1. {{Retraction notice to « The developmental pattern of the RAS/RAF/Erk1/2 pathway in the BTBR autism mouse model » [Int. J. Dev. Neurosci. 39 (2014) 2-8]}}. {Int J Dev Neurosci};2015 (Aug);44:102.
2. Aabbassi B, Benali A, Asri F. {{Risperidone-induced priapism in an autistic child: a case report}}. {J Med Case Rep};2016;10:164.
BACKGROUND: Priapism is a prolonged stimulation with painful, persistent penile erection unaccompanied by sexual desire. It is a rare but serious urological emergency. Risperidone is an atypical antipsychotic widely prescribed for the treatment of behavior problems in children with autism spectrum disorder. It seems associated with priapism in children. CASE PRESENTATION: We present a case of a 12-year-old Moroccan boy diagnosed with autism spectrum disorder who developed priapism while on an existing regimen of risperidone, and we report the treatment decisions that followed. CONCLUSIONS: Clinicians who prescribe risperidone should be aware of the possibility of this rare complication in their patients. Information about this possible side effect and instructions regarding appropriate response should be made available to caregivers of those in the at-risk group of young patients.
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3. Broihier HT. {{BMP signaling turns up in fragile X syndrome: FMRP represses BMPR2}}. {Sci Signal};2016;9(431):fs12.
Fragile X syndrome is the most common inherited form of intellectual disability and results from a loss of function of the translational repressor FMRP. In this issue of Science Signaling, Kashima et al find that FMRP binds to and represses a specific isoform of BMPR2, a type II bone morphogenetic protein (BMP) receptor. Reducing signaling through this BMP pathway reverses neuroanatomical defects observed in fragile X models.
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4. Cole A. {{Autism services ‘let people down’}}. {Nurs Stand};2016 (Jun 1);30(40):18-20.
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5. Craig F, Margari F, Legrottaglie AR, Palumbi R, de Giambattista C, Margari L. {{A review of executive function deficits in autism spectrum disorder and attention-deficit/hyperactivity disorder}}. {Neuropsychiatr Dis Treat};2016;12:1191-1202.
Executive dysfunction has been shown to be a promising endophenotype in neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). This article reviewed 26 studies that examined executive function comparing ASD and/or ADHD children. In light of findings from this review, the ASD + ADHD group appears to share impairment in both flexibility and planning with the ASD group, while it shares the response inhibition deficit with the ADHD group. Conversely, deficit in attention, working memory, preparatory processes, fluency, and concept formation does not appear to be distinctive in discriminating from ASD, ADHD, or ASD + ADHD group. On the basis of neurocognitive endophenotype, the common co-occurrence of executive function deficits seems to reflect an additive comorbidity, rather than a separate condition with distinct impairments.
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6. DuBois D, Ameis SH, Lai MC, Casanova MF, Desarkar P. {{Interoception in Autism Spectrum Disorder: A Review}}. {Int J Dev Neurosci};2016 (Jun 3)
PURPOSE: This review article summarizes original scientific research published to date on interoception in individuals with Autism Spectrum Disorder (ASD). Sensory processing has been shown to be atypical in ASD, yet physiological processing and subjective experience of internal sensation processing, namely interoception, has not been reported sufficiently in research or clinical settings. BACKGROUND: There is a small but growing body of scientific research on interoception in ASD, which is relevant to understanding the behavioral and cognitive characteristics inherent in this condition, and may provide a foundation for clinical interventions such as biofeedback, pain management, and brain stimulation techniques. METHODS: A literature review of original research was performed using major scientific databases. RESULTS: Interoception, which occurs due to multisensory connection and integration of internal afferents in cortical and subcortical areas, is atypical in ASD, but the degree and directionality of this abnormality is not yet clear due to the heterogeneity of the condition. Between-group interoceptive differences in individuals with and without ASD have been repeatedly demonstrated, with a slight tendency towards hyporeactivity in interoceptive awareness in individuals with ASD. SIGNIFICANCE: Multidimensional research combining neuroimaging with psychophysiological and self-report measures guided by a clear theoretical model is necessary to understand how interoceptive differences link to the behavioral and cognitive characteristics of ASD. Sensory processing models and autism theory should also be updated to incorporate these recent findings.
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7. Garbugino L, Centofante E, D’Amato FR. {{Early Social Enrichment Improves Social Motivation and Skills in a Monogenic Mouse Model of Autism, the Oprm1 (-/-) Mouse}}. {Neural Plast};2016;2016:5346161.
Environmental enrichment has been proven to have positive effects on both behavioral and physiological phenotypes in rodent models of mental and neurodevelopmental disorders. In this study, we used mice lacking the micro-opioid receptor gene (Oprm1 (-/-)), which has been shown to have deficits in social competence and communication, to assess the hypothesis that early enrichment can ameliorate sociability during development and adulthood. Due to the immaturity of sensory-motor capabilities of young pups, we chose as environmental stimulation a second lactating female, who provided extra maternal care and stimulation from birth. The results show that double mothering normalized the abnormal response to maternal separation in Oprm1 (-/-) pups and increased social motivation in juveniles and adult knockout mice. Additionally, we observed that Oprm1 (-/-) mice act as less attractive social partners than wild types, which suggests that social motivation can be modulated by the stimulus employed. This experiment supports previous findings suggesting that early social environmental stimulation has profound and long-term beneficial effects, encouraging the use of nonpharmacological interventions for the treatment of social defects in neurodevelopmental diseases.
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8. Harrison AJ, Long KA, Manji KP, Blane KK. {{Development of a Brief Intervention to Improve Knowledge of Autism and Behavioral Strategies Among Parents in Tanzania}}. {Intellect Dev Disabil};2016 (Jun);54(3):187-201.
Despite the global presence of autism spectrum disorder (ASD), a paucity of treatment services exists in Tanzania and other low- and middle-income countries. The effect of delayed or low-quality treatments is enduring and contributes to lifelong variability in ASD-related functional impairments. Service disparities in Tanzania derive in part from a widespread lack of national ASD knowledge. Historically, in Western countries, parents have played a major role in increasing ASD awareness, advancing research, and encouraging empirically supported treatments. In the absence of established treatment services, parents of children with ASD have also learned to implement behavioral interventions to reduce the widening skills gaps. This article describes the development of an intervention designed to inform parents in Tanzania about ASD and empirically supported behavioral strategies. Preliminary data, collected from a clinical implementation with 29 Tanzanian families of children diagnosed with ASD or general developmental delays, support the initial feasibility and acceptability of this intervention. This brief intervention may help to ameliorate treatment disparities due to insufficient regional knowledge, language barriers, or limited service availability and may help improve functional outcomes among Tanzanian children with ASD.
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9. Havercamp SM, Ratliff-Schaub K, Macho PN, Johnson CN, Bush KL, Souders HT. {{Preparing Tomorrow’s Doctors to Care for Patients With Autism Spectrum Disorder}}. {Intellect Dev Disabil};2016 (Jun);54(3):202-216.
People with autism spectrum disorder (ASD) and other developmental disabilities have poorer health and face unique barriers to health care compared to people without disabilities. These health disparities can be partially attributed to physicians’ limited knowledge about caring for patients with developmental disabilities. The purpose of this study was to determine the effectiveness of ASD training for medical students. Our training included a lecture and a panel presentation that featured people with ASD and family members. Students reported improved knowledge, skills, confidence, and comfort in caring for patients with ASD.
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10. Heifert TA, Susi A, Hisle-Gorman E, Erdie-Lalena CR, Gorman G, Min SB, Nylund CM. {{Feeding Disorders in Children with Autism Spectrum Disorders Are Associated with Eosinophilic Esophagitis}}. {J Pediatr Gastroenterol Nutr};2016 (Jun 8)
OBJECTIVE: Eosinophilic esophagitis (EoE) can present as food selectivity or feeding disorders in children. Children with autism spectrum disorders (ASD) commonly demonstrate behavioral food selectivity in type and texture, which often leads to the diagnosis of feeding disorder. We sought to evaluate the association of ASD with EoE. METHODS: A retrospective matched case-cohort study was performed using the Military Health System database from Oct 2008 to Sept 2013. We performed a 1:5 case:control match by age, gender, and enrollment timeframe. Feeding disorders, EoE, and atopic disorders were defined utilizing diagnostic and procedure codes. RESULTS: There were 45,286 children with ASD and 226,430 matched controls. EoE was more common in children with ASD (0.4%) compared to controls (0.1%). Feeding disorders were associated with EoE in both children with ASD and controls. Feeding disorders also had a higher odds ratio for EoE compared to other atopic conditions, among both children with ASD (7.17, 95% CI 4.87-10.5) and controls (11.5, 95% CI 7.57-17.5). Compared to controls with a feeding disorder, children with ASD and a feeding disorder had no difference in the rate of diagnosed EoE (0.85, 0.95% CI 0.39-1.88). CONCLUSIONS: Children with ASD are more likely to be diagnosed with EoE compared to controls; however, among children with feeding disorders, there is no difference in the odds of EoE. A diagnosis of feeding disorder was strongly associated with EoE. Feeding disorders in children with ASD should not be assumed to be solely behavioral and an esophagogastroduodenoscopy should be performed to evaluate for EoE.
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11. Kashima R, Roy S, Ascano M, Martinez-Cerdeno V, Ariza-Torres J, Kim S, Louie J, Lu Y, Leyton P, Bloch KD, Kornberg TB, Hagerman PJ, Hagerman R, Lagna G, Hata A. {{Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome}}. {Sci Signal};2016;9(431):ra58.
Epigenetic silencing of fragile X mental retardation 1 (FMR1) causes fragile X syndrome (FXS), a common inherited form of intellectual disability and autism. FXS correlates with abnormal synapse and dendritic spine development, but the molecular link between the absence of the FMR1 product FMRP, an RNA binding protein, and the neuropathology is unclear. We found that the messenger RNA encoding bone morphogenetic protein type II receptor (BMPR2) is a target of FMRP. Depletion of FMRP increased BMPR2 abundance, especially that of the full-length isoform that bound and activated LIM domain kinase 1 (LIMK1), a component of the noncanonical BMP signal transduction pathway that stimulates actin reorganization to promote neurite outgrowth and synapse formation. Heterozygosity for BMPR2 rescued the morphological abnormalities in neurons both in Drosophila and in mouse models of FXS, as did the postnatal pharmacological inhibition of LIMK1 activity. Compared with postmortem prefrontal cortex tissue from healthy subjects, the amount of full-length BMPR2 and of a marker of LIMK1 activity was increased in this brain region from FXS patients. These findings suggest that increased BMPR2 signal transduction is linked to FXS and that the BMPR2-LIMK1 pathway is a putative therapeutic target in patients with FXS and possibly other forms of autism.
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12. Libero LE, Nordahl CW, Li DD, Ferrer E, Rogers SJ, Amaral DG. {{Persistence of megalencephaly in a subgroup of young boys with autism spectrum disorder}}. {Autism Res};2016 (Jun 8)
A recurring finding in autism spectrum disorder research is that head and brain growth is disproportionate to body growth in early childhood. Nordahl et al. (2011) demonstrated that this occurs in approximately 15% of boys with autism. While the literature suggests that brain growth normalizes at older ages, this has never been evaluated in a longitudinal study. The current study evaluated head circumference and total cerebral volume in 129 male children with autism and 49 age-matched, typically developing controls. We determined whether 3-year-old boys with brain size disproportionate to height (which we call disproportionate megalencephaly) demonstrated an abnormal trajectory of head growth from birth and whether they maintained an enlarged brain at 5 years of age. Findings were based on longitudinal, structural MRI data collected around 3, 4, and 5 years of age and head circumference data from medical records. At 3 years of age, 19 boys with autism had enlarged brains while 110 had brain sizes in the normal range. Boys with disproportionate megalencephaly had greater total cerebral, gray matter, and white matter volumes from 3-5 years compared to boys with autism and normal sized brains and typically developing boys, but no differences in body size. While head circumference did not differ between groups at birth, it was significantly greater in the disproportionate megalencephaly group by around 2 years. These data suggest that there is a subgroup of boys with autism who have brains disproportionate to body size and that this continues until at least 5 years of age. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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13. Lin P, Nicholls L, Assareh H, Fang Z, Amos TG, Edwards RJ, Assareh AA, Voineagu I. {{Transcriptome analysis of human brain tissue identifies reduced expression of complement complex C1Q Genes in Rett syndrome}}. {BMC Genomics};2016;17(1):427.
BACKGROUND: MECP2, the gene mutated in the majority of Rett syndrome cases, is a transcriptional regulator that can activate or repress transcription. Although the transcription regulatory function of MECP2 has been known for over a decade, it remains unclear how transcriptional dysregulation leads to the neurodevelopmental disorder. Notably, little convergence was previously observed between the genes abnormally expressed in the brain of Rett syndrome mouse models and those identified in human studies. METHODS: Here we carried out a comprehensive transcriptome analysis of human brain tissue from Rett syndrome brain using both RNA-seq and microarrays. RESULTS: We identified over two hundred differentially expressed genes, and identified the complement C1Q complex genes (C1QA, C1QB and C1QC) as a point of convergence between gene expression changes in human and mouse Rett syndrome brain. CONCLUSIONS: The results of our study support a role for alterations in the expression level of C1Q complex genes in RTT pathogenesis.
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14. Magana S, Parish S, Morales MA, Li H, Fujiura G. {{Racial and Ethnic Health Disparities Among People With Intellectual and Developmental Disabilities}}. {Intellect Dev Disabil};2016 (Jun);54(3):161-172.
Racial and ethnic health disparities are a pervasive public health problem. Emerging research finds similar health disparities among people with intellectual and developmental disabilities (IDD) compared to nondisabled adults. However, few studies have examined racial and ethnic health disparities among adults with IDD. Using national data, we examined racial and ethnic disparities in health status among adults with IDD, and investigated differences in health status between adults with IDD and nondisabled adults within each racial and ethnic group. We found that Latino and Black adults with IDD had worse health outcomes compared to White adults with IDD, and Latino and Black adults with IDD had worse health outcomes than nondisabled adults from the same racial and ethnic group.
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15. Meguid N, Anwar M, Zaki S, Kandeel W, Ahmed N, Tewfik I. {{Dietary Patterns of Children with Autism Spectrum Disorder: A Study Based in Egypt}}. {Open Access Maced J Med Sci};2015 (Jun 15);3(2):262-267.
AIM: In the hope to assist in tailoring individualized nutritional therapy, this study aimed to assess the nutritional status of autistic children. MATERIAL AND METHODS: This cross-sectional study included 80 autistic children, divided into two groups: group 1 (aged 3- 5 years) and group 2 (aged 6-9 years). Diagnosis was performed based on the criteria for autistic disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Autism Diagnostic Interview Revised and Autism Rating Scale. RESULTS: Socio-demographic data, anthropometric measurements and dietary intake patterns were recorded using a validated questionnaire. The daily intakes of calories and nutrients were converted to percentages of the Recommended Dietary Allowance or Dietary Reference Intake based on age- and gender-normalized DRIs. Plotting on the Egyptian sex-specific growth chart, BMI-z scores of both age groups were slightly overweight. Autistic children suffered inadequate intake of some micronutrients such as vitamin D and C, calcium, folate, magnesium, phosphorus, zinc, and iron, some deficiencies were highly significant especially at older age. CONCLUSIONS: Tailoring a specially designed balanced diet with appropriate micronutrient supplementation may ameliorate the severity of autism symptoms and related abnormal behaviours.
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16. Muller E, Cannon LR, Kornblum C, Clark J, Powers M. {{Description and Preliminary Evaluation of a Curriculum for Teaching Conversational Skills to Children With High-Functioning Autism and Other Social Cognition Challenges}}. {Lang Speech Hear Serv Sch};2016 (Jun 8):1-18.
Purpose: The purpose of this clinical focus article is to provide (a) a detailed description of a school-based intervention designed to teach children with high-functioning autism spectrum disorders (HF-ASDs) and other social cognition challenges both the how and the why of conversation and (b) a preliminary evaluation of program outcomes. Method: This pilot study involved (a) qualitative and quantitative analysis of video footage of participants’ conversational skills at baseline, during intervention, and postintervention; (b) interviews with participants’ speech-language pathologist (third author) about individual participant progress; and (c) interviews with instructors responsible for implementing the curriculum regarding overall program effectiveness. Participants were four elementary-aged children with HF-ASDs and other social cognition challenges with deficits in expressive language and auditory processing and comprehension. Results: Analyses of video-recorded footage indicated increases for all four participants in terms of peer-directed interactions, questions asked, use of wh-words to introduce new topics and/or extend conversation on existing topics, and attempts at conversational repair. Three participants also demonstrated increased use of attention-gaining behaviors. Qualitative analysis of transcripts, as well as in-depth interviews with the participants’ speech-language pathologist and other program instructors, supported these findings. Conclusions: Preliminary findings from this pilot study suggest that providing comprehensive instruction in many of the basic components required for successful conversation, including explanations for why these components are necessary, may be a promising means of teaching children with HF-ASDs and other social cognition challenges to engage in successful peer-to-peer conversation.
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17. Muller N, Baumeister S, Dziobek I, Banaschewski T, Poustka L. {{Validation of the Movie for the Assessment of Social Cognition in Adolescents with ASD: Fixation Duration and Pupil Dilation as Predictors of Performance}}. {J Autism Dev Disord};2016 (Jun 6)
Impaired social cognition is one of the core characteristics of autism spectrum disorders (ASD). Appropriate measures of social cognition for high-functioning adolescents with ASD are, however, lacking. The Movie for the Assessment of Social Cognition (MASC) uses dynamic social stimuli, ensuring ecological validity, and has proven to be a sensitive measure in adulthood. In the current study, 33 adolescents with ASD and 23 controls were administered the MASC, while concurrent eye tracking was used to relate gaze behavior to performance levels. The ASD group exhibited reduced MASC scores, with social cognition performance being explained by shorter fixation duration on eyes and decreased pupil dilation. These potential diagnostic markers are discussed as indicators of different processing of social information in ASD.
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18. Newbutt N, Sung C, Kuo HJ, Leahy MJ, Lin CC, Tong B. {{Brief Report: A Pilot Study of the Use of a Virtual Reality Headset in Autism Populations}}. {J Autism Dev Disord};2016 (Jun 7)
The application of virtual reality technologies (VRTs) for users with autism spectrum disorder (ASD) has been studied for decades. However, a gap remains in our understanding surrounding VRT head-mounted displays (HMDs). As newly designed HMDs have become commercially available (in this study the Oculus Rift) the need to investigate newer devices is immediate. This study explored willingness, acceptance, sense of presence and immersion of ASD participants. Results revealed that all 29 participants (mean age = 32; 33 % with IQ < 70) were willing to wear the HMD. The majority of the participants reported an enjoyable experience, high levels of 'presence', and were likely to use HMDs again. IQ was found to be independent of the willingness to use HMDs and related VRT immersion experience. Lien vers le texte intégral (Open Access ou abonnement)
19. Nicolaidis C, Raymaker D, McDonald K, Kapp S, Weiner M, Ashkenazy E, Gerrity M, Kripke C, Platt L, Baggs A. {{The Development and Evaluation of an Online Healthcare Toolkit for Autistic Adults and their Primary Care Providers}}. {J Gen Intern Med};2016 (Jun 6)
BACKGROUND: The healthcare system is ill-equipped to meet the needs of adults on the autism spectrum. OBJECTIVE: Our goal was to use a community-based participatory research (CBPR) approach to develop and evaluate tools to facilitate the primary healthcare of autistic adults. DESIGN: Toolkit development included cognitive interviewing and test-retest reliability studies. Evaluation consisted of a mixed-methods, single-arm pre/post-intervention comparison. PARTICIPANTS: A total of 259 autistic adults and 51 primary care providers (PCPs) residing in the United States. INTERVENTIONS: The AASPIRE Healthcare toolkit includes the Autism Healthcare Accommodations Tool (AHAT)-a tool that allows patients to create a personalized accommodations report for their PCP-and general healthcare- and autism-related information, worksheets, checklists, and resources for patients and healthcare providers. MAIN MEASURES: Satisfaction with patient-provider communication, healthcare self-efficacy, barriers to healthcare, and satisfaction with the toolkit’s usability and utility; responses to open-ended questions. KEY RESULTS: Preliminary testing of the AHAT demonstrated strong content validity and adequate test-retest stability. Almost all patient participants (>94 %) felt that the AHAT and the toolkit were easy to use, important, and useful. In pre/post-intervention comparisons, the mean number of barriers decreased (from 4.07 to 2.82, p < 0.0001), healthcare self-efficacy increased (from 37.9 to 39.4, p = 0.02), and satisfaction with PCP communication improved (from 30.9 to 32.6, p = 0.03). Patients stated that the toolkit helped clarify their needs, enabled them to self-advocate and prepare for visits more effectively, and positively influenced provider behavior. Most of the PCPs surveyed read the AHAT (97 %), rated it as moderately or very useful (82 %), and would recommend it to other patients (87 %). CONCLUSIONS: The CBPR process resulted in a reliable healthcare accommodation tool and a highly accessible healthcare toolkit. Patients and providers indicated that the tools positively impacted healthcare interactions. The toolkit has the potential to reduce barriers to healthcare and improve healthcare self-efficacy and patient-provider communication. Lien vers le texte intégral (Open Access ou abonnement)
20. Siu WK, Lam CW, Mak CM, Lau ET, Tang MH, Tang WF, Poon-Mak RS, Lee CC, Hung SF, Leung PW, Kwong KL, Yau EK, Ng GS, Fong NC, Chan KY. {{Diagnostic yield of array CGH in patients with autism spectrum disorder in Hong Kong}}. {Clin Transl Med};2016 (Dec);5(1):18.
BACKGROUND: Chromosomal microarray offers superior sensitivity for identification of submicroscopic copy number variants (CNV) and it is advocated to be the first tier genetic testing for patients with autism spectrum disorder (ASD). In this regard, diagnostic yield of array comparative genomic hybridization (CGH) for ASD patients is determined in a cohort of Chinese patients in Hong Kong. METHODS: A combined adult and paediatric cohort of 68 Chinese ASD patients (41 patients in adult group and 27 patients in paediatric group). The genomic DNA extracted from blood samples were analysed by array CGH using NimbleGen CGX-135K oligonucleotide array. RESULTS: We identified 15 CNV and eight of them were clinically significant. The overall diagnostic yield was 11.8 %. Five clinically significant CNV were detected in the adult group and three were in the paediatric group, providing diagnostic yields of 12.2 and 11.1 % respectively. The most frequently detected CNV was 16p13.11 duplications which were present in 4 patients (5.9 % of the cohort). CONCLUSIONS: In this study, a satisfactory diagnostic yield of array CGH was demonstrated in a Chinese ASD patient cohort which supported the clinical usefulness of array CGH as the first line testing of ASD in Hong Kong.
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21. Spriggs AD, Gast DL, Knight VF. {{Video Modeling and Observational Learning to Teach Gaming Access to Students with ASD}}. {J Autism Dev Disord};2016 (Jun 6)
The purpose of this study was to evaluate both video modeling and observational learning to teach age-appropriate recreation and leisure skills (i.e., accessing video games) to students with autism spectrum disorder. Effects of video modeling were evaluated via a multiple probe design across participants and criteria for mastery were based on these results. Secondary measures were collected on observational learning across participants and behaviors. Participants included 4 children with autism, ages 8-11, who were served in self-contained special education classrooms. Results indicated a functional relation between video modeling and increased independence in gaming; observational learning occurred for at least some steps across students. Results, implications for practitioners, limitations, and ideas for future research are discussed.
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22. Szego MJ, Zawati MH. {{Whole Genome Sequencing as a Genetic Test for Autism Spectrum Disorder: From Bench to Bedside and then Back Again}}. {J Can Acad Child Adolesc Psychiatry};2016 (Spring);25(2):116-121.
Autism spectrum disorder (ASD) is characterized by repetitive patterns of behaviour and impairments in social interactions and communication abilities. Although ASD is a heterogeneous disorder, it is a highly genetic condition for which genetic testing is routinely performed. Microarray analysis is currently the standard of care genetic test for ASD, however whole genome sequencing offers several key advantages and will likely replace microarrays as a frontline genetic test in the near future. The 2nd Consultation on Translation of Genomic Advances into Health Applications took place in the spring of 2014 to broadly explore the current and potential impacts of genomic advances in supporting personalized and family-centered care for autism and related developmental conditions. In anticipation of WGS becoming a standard of care test, we examine the policy landscape and highlight the lack of consistency among guidelines regarding what genomic information should be returned to patients and their families. We also discuss the need to create the infrastructure to share clinical WGS data with researchers in a systematic and ethically defensible manner.
23. Willyard C. {{New efforts to design better tools to track autism therapy response}}. {Nat Med};2016 (Jun 7);22(6):570-571.
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24. Xing J, Kimura H, Wang C, Ishizuka K, Kushima I, Arioka Y, Yoshimi A, Nakamura Y, Shiino T, Oya-Ito T, Takasaki Y, Uno Y, Okada T, Iidaka T, Aleksic B, Mori D, Ozaki N. {{Resequencing and Association Analysis of Six PSD-95-Related Genes as Possible Susceptibility Genes for Schizophrenia and Autism Spectrum Disorders}}. {Sci Rep};2016;6:27491.
PSD-95 associated PSD proteins play a critical role in regulating the density and activity of glutamate receptors. Numerous previous studies have shown an association between the genes that encode these proteins and schizophrenia (SZ) and autism spectrum disorders (ASD), which share a substantial portion of genetic risks. We sequenced the protein-encoding regions of DLG1, DLG2, DLG4, DLGAP1, DLGAP2, and SynGAP in 562 cases (370 SZ and 192 ASD patients) on the Ion PGM platform. We detected 26 rare (minor allele frequency <1%), non-synonymous mutations, and conducted silico functional analysis and pedigree analysis when possible. Three variants, G344R in DLG1, G241S in DLG4, and R604C in DLGAP2, were selected for association analysis in an independent sample set of 1315 SZ patients, 382 ASD patients, and 1793 healthy controls. Neither DLG4-G241S nor DLGAP2-R604C was detected in any samples in case or control sets, whereas one additional SZ patient was found that carried DLG1-G344R. Our results suggest that rare missense mutations in the candidate PSD genes may increase susceptibility to SZ and/or ASD. These findings may strengthen the theory that rare, non-synonymous variants confer substantial genetic risks for these disorders. Lien vers le texte intégral (Open Access ou abonnement)
25. Yang WY, He F, Strack RL, Oh SY, Frazer M, Jaffrey SR, Todd PK, Disney MD. {{Small Molecule Recognition and Tools to Study Modulation of r(CGG)exp in Fragile X-Associated Tremor Ataxia Syndrome}}. {ACS Chem Biol};2016 (Jun 8)
RNA transcripts containing expanded nucleotide repeats cause many incurable diseases via various mechanisms. One such disorder, Fragile X-associated tremor ataxia syndrome (FXTAS), is caused by a non-coding r(CGG) repeat expansion (r(CGG)exp) that: (i) sequesters proteins involved in RNA metabolism in nuclear foci, causing deregulation of alternative pre-mRNA splicing; and (ii) undergoes repeat associated non-ATG translation (RANT), which produces toxic homopolymeric proteins without using a start codon. Here we describe the design of two small molecules that inhibit both modes of toxicity and the implementation of various tools to study perturbation of these cellular events. Competitive Chemical Cross Linking and Isolation by Pull Down (C-Chem-CLIP) established that compounds bind r(CGG)exp in cells and also defined small molecule occupancy of RNA targets in cells, the first approach to do so. Using an RNA GFP mimic, r(CGG)exp-Spinach2, we observe that our optimal designed compound binds r(CGG)exp and affects RNA localization by disrupting pre-formed RNA foci. These events correlate with improvement of pre-mRNA splicing defects caused by RNA gain-of-function. In addition, the compounds reduced the formation of toxic homopolymeric proteins formed via RANT. Polysome profiling studies showed that small molecules decreased loading of polysomes onto r(CGG)exp, explaining decreased translation.
