequencing (WGS) increase the diagnostic yield in autism spectrum disorder (ASD) compared to chromosomal microarray (CMA), but there have been no comprehensive cost analyses. The objective was to perform such an assessment of CMA, WES, and WGS and compare the incremental cost per additional positive finding in hypothetical testing scenarios.MethodsFive-year patient and program costs were estimated from an institutional perspective. WES and WGS estimates were based on HiSeq 2500 with an additional WGS estimate for HiSeq X platforms. Parameter uncertainty was assessed with probabilistic and deterministic sensitivity analysis.ResultsThe cost per ASD sample was CAD$1,655 (95% CI: 1,611; 1,699) for WES, CAD$2,851 (95% CI: 2,750; 2,956) for WGS on HiSeq X, and CAD$5,519 (95% CI: 5,244; 5,785) on HiSeq 2500, compared to CAD$744 (95% CI 714, 773) for CMA. The incremental cost was over CAD$25,000 per additional positive finding if CMA was replaced by newer technology.ConclusionWhile costs for WES and WGS remain high, future reductions in material and equipment costs, and increased understanding of newly discovered variants and variants of unknown significance will lead to improved value.GENETICS in MEDICINE advance online publication, 4 May 2017; doi:10.1038/gim.2017.47.
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26. Van der Merwe C, Bornman J, Donohue D, Harty M. {{The attitudes of typically developing adolescents towards their sibling with autism spectrum disorder}}. {S Afr J Commun Disord};2017 (Apr 26);64(1):e1-e7.
BACKGROUND: Understanding how the cognitive, emotional and behavioural components of sibling attitudes interact with one another at various stages of a sibling’s lifespan will allow clinicians to provide better support to children with autism spectrum disorder (ASD) and their families. However, no research exists which focusses on describing the attitudes of adolescent siblings of children with ASD within the South African context towards their sibling with an ASD. The primary aim of this study was to investigate how typically developing adolescents recall their past attitudes and describe their present attitudes towards their sibling with an ASD. METHODS: Thirty typically developing adolescents who have siblings with ASD were selected to complete the survey instrument, the Lifespan Sibling Relationship Scale, using a cross-sectional design. RESULTS: Results indicate that the measure has internal consistency within this sample. Wilcoxon signed-ranks tests were used to test for significant differences between the mean values for the two self-reported time periods. Friedman analysis of variances (ANOVAs) was used to test for significant differences in the three components of attitudes, namely affect, behaviour and cognition. Results indicate that participants held more positive attitudes towards their siblings with ASD as adolescents compared with when they were younger and that adolescents rated their current emotions towards and beliefs about their sibling with ASD to be more positive than their current interaction experiences. CONCLUSION: As siblings’ attitudes appear to change over time, clinicians should use a lifespan approach to sibling attitudes when designing and implementing supports for siblings of children with ASD.
27. Wang C, Geng H, Liu W, Zhang G. {{Prenatal, perinatal, and postnatal factors associated with autism: A meta-analysis}}. {Medicine (Baltimore)};2017 (May);96(18):e6696.
BACKGROUND: The aim of this meta-analysis was to investigate the prenatal, perinatal, and postnatal risk factors for children autism. METHODS: PubMed, Embase, Web of Science were used to search for studies that examined the prenatal, perinatal, and postnatal risk factors for children autism. A fixed-effects model or random-effects model was used to pool the overall effect estimates. RESULTS: Data from 37,634 autistic children and 12,081,416 nonautistic children enrolled in 17 studies were collated. During the prenatal period, the factors associated with autism risk were maternal and paternal age>/=35 years, mother’s and father’s race: White and Asian, gestational hypertension, gestational diabetes, maternal and paternal education college graduate+, threatened abortion, and antepartum hemorrhage. During perinatal period, the factors associated with autism risk were caesarian delivery, gestational age/=4, spontaneous labor, induced labor, no labor, breech presentation, preeclampsia, and fetal distress. During the postnatal period, the factors associated with autism risk were low birth weight, postpartum hemorrhage, male gender, and brain anomaly. Parity>/=4 and female were associated with a decreased risk of autism. In addition, exposure to cigarette smoking, urinary infection, mother’s and father’s race: Black and Hispanic, mother’s country of birth outside Europe and North America, umbilical cord around neck, premature membrane rupture, 5-minutes Apgar score<7, and respiratory infection were not associated with increased risk of autism. CONCLUSION: The present meta-analysis confirmed the relation between some prenatal, perinatal, and postnatal factors with autism. All these factors were examined individually, thus it was still unclear that whether these factors are causal or play a secondary role in the development of autism. Further studies are needed to verify our findings, and investigate the effects of multiple factors on autism, rather than the single factor. Lien vers le texte intégral (Open Access ou abonnement)
28. Zahid S, Upthegrove R. {{Suicidality in Autistic Spectrum Disorders}}. {Crisis};2017 (May 03):1-10.
BACKGROUND: It is suggested that people with autistic spectrum disorders (ASD) may be at increased risk of suicide; however, research on this topic has been minimal and there are conflicting reports in existing studies. AIM: To bring together research investigating the prevalence, risk factors, and comorbid factors of suicidality in ASD. METHOD: A systematic search was performed of Medline, Psych Info, Embase, and the Web of Science following PRISMA guidelines. After exclusion criteria were applied, 70 full-text articles were screened. The final review contained 12 papers with a total sample size of 2,651. RESULTS: Prevalence of suicide attempts varied between 7% and 47%, while suicidal ideation was reported in up to 72% of cases. Being male and having a history of self-harm and depression were cited as significant risk factors. LIMITATIONS: Papers were cross sectional and contained a number of limitations. Only one paper used the gold standard for diagnosis of ASD and one a standardized measure of suicidal behavior. CONCLUSION: Suicidal attempts and ideation are increased in ASD; however, the extent of the increase and the risk factors identified within this group remain under-investigated. There is a lack of research on protective factors. The correlation between ASD and suicidality needs further examination with longitudinal research.
