1. Agrawal S, Rao SC, Bulsara MK, Patole SK. {{Prevalence of Autism Spectrum Disorder in Preterm Infants: A Meta-analysis}}. {Pediatrics}. 2018.
CONTEXT: Evidence is emerging that preterm infants are at risk for autism spectrum disorder (ASD). OBJECTIVES: To conduct a systematic review and meta-analysis to estimate the prevalence of ASD in preterm infants. DATA SOURCES: Medline (via PubMed and Ovid), Embase, PsycINFO, and relevant conference proceedings were searched in May 2017. STUDY SELECTION: Original studies in which researchers report on the prevalence of ASD using diagnostic tests in children born preterm were included. Studies in which researchers used only ASD screening tools were excluded. DATA EXTRACTION: Relevant data were extracted independently by 3 authors. RESULTS: Researchers in a total of 18 studies (3366 preterm infants) used ASD diagnostic tools. The median gestation, birth weight, and age at assessment were 28.0 weeks (range: 25.1-31.3 weeks), 1055 g (range: 719-1565 g), and 5.7 years (range: 1.5-21 years), respectively. Meta-analysis revealed that the overall prevalence rate for ASD was 7% (95% confidence interval: 4% to 9%). The funnel plot and Egger’s test revealed that there was probably no evidence of publication bias. LIMITATIONS: The limitations were significant heterogeneity and a lack of studies from middle- and low-income countries. CONCLUSIONS: The prevalence of ASD is significantly high in the preterm population. Adequate resources are needed to improve the outcomes of these children.
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2. Akouchekian M, Hakim Shooshtari M, Heidary H, Zahedi Abghari F, Moeinian P. {{The causative variants of amyloidosis in the autism}}. {Int J Neurosci}. 2018: 1-14.
PURPOSE: Autism spectrum disorders (ASD) consist of a group of neurodevelopmental disorders that include autistic behavior, Asperger’s syndrome and pervasive developmental disabilities. According to the increasing observations that patients with mitochondrial disorders have symptoms associated with ASD, we have aimed to analyze the role of mitochondrial DNA (mtDNA) variation in autistic patients. MATERIAL AND METHODS: We selected children with autistic behaviors (15-60 CARS Score). The mitochondrial DNA extraction process was done by GeNet Bio DNA extraction kit. The regions of interest were amplified using independent PCR runs. After purification of PCR products, both strands were sequenced by Big Dye Termination system in a directly determined automated sequencing on an ABI 3700 capillary sequencer machine using both primers. All sequencing results were analyzed using bioinformatics’ tools sequencher software 5. RESULTS: In this study, 31 samples were examined, which 15 unique variants were detected in genes related to COXI-III. The most frequent variant (30.76%) were related to COX1 with amino acid change A–>A. The only significant pathogenic variant was C8264G, except for C8264G, all variants seemed to be homoplasmic substitution. CONCLUSION: In our study, among the variations we found, one variant what probably had an interesting association with possible amyloidosis, had been reported in patient with autism previously. It is hoped that with finding more definable genetic and biological markers, the autistic children diagnosis and treatment will be more effective.
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3. Barnhill K, Devlin M, Moreno HT, Potts A, Richardson W, Schutte C, Hewitson L. {{Brief Report: Implementation of a Specific Carbohydrate Diet for a Child with Autism Spectrum Disorder and Fragile X Syndrome}}. {J Autism Dev Disord}. 2018.
This brief report examines the implementation of dietary intervention utilizing the specific carbohydrate diet (SCD) for the management of gastrointestinal issues in a 4 year old boy diagnosed with Autism Spectrum Disorder (ASD) and Fragile X Syndrome (FXS). Data relating to anthropometrics, dietary intake, blood markers, gastrointestinal (GI) symptoms, sleep issues, and behavioral concerns were gathered at baseline and after 4 months of dietary intervention. The dietary intervention was well tolerated. Improvements in nutrient status, GI symptoms, and behavioral domains were reported. The use of the SCD protocol in children with ASD/FXS and GI symptoms warrants further investigation.
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4. Chen LS, Min J, Zhao S, Yeh YC, Huang TY. {{Information needs in genetic testing: A needs assessment survey among Taiwanese parents of children with autism spectrum disorders}}. {Autism}. 2018: 1362361318778903.
We conducted the first needs assessment study by examining the information needs in genetic testing for autism spectrum disorders among parents of children with autism spectrum disorders in Taiwan. Parents of children with autism spectrum disorders in 236 public elementary schools with special education services were invited to complete a survey. About two-thirds of participants (65.7%) had never heard about genetic testing for autism spectrum disorders. Yet, the majority (71.4%) expressed an interest in learning about this testing. The top three topics participants identified to assist them in making informed decisions before undergoing genetic testing (for themselves, their affected children, or other family members) were testing accuracy (79.7%), genetic causes of autism spectrum disorders (79.4%), and the link between testing and treatment (79.4%). A health education brochure (47.2%) was the most desired educational approach. Our results can be utilized to develop information and counseling materials for genetic testing for autism spectrum disorders in Taiwan as well as to address the needs of parents of children with autism spectrum disorders, particularly in informed decisions-making. Moreover, to promote better communication between the providers and parents, when discussing genetic testing for autism spectrum disorders with Taiwanese parents of children with autism spectrum disorders, healthcare professionals’ priorities should be in line with the preferred topics identified in this study.
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5. Cook A, Ogden J, Winstone N. {{The impact of a school-based musical contact intervention on prosocial attitudes, emotions and behaviours: A pilot trial with autistic and neurotypical children}}. {Autism}. 2018: 1362361318787793.
Children with autism are more likely to be socially excluded than their neurotypical peers. Since the majority of children with autism attend mainstream schools, interventions are needed to improve the attitudes and behaviours of their peers. Many studies highlight the influence of contact on positive attitudes and reduced discrimination. Group music-making provides an ideal opportunity for positive contact to occur in the classroom. This study evaluated the impact of music-based contact with autistic peers on the attitudes, emotions and behaviours of neurotypical children. Changes in those with autism were also assessed. Neurotypical participants ( n = 55) aged 10-11 years took part in an 11-week music programme designed to increase social interaction, which either did or did not include contact with autistic children ( n = 10). Measures of attitudes, emotions and behaviours were assessed at baseline and follow-up. In response to a hypothetical scenario depicting social exclusion of a child with autism, neurotypical participants in the contact group showed a greater increase in prosocial emotions and a greater decrease in tendency to be a victim than those in the no-contact group. Participants with autism also showed a 19.7% decrease in victimisation. Implications of group music-making for tackling social exclusion of children with autism are discussed.
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6. Heasman B, Gillespie A. {{Neurodivergent intersubjectivity: Distinctive features of how autistic people create shared understanding}}. {Autism}. 2018: 1362361318785172.
Autistic people are neurologically divergent, yet approaches to studying autism are framed by neurotypical definitions of being social. Using the concept of intersubjectivity, which conceptualises a variety of ways of socially relating, we investigate distinctive features of how autistic people build social understanding. A total of 30 members of a charity supporting adults with autism were video-recorded during a social activity they enjoyed, namely collaborative video gaming. Mapping the coherence, affect and symmetry of each conversational turn revealed shifting patterns of intersubjectivity within each interaction. Focussing on clusters of consistent and fragmented turns led us to identify two features of neurodivergent intersubjectivity: a generous assumption of common ground that, when understood, led to rapid rapport, and, when not understood, resulted in potentially disruptive utterances; and a low demand for coordination that ameliorated many challenges associated with disruptive turns. Our findings suggest that neurodivergent intersubjectivity reveals potential for unconventional forms of social relating and that a within-interaction analysis is a viable methodology for exploring neurodivergent communication. Future research should examine the varieties of neurodivergent intersubjectivity, with associated problems and potentials, and how those forms of intersubjectivity can be enabled to flourish, particularly in autistic-to-neurotypical encounters.
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7. Hlushchenko I, Khanal P, Abouelezz A, Paavilainen VO, Hotulainen P. {{ASD-Associated De Novo Mutations in Five Actin Regulators Show Both Shared and Distinct Defects in Dendritic Spines and Inhibitory Synapses in Cultured Hippocampal Neurons}}. {Frontiers in cellular neuroscience}. 2018; 12: 217.
Many actin cytoskeleton-regulating proteins control dendritic spine morphology and density, which are cellular features often altered in autism spectrum disorder (ASD). Recent studies using animal models show that autism-related behavior can be rescued by either manipulating actin regulators or by reversing dendritic spine density or morphology. Based on these studies, the actin cytoskeleton is a potential target pathway for developing new ASD treatments. Thus, it is important to understand how different ASD-associated actin regulators contribute to the regulation of dendritic spines and how ASD-associated mutations modulate this regulation. For this study, we selected five genes encoding different actin-regulating proteins and induced ASD-associated de novo missense mutations in these proteins. We assessed the functionality of the wild-type and mutated proteins by analyzing their subcellular localization, and by analyzing the dendritic spine phenotypes induced by the expression of these proteins. As the imbalance between excitation and inhibition has been suggested to have a central role in ASD, we additionally evaluated the density, size and subcellular localization of inhibitory synapses. Common for all the proteins studied was the enrichment in dendritic spines. ASD-associated mutations induced changes in the localization of alpha-actinin-4, which localized less to dendritic spines, and for SWAP-70 and SrGAP3, which localized more to dendritic spines. Among the wild-type proteins studied, only alpha-actinin-4 expression caused a significant change in dendritic spine morphology by increasing the mushroom spine density and decreasing thin spine density. We hypothesized that mutations associated with ASD shift dendritic spine morphology from mushroom to thin spines. An M554V mutation in alpha-actinin-4 (ACTN4) resulted in the expected shift in dendritic spine morphology by increasing the density of thin spines. In addition, we observed a trend toward higher thin spine density with mutations in myosin IXb and SWAP-70. Myosin IIb and myosin IXb expression increased the proportion of inhibitory synapses in spines. The expression of mutated myosin IIb (Y265C), SrGAP3 (E469K), and SWAP-70 (L544F) induced variable changes in inhibitory synapses.
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8. Holopainen A, de Veld DMJ, Hoddenbach E, Begeer S. {{Does Theory of Mind Training Enhance Empathy in Autism?}}. {J Autism Dev Disord}. 2018.
Youth with ASD often show limited or atypical empathic responsiveness. The direct effects of social skills interventions on enhancing empathic responsiveness is unknown. Data from a randomized controlled trial were used to investigate whether a Theory of Mind training improves the empathic responsiveness, measured through structured observations. The current study included a large sample (n = 135) of 8-13-year-old children with ASD. When comparing the change scores of empathic responsiveness from baseline to post-test, the intervention group performed significantly better than the waitlist group. Thus, the current findings support the use of Theory of Mind training as intervention of ASD by showing its efficacy also in improving one’s empathic responsiveness, in addition to previous knowledge regarding the improvements in empathic understanding.
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9. Hosie S, Malone DT, Liu S, Glass M, Adlard PA, Hannan AJ, Hill-Yardin EL. {{Altered Amygdala Excitation and CB1 Receptor Modulation of Aggressive Behavior in the Neuroligin-3(R451C) Mouse Model of Autism}}. {Frontiers in cellular neuroscience}. 2018; 12: 234.
Understanding neuronal mechanisms underlying aggression in patients with autism spectrum disorder (ASD) could lead to better treatments and prognosis. The Neuroligin-3 (NL3)(R451C) mouse model of ASD has a heightened aggressive phenotype, however the biological mechanisms underlying this behavior are unknown. It is well established that NL3(R451C) mice have imbalanced excitatory and inhibitory synaptic activity in the hippocampus and somatosensory cortex. The amygdala plays a role in modulating aggressive behavior, however potential changes in synaptic activity in this region have not previously been assessed in this model. We investigated whether aggressive behavior is robustly present in mice expressing the R451C mutation, following back-crossing onto a congenic background strain. Endocannabinoids influence social interaction and aggressive behavior, therefore we also studied the effects of cannabinoid receptor 1 (CB1) agonist on NL3(R451C) mice. We report that NL3(R451C) mice have increased amplitude of miniature excitatory postsynaptic currents (EPSCs) with a concomitant decrease in the amplitude of inhibitory postsynaptic currents (IPSCs) in the basolateral amygdala. Importantly, we demonstrated that NL3(R451C) mice bred on a C57Bl/6 background strain exhibit an aggressive phenotype. Following non-sedating doses (0.3 and 1.0 mg/kg) of the CB1 receptor agonist WIN55,212-2 (WIN), we observed a significant reduction in aggressive behavior in NL3(R451C) mice. These findings demonstrate altered synaptic activity in the basolateral amygdala and suggest that the NL3(R451C) mouse model is a useful preclinical tool to understand the role of CB1 receptor function in aggressive behavior.
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10. Krasovska V, Doering LC. {{Regulation of IL-6 Secretion by Astrocytes via TLR4 in the Fragile X Mouse Model}}. {Front Mol Neurosci}. 2018; 11: 272.
Fragile X syndrome (FXS) is identified by abnormal dendrite morphology and altered synaptic protein expression. Astrocyte secreted factors such as Tenascin C (TNC), may contribute to the synaptic changes, including maturation of the synapse. TNC is a known endogenous ligand of toll-like receptor 4 (TLR4) that has been shown to induce the expression of pro-inflammatory cytokines such as interleukin-6 (IL-6). At the molecular level, elevated IL-6 promotes excitatory synapse formation and increases dendrite spine length. With these molecular changes linked to the phenotype of FXS, we examined the expression and the mechanism of the endogenous TLR4 activator TNC, and its downstream target IL-6 in astrocytes from the Fragile X Mental Retardation 1 (FMR1) knockout (KO) mouse model. Secreted TNC and IL-6 were significantly increased in FMR1 KO astrocytes. Addition of TNC and lipopolysaccharide (LPS) induced IL-6 secretion, whereas the antagonist of TLR4 (LPS-RS) had an opposing effect. Cortical protein expression of TNC and IL-6 were also significantly elevated in the postnatal FMR1 KO mouse. In addition, there was an increase in the number of vesicular glutamate transporter 1 (VGLUT1)/post synaptic density protein 95 (PSD95) positive synaptic puncta of both wild-type (WT) and FMR1 KO neurons when plated with astrocyte conditioned media (ACM) from FMR1 KO astrocytes, compared to those plated with media from wild type astrocytes. By assessing the cellular mechanisms involved, a novel therapeutic option could be made available to target abnormalities of synaptic function seen in FXS.
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11. Kuiper MW, Verhoeven EW, Geurts HM. {{The Dutch Glasgow Sensory Questionnaire: Psychometric properties of an autism-specific sensory sensitivity measure}}. {Autism}. 2018: 1362361318788065.
Sensory sensitivity is common in autistic people and since the Diagnostic and Statistical Manual of Mental Disorders (5th ed.), hypo- and hyper-responsiveness to sensory stimuli are part of one of the criteria domains for an autism spectrum disorder classification. For scientific research and the clinical practice, one needs reliable and valid questionnaires that measure sensory sensitivity and can distinguish between hypo- and hyper-responsiveness. We translated the Glasgow Sensory Questionnaire into Dutch. The aim was to examine the psychometric properties and the clinical use of the Dutch Glasgow Sensory Questionnaire in 78 autistic and 68 typically developing adults (18-45 years; IQ > 70). Just like the original Glasgow Sensory Questionnaire, the Dutch Glasgow Sensory Questionnaire is a reliable and valid questionnaire. The Dutch Glasgow Sensory Questionnaire had reliable hypo- and hyper-responsiveness subscales, reasonable to good modality subscales and was stable over time. Moreover, using the 95th percentile of the typically developing group as cut-off, we showed that two thirds of the autistic adults had heightened sensory sensitivity. We also showed that hypo- and hyper-responsiveness do co-exist in both autistic and typically developing adults. In sum, we conclude that the Dutch Glasgow Sensory Questionnaire is suitable to be used in scientific research as well as in the clinical practice.
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12. Murias M, Major S, Compton S, Buttinger J, Sun JM, Kurtzberg J, Dawson G. {{Electrophysiological Biomarkers Predict Clinical Improvement in an Open-Label Trial Assessing Efficacy of Autologous Umbilical Cord Blood for Treatment of Autism}}. {Stem cells translational medicine}. 2018.
This study was a phase I, single-center, and open-label trial of a single intravenous infusion of autologous umbilical cord blood in young children with autism spectrum disorder (ASD). Twenty-five children between the ages of 2 and 6 with a confirmed diagnosis of ASD and a qualified banked autologous umbilical cord blood unit were enrolled. Safety results and clinical outcomes measured at 6 and 12 months post-infusion have been previously published. The purpose of the present analysis was to explore whether measures of electroencephalography (EEG) theta, alpha, and beta power showed evidence of change after treatment and whether baseline EEG characteristics were predictive of clinical improvement. The primary endpoint was the parent-reported Vineland adaptive behavior scales-II socialization subscale score, collected at baseline, 6- and 12-month visits. In addition, the expressive one word picture vocabulary test 4 and the clinical global impression-improvement scale were administered. Electrophysiological recordings were taken during viewing of dynamic social and nonsocial stimuli at 6 and 12 months post-treatment. Significant changes in EEG spectral characteristics were found by 12 months post-infusion, which were characterized by increased alpha and beta power and decreased EEG theta power. Furthermore, higher baseline posterior EEG beta power was associated with a greater degree of improvement in social communication symptoms, highlighting the potential for an EEG biomarker to predict variation in outcome. Taken together, the results suggest that EEG measures may be useful endpoints for future ASD clinical trials.
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13. Novin S, Broekhof E, Rieffe C. {{Bidirectional relationships between bullying, victimization and emotion experience in boys with and without autism}}. {Autism}. 2018: 1362361318787446.
Adolescents with autism are more often victims of bullying than peers without autism. Although prior work indicates that emotions play an important role, bidirectional relationships are yet unknown. This study examines the longitudinal associations of anger, fear, guilt and shame with being victimized and bullying others in adolescent boys with and without autism. On three occasions (9 months in between) 169 boys (43% with autism, 11.6 years at T1) completed self-reports. Findings show that more anger and less guilt predicted bullying behaviour, and vice versa, in both groups. In addition, more anger and fear predicted victimization. Fear was a stronger predictor in boys without autism. In turn, victimization predicted more anger, fear and shame. Especially, boys with autism reported more anger after being bullied, suggesting a tenacious vicious circle: these youngsters are likely to be angered when being bullied, which, in turn, makes them a target for bullies. Our findings provide new theoretical insights in the role emotions play in the emergence and maintenance of victimization/bullying others in boys with and without autism.
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14. Scott JA, Hansen SG. {{Working with Dual Diagnoses: A Survey of Teachers Serving Deaf or Hard of Hearing Children Who Have Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2018.
Although a sizable minority of students who are deaf or hard of hearing (DHH) are also diagnosed with autism spectrum disorder (ASD), there is little research examining teachers’ feelings of aptitude for working with these students, nor the instructional strategies used with this population. This study reports results from a researcher-designed survey of teachers working with children who are both DHH and have ASD. Our results suggest that teachers working with this population felt under-resourced, under-prepared, and under-supported in their work with dually diagnosed students. Perhaps as a result, participants tended to use instructional strategies common to their certification area. We identify a need for cross-training teachers across disability areas. In addition, we call for research that tests the applicability of practices in either Deaf Education or ASD Education for dually diagnosed children who may have needs that are unique from children either group.
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15. Scott M, Milbourn B, Falkmer M, Black M, Blte S, Halladay A, Lerner M, Taylor JL, Girdler S. {{Factors impacting employment for people with autism spectrum disorder: A scoping review}}. {Autism}. 2018: 1362361318787789.
The aim of this study is to holistically synthesise the extent and range of literature relating to the employment of individuals with autism spectrum disorder. Database searches of Medline, CINAHL, PsychINFO, Scopus, ERIC, Web of Science and EMBASE were conducted. Studies describing adults with autism spectrum disorder employed in competitive, supported or sheltered employment were included. Content analysis was used to identify the strengths and abilities in the workplace of employees with autism spectrum disorder. Finally, meaningful concepts relating to employment interventions were extracted and linked to the International Classification of Functioning, Disability and Health Core Sets for autism spectrum disorder. The search identified 134 studies for inclusion with methodological quality ranging from limited to strong. Of these studies, only 36 evaluated employment interventions that were coded and linked to the International Classification of Functioning, Disability and Health, primarily focusing on modifying autism spectrum disorder characteristics for improved job performance, with little consideration of the impact of contextual factors on work participation. The International Classification of Functioning, Disability and Health Core Sets for autism spectrum disorder are a useful tool in holistically examining the employment literature for individuals with autism spectrum disorder. This review highlighted the key role that environmental factors play as barriers and facilitators in the employment of people with autism spectrum disorder and the critical need for interventions which target contextual factors if employment outcomes are to be improved.
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16. Tomiyama S, Kikuchi M, Yoshimura Y, Hasegawa C, Ikeda T, Saito DN, Kumazaki H, Naito N, Minabe Y. {{Changes in maternal feelings for children with autism spectrum disorder after childbirth: The impact of knowledge about the disorder}}. {PLoS One}. 2018; 13(8): e0201862.
The social interactions between caregivers and their children play a crucial role in childhood development; therefore, caregivers’ feelings for children are critical for the development of social minds. Mothers of children with autism spectrum disorder (ASD) are known to experience higher levels of stress. However, knowledge regarding mothers’ feelings for their children before receiving a clinical diagnosis is limited. This study retrospectively investigated the time course of mothers’ feelings from the time of birth and the effect of protective factors. The participants were 5- to 8-year-old children with an ASD diagnosis and their mothers. The mothers of the children with ASD had less positive feelings toward their children than the mothers of the typically developed (TD) children before receiving a clinical diagnosis. Intriguingly, prior knowledge of ASD may relieve maternal mental distress during the child-rearing years and at the time of diagnosis.
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17. Toscano CVA, Ferreira JP, Gaspar JM, Carvalho HM. {{Growth and weight status of Brazilian children with autism spectrum disorders: A mixed longitudinal study}}. {J Pediatr (Rio J)}. 2018.
OBJECTIVE: This study examined the growth status and physical development of Brazilian children with autism spectrum disorders from 4 to 15 years of age. Furthermore, it was examined whether variation in growth patterns and weight status was influenced by the use of psychotropic medications. METHODS: One-hundred and twenty children aged 3.6-12.1 years at baseline (average=7.2 years, SD=2.3 years) diagnosed with autism spectrum disorders were measured on three repeated occasions across a 4-year period. Stature, body mass, and body mass index were considered. Bayesian multilevel modeling was used to describe the individual growth patterns. RESULTS: Growth in stature was comparable to the age-specific 50th percentile for Centers for Disease Control and Prevention reference data until approximately 8 years, but a substantial decrease in growth rate was observed thereafter, reaching the age-specific 5th percentile at 15 years of age. Both body mass and body mass index values were, on average, higher than both the Brazilian and Centers for Disease Control and Prevention age-specific 95th percentile reference until 8 years, but below the 50th specific-age percentile at the age of 15 years. CONCLUSIONS: Brazilian boys with autism spectrum disorders between 4 and 15 years appear to have impaired growth in stature after 8-9 years of age, likely impacting pubertal growth. A high prevalence of overweight and obesity was observed in early childhood, although a trend of substantial decrease in body mass and body mass index was apparent when children with autism spectrum disorders entered the years of pubertal development.
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18. Wachtel LE. {{The multiple faces of catatonia in autism spectrum disorders: descriptive clinical experience of 22 patients over 12 years}}. {Eur Child Adolesc Psychiatry}. 2018.
A retrospective review was conducted from the inpatient and outpatient records of twenty-two autistic youth presenting to a neurobehavioral service over a twelve-year period for combined psychiatric and behavioral pathology who also met DSM5 criteria for catatonia. Six autistic girls and 16 autistic boys ranging from ages eight to 26 years old were identified, and their variegated symptoms evaluated. Stereotypy, posturing, negativism, mutism and stupor were the most common catatonic symptoms, each present in more than half of the study patients. One patient had abnormal vital signs indicative of malignant catatonia. Twenty patients had concomitant repetitive self-injurious behaviors that had led to significant tissue injury and were refractory to psychotropic and behavioral interventions. The sample was weighted towards patients with severe self-injurious behavior, which often was the reason for admission. The many « faces » of catatonia in autism spectrum disorders are seen in this sample, and the novel recognition of repetitive self-injury as an under-recognized motor symptom of catatonia is highlighted. The preliminary findings in this study open many important future vistas for ongoing research regarding catatonia in ASDs.
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19. Zhang Z, Marro SG, Zhang Y, Arendt KL, Patzke C, Zhou B, Fair T, Yang N, Sudhof TC, Wernig M, Chen L. {{The fragile X mutation impairs homeostatic plasticity in human neurons by blocking synaptic retinoic acid signaling}}. {Science translational medicine}. 2018; 10(452).
Fragile X syndrome (FXS) is an X chromosome-linked disease leading to severe intellectual disabilities. FXS is caused by inactivation of the fragile X mental retardation 1 (FMR1) gene, but how FMR1 inactivation induces FXS remains unclear. Using human neurons generated from control and FXS patient-derived induced pluripotent stem (iPS) cells or from embryonic stem cells carrying conditional FMR1 mutations, we show here that loss of FMR1 function specifically abolished homeostatic synaptic plasticity without affecting basal synaptic transmission. We demonstrated that, in human neurons, homeostatic plasticity induced by synaptic silencing was mediated by retinoic acid, which regulated both excitatory and inhibitory synaptic strength. FMR1 inactivation impaired homeostatic plasticity by blocking retinoic acid-mediated regulation of synaptic strength. Repairing the genetic mutation in the FMR1 gene in an FXS patient cell line restored fragile X mental retardation protein (FMRP) expression and fully rescued synaptic retinoic acid signaling. Thus, our study reveals a robust functional impairment caused by FMR1 mutations that might contribute to neuronal dysfunction in FXS. In addition, our results suggest that FXS patient iPS cell-derived neurons might be useful for studying the mechanisms mediating functional abnormalities in FXS.
