1. {{Introduction: Shankopathies and related autism spectrum disorders}}. {Dev Neurobiol};2013 (Nov 19)
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2. Abdala AP, Lioy DT, Garg SK, Knopp SJ, Paton JF, Bissonnette JM. {{Effect of Sarizotan, a 5-HT and D2-Like Receptor Agonist, on Respiration in Three Mouse Models of Rett Syndrome}}. {Am J Respir Cell Mol Biol};2013 (Dec 18)
Rationale: Disturbances in respiration are common and debilitating features of Rett syndrome (RTT). A previous study showed that the 5-HT1a receptor agonist 8-OH-DPAT significantly reduced the incidence of apnea and the irregular breathing pattern in a mouse model of the disorder. 8-OH-DPAT, however, is not available for clinical practice. Sarizotan, a full 5-HT1a agonist, dopamine D2-like agonist/partial agonist has been used in clinical trials for the treatment of L-dopa induced dyskinesia. Objectives: To evaluate the effects of sarizotan on respiration and locomotion in mouse models of RTT. Methods: Studies were carried out in Bird and Jaenisch strains of methyl-CpG-binding protein 2 deficient heterozygous female and Jaenisch strain Mecp2 null male mice and in knock-in heterozygous females of a common nonsense mutation (R168X). Respiratory pattern was determined with body plethysmography and locomotion with open-field recording. Sarizotan or vehicle was administered 20 min prior to a 30 min recording of respiratory pattern or motor behavior. In separate studies, a crossover design was used to administer the drug for 7 and for 14 days. Measurements and Main Results: Sarizotan reduced the incidence of apnea in all three RTT mouse models to ~15% of their pre-treatment levels. In addition, the irregular breathing pattern was corrected to that of wild type (WT) littermates. When administered for 7 or 14 days apnea decreased to 25-33% of the incidence seen with vehicle. Conclusions: This study indicates that the clinically approved drug sarizotan is an effective treatment for respiratory disorders in mouse models of RTT. Word count: 248.
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3. Baird G. {{Commentary: Diverging trajectories from a similar starting point: the outcome in adults whose autism was diagnosed in childhood – reflections on Howlin et al. (2013)}}. {J Child Psychol Psychiatry};2014 (Jan);55(1):59-60.
Howlin and colleagues are to be congratulated on a further follow up from the cohort of children first diagnosed by Rutter at the age of 2-13 years nearly 40 years ago (Howlin, Savage, Moss, Tempier, & Rutter, 2013).
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4. Ben-Cheikh I, Rousseau C. {{[Autism and social support in recently immigrated families : experience of parents from Maghreb]}}. {Sante Ment Que};2013 (Spring);38(1):189-205.
This qualitative exploratory study examines the impact of an autism diagnosis on the social support networks of North African’s parents recently immigrated to Quebec and having a child diagnosed with pervasive developmental disorder. Semi-structured interviews were conducted with ten parents and participant observation took place during support meetings for the mothers. Our results highlight how the autism diagnosis transforms the parents’ family and community networks, creating tensions and losses while also generating new links, sources of support. Group meetings between mothers of the same community experiencing the same problem are perceived particularly beneficial. The analysis of the relationship between professional service providers and families underlines how the development of a therapeutic alliance is threatened by major problems caused by administrative obstacles and intercultural communication difficulties. A greater awareness by health and social professionals of the interaction between the migratory context and the social network challenges associated with autism diagnostic for immigrant families would help ease these parents’ loneliness and suffering.
5. Butterworth TW, Hodge MA, Sofronoff K, Beaumont R, Gray KM, Roberts J, Horstead SK, Clarke KS, Howlin P, Taffe JR, Einfeld SL. {{Validation of the Emotion Regulation and Social Skills Questionnaire for Young People with Autism Spectrum Disorders}}. {J Autism Dev Disord};2013 (Dec 14)
The current study aims to evaluate the psychometric properties of the Emotion Regulation and Social Skills Questionnaire (ERSSQ), a rating scale designed specifically to assess the social skills of young people with Autism Spectrum Disorder (ASD). The participants were 84 children and young adolescents with ASD, aged between 7.97 and 14.16 years with a mean IQ score of 90.21 (SD = 18.82). The results provide evidence for the concurrent and criterion validity of the ERSSQ Parent form, and the concurrent validity of the ERSSQ Teacher form. The clinical and theoretical implications are discussed, including the necessity of ratings across multiple contexts and the potential use of the ERSSQ in identifying individuals most in need of intervention and for planning and assessing the outcomes of social skills interventions.
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6. Buxbaum JD, Baron-Cohen S. {{Capping four years of growth of Molecular Autism: impact factor coming in 2014}}. {Mol Autism};2013 (Dec 16);4(1):50.
We are pleased to announce that Molecular Autism has been accepted by Thomson Reuters for tracking and is due to receive its first official Impact Factor in June 2014.
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7. Corbett BA, Swain DM, Newsom C, Wang L, Song Y, Edgerton D. {{Biobehavioral profiles of arousal and social motivation in autism spectrum disorders}}. {J Child Psychol Psychiatry};2013 (Dec 12)
BACKGROUND: Children with autism spectrum disorder (ASD) are impaired in social communication and interaction with peers, which may reflect diminished social motivation. Many children with ASD show enhanced stress when playing with other children. This study investigated social and stress profiles of children with ASD during play. METHODS: We utilized a peer interaction paradigm in a natural playground setting with 66 unmedicated, prepubertal, children aged 8-12 years [38 with ASD, 28 with typical development (TD)]. Salivary cortisol was collected before and after a 20-min playground interaction that was divided into periods of free and solicited play facilitated by a confederate child. Statistical analyses included Wilcoxon rank-sum tests, mixed effects models, and Spearman correlations to assess the between-group differences in social and stress functioning, identify stress responders, and explore associations between variables, respectively. RESULTS: There were no differences between the groups during unsolicited free play; however, during solicited play by the confederate, significant differences emerged such that children with ASD engaged in fewer verbal interactions and more self-play than the TD group. Regarding physiological arousal, children with ASD as a group showed relatively higher cortisol in response to social play; however, there was a broad range of responses. Moreover, those with the highest cortisol levels engaged in less social communication. CONCLUSIONS: The social interaction of children with ASD can be facilitated by peer solicitation; however, it may be accompanied by increased stress. The children with ASD that have the highest level of cortisol show less social motivation; yet, it is unclear if it reflects an underlying state of heightened arousal or enhanced reactivity to social engagement, or both.
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8. Crais ER, Watson LR. {{Challenges and opportunities in early identification and intervention for children at-risk for autism spectrum disorders}}. {Int J Speech Lang Pathol};2013 (Dec 13)
This response to Camarata (2014) both agrees and disagrees with a number of points relative to early identification and intervention for children with autism spectrum disorders (ASD). The authors, too, recognize the difficulties of identifying toddlers with ASD and the complexities of intervening with these children. It is, however, suggested that there are alternatives to choosing to wait until diagnoses for at-risk children are stable and it is believed that there are many potential benefits from intervening, even when stable diagnoses cannot be made at the time, but risk markers are present. Specifically, it is suggested that it is not necessary to differentially diagnose children in efforts to evaluate treatment effects and suggestions are provided for alternative methods. This commentary also acknowledges the importance of effective ASD screening tools, along with expert clinical opinion, to help identify these toddlers with and at-risk for ASD. Both the available literature from other researchers as well as the authors’ own work in these areas are used to make these arguments.
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9. Dalton N, Chandler S, Turner C, Charman T, Pickles A, Loucas T, Simonoff E, Sullivan P, Baird G. {{Gut Permeability in Autism Spectrum Disorders}}. {Autism Res};2013 (Dec 12)
OBJECTIVE: To test whether gut permeability is increased in autism spectrum disorders (ASD) by evaluating gut permeability in a population-derived cohort of children with ASD compared with age- and intelligence quotient-matched controls without ASD but with special educational needs (SEN). PATIENTS AND METHODS: One hundred thirty-three children aged 10-14 years, 103 with ASD and 30 with SEN, were given an oral test dose of mannitol and lactulose and urine collected for 6 hr. Gut permeability was assessed by measuring the urine lactulose/mannitol (L/M) recovery ratio by electrospray mass spectrometry-mass spectrometry. The ASD group was subcategorized for comparison into those without (n = 83) and with (n = 20) regression. RESULTS: There was no significant difference in L/M recovery ratio (mean (95% confidence interval)) between the groups with ASD: 0.015 (0.013-0.018), and SEN: 0.014 (0.009-0.019), nor in lactulose, mannitol, or creatinine recovery. No significant differences were observed in any parameter for the regressed versus non-regressed ASD groups. Results were consistent with previously published normal ranges. Eleven children (9/103 = 8.7% ASD and 2/30 = 6.7% SEN) had L/M recovery ratio > 0.03 (the accepted normal range cut-off), of whom two (one ASD and one SEN) had more definitely pathological L/M recovery ratios > 0.04. CONCLUSION: There is no statistically significant group difference in small intestine permeability in a population cohort-derived group of children with ASD compared with a control group with SEN. Of the two children (one ASD and one SEN) with an L/M recovery ratio of > 0.04, one had undiagnosed asymptomatic celiac disease (ASD) and the other (SEN) past extensive surgery for gastroschisis. Autism Res 2013, : -. (c) 2013 International Society for Autism Research, Wiley Periodicals, Inc.
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10. Dawson G, Bernier R. {{A quarter century of progress on the early detection and treatment of autism spectrum disorder}}. {Dev Psychopathol};2013 (Nov);25(4 Pt 2):1455-1472.
The last 25 years have witnessed tremendous changes in our ability to detect autism very early in life and provide interventions that can significantly influence children’s outcomes. It was once questioned whether autism could be recognized before children had developed language and symbolic play skills; now changes in early behaviors, as well as structural brain changes, have been documented in infants 6-12 months of age who later develop autism. Advances in brain imaging and genetics offer the possibility of detecting autism before the syndrome is fully manifest, thereby reducing or preventing symptoms from developing. Whereas the primary mode of behavioral intervention a few decades ago relied on operant conditioning, recent approaches integrate the methods of applied behavioral analysis within a developmental, relationship-focused intervention model that are implemented by both parents and clinicians. These interventions have been found to have positive effects on children’s developmental trajectory, as measured by both behavioral and neurophysiological assessments. Future approaches will likely combine both behavioral and pharmacological treatments for children who have less robust responses to behavioral interventions. There has been a paradigm shift in the way that autism is viewed, evolving from a lifelong condition with a very poor prognosis to one in which significant gains and neuroplasticity is expected, especially when the condition is detected early and appropriate interventions are provided. The grand challenge for the future is to bridge the tremendous gap between research and the implementation of evidence-based practices in the broader community, both in the United States and worldwide. Significant disparities in access to appropriate health care for children with autism exist that urgently require advocacy and more resources.
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11. de Theije CG, Wopereis H, Ramadan M, van Eijndthoven T, Lambert J, Knol J, Garssen J, Kraneveld AD, Oozeer R. {{Altered gut microbiota and activity in a murine model of autism spectrum disorders}}. {Brain Behav Immun};2013 (Dec 11)
Autism spectrum disorder (ASD) is a heterogeneous group of complex neurodevelopmental disorders with evidence of genetic predisposition. Intestinal disturbances are reported in ASD patients and compositional changes in gut microbiota are described. However, the role of microbiota in brain disorders is poorly documented. Here, we used a murine model of ASD to investigate the relation between gut microbiota and autism-like behaviour. Using next generation sequencing technology, microbiota composition was investigated in mice in utero exposed to valproic acid (VPA). Moreover, levels of short chain fatty acids (SCFA) and lactic acid in caecal content were determined. Our data demonstrate a transgenerational impact of in utero VPA exposure on gut microbiota in the offspring. Prenatal VPA exposure affected operational taxonomic units (OTUs) assigned to genera within the main phyla of Bacteroidetes and Firmicutes and the order of Desulfovibrionales, corroborating human ASD studies. In addition, OTUs assigned to genera of Alistipes, Enterorhabdus, Mollicutes and Erysipelotrichalis were especially associated with male VPA-exposed offspring. The microbial differences of VPA in utero-exposed males deviated from those observed in females and was (i) positively associated with increased levels of caecal butyrate as well as ileal neutrophil infiltration and (ii) inversely associated with intestinal levels of serotonin and social behaviour scores. These findings show that autism-like behaviour and its intestinal phenotype is associated with altered microbial colonization and activity in a murine model for ASD, with preponderance in male offspring. These results open new avenues in the scientific trajectory of managing neurodevelopmental disorders by gut microbiome modulation.
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12. de Theije CG, Wu J, Koelink PJ, Korte-Bouws GA, Borre Y, Kas MJ, Silva SL, Korte SM, Olivier B, Garssen J, Kraneveld AD. {{Autistic-like behavioural and neurochemical changes in a mouse model of food allergy}}. {Behav Brain Res};2013 (Dec 12)
Food allergy has been suggested to contribute to the expression of psychological and psychiatric traits, including disturbed social behaviour and repetitive behaviour inherent in autism spectrum disorders (ASD). Most research in this field receives little attention, since fundamental evidence showing direct effects of food allergic immune responses on social behaviour is very limited. In the present study, we show that a food allergic reaction to cow’s milk protein, induced shortly after weaning, reduced social behaviour and increased repetitive behaviour in mice. This food allergic reaction increased levels of serotonin (5-hydroxytryptamine; 5-HT) and the number of 5-HT positive cells, and decreased levels of 5-hydroxyindoleacetic acid (5-HIAA) in the intestine. Behavioural changes in food allergic mice were accompanied by reduced dopaminergic activity in the prefrontal cortex. Furthermore, neuronal activation (c-fos expression) was increased in the prefrontal cortex and reduced in the paraventricular nucleus of the hypothalamus after exposure to a social target. We hypothesize that an intestinal allergic response regulates complex, but critical, neuroimmune interactions, thereby affecting brain circuits involved in social interaction, repetitive behaviour and cognition. Together with a genetic predisposition and multiple environmental factors, these effects of allergic immune activation may exacerbate behavioural abnormalities in patients with ASD.
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13. D’Urso G, Ferrucci R, Bruzzese D, Pascotto A, Priori A, Alfredo Altamura C, Galderisi S, Bravaccio C. {{Transcranial Direct Current Stimulation for Autistic Disorder}}. {Biol Psychiatry};2013 (Nov 15)
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14. Enticott PG, Kennedy HA, Johnston PJ, Rinehart NJ, Tonge BJ, Taffe JR, Fitzgerald PB. {{Emotion recognition of static and dynamic faces in autism spectrum disorder}}. {Cogn Emot};2013 (Dec 16)
There is substantial evidence for facial emotion recognition (FER) deficits in autism spectrum disorder (ASD). The extent of this impairment, however, remains unclear, and there is some suggestion that clinical groups might benefit from the use of dynamic rather than static images. High-functioning individuals with ASD (n = 36) and typically developing controls (n = 36) completed a computerised FER task involving static and dynamic expressions of the six basic emotions. The ASD group showed poorer overall performance in identifying anger and disgust and were disadvantaged by dynamic (relative to static) stimuli when presented with sad expressions. Among both groups, however, dynamic stimuli appeared to improve recognition of anger. This research provides further evidence of specific impairment in the recognition of negative emotions in ASD, but argues against any broad advantages associated with the use of dynamic displays.
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15. Faja S, Dawson G. {{Reduced delay of gratification and effortful control among young children with autism spectrum disorders}}. {Autism};2013 (Dec 11)
We explored internal control of behavior using direct observation and parent report. Previous research has found that both the delay of gratification task and parent-reported effortful control predict later social ability and more positive outcomes in typically developing children. Children with autism spectrum disorder have previously been reported to have reduced effortful control, whereas delay of gratification ability has not been tested in a group with autism spectrum disorder. The current study compared 21 children with autism spectrum disorder and 21 typically developing children between 6 and 7 years of age-all of whom had cognitive ability at or above the average range. Children with autism spectrum disorder were less able to delay gratification, and their parents reported significantly reduced effortful control; however, scores on these measures were unrelated within the group with autism spectrum disorder. Among the children with autism spectrum disorder, lower effortful control was associated with more severe clinician-observed social symptoms.
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16. Hadjikhani N, Zurcher NR, Rogier O, Ruest T, Hippolyte L, Ben-Ari Y, Lemonnier E. {{Improving emotional face perception in autism with diuretic bumetanide: A proof-of-concept behavioral and functional brain imaging pilot study}}. {Autism};2013 (Dec 16)
Clinical observations have shown that GABA-acting benzodiazepines exert paradoxical excitatory effects in autism, suggesting elevated intracellular chloride (Cl-)i and excitatory action of GABA. In a previous double-blind randomized study, we have shown that the diuretic NKCC1 chloride importer antagonist bumetanide, that decreases (Cl-)i and reinforces GABAergic inhibition, reduces the severity of autism symptoms. Here, we report results from an open-label trial pilot study in which we used functional magnetic resonance imaging and neuropsychological testing to determine the effects of 10 months bumetanide treatment in adolescents and young adults with autism. We show that bumetanide treatment improves emotion recognition and enhances the activation of brain regions involved in social and emotional perception during the perception of emotional faces. The improvement of emotion processing by bumetanide reinforces the usefulness of bumetanide as a promising treatment to improve social interactions in autism.
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17. Hudepohl MB, Robins DL, King TZ, Henrich CC. {{The role of emotion perception in adaptive functioning of people with autism spectrum disorders}}. {Autism};2013 (Dec 11)
Cognitive functioning has historically been used to predict adaptive outcomes of people with autism spectrum disorders; however, research shows that it is not a complete predictor. The current study explored whether emotion perception was a predictor of adaptive outcomes, and more specifically, hypothesized that emotion perception (Diagnostic Analysis of Nonverbal Accuracy-2 error scores) would mediate adaptive functioning of people with autism spectrum disorder (Vineland Adaptive Behavior Scales, Second Edition). People with autism spectrum disorders demonstrated significantly lower adaptive functioning and emotion perception skills compared to typically developing individuals. Emotion perception acted as a significant mediator for socialization, but not communication or daily living skills, highlighting that in people with autism spectrum disorders, lower socialization abilities is the result, in part, of emotion perception deficits. It was unexpected that emotion perception was not a mediator for communication skills. This may be related to sample restrictions, or the narrow focus on emotion perception. Future research should involve a larger, more inclusive autism spectrum disorder sample, broaden approaches to exploring relationships between social perception and adaptive outcomes, and relate findings to brain mechanisms underlying emotion perception.
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18. Huws JC, Jones RS. {{‘I’m really glad this is developmental’: Autism and social comparisons – an interpretative phenomenological analysis}}. {Autism};2013 (Dec 11)
The present qualitative study comprised interviews with nine young people with autism (aged 16-21 years) about their perceptions of autism. Using interpretative phenomenological analysis, three underlying themes were illuminated, and all these formed the superordinate theme Making Comparisons: (a) Changes over time: ‘I’m really glad this is developmental’; (b) Degrees of autism: ‘They’ve got it really bad’; and (c) Degrees of ability: ‘I’m not really disabled-disabled’. Such comparisons were not explicitly sought at the outset of the study, and instead emerged from their conceptualisations of the autism concept. When comparing how they perceived themselves now, and how they perceived themselves in the past, the young people viewed themselves more positively in the present. In addition, when making comparisons with other people with autism, they tended to locate themselves as being in a better position than others were. The perspective of being in a more fortunate position because of heightened abilities also emerged from the comparisons made with people who did not have autism. Furthermore, similar comparisons were made when autism was compared to disability, with autism being evaluated as being more favourable than what was termed ‘proper’ disability. The results of this study are discussed in relation to the existent social comparison literature.
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19. Ionita-Laza I, Xu B, Makarov V, Buxbaum JD, Roos JL, Gogos JA, Karayiorgou M. {{Scan statistic-based analysis of exome sequencing data identifies FAN1 at 15q13.3 as a susceptibility gene for schizophrenia and autism}}. {Proc Natl Acad Sci U S A};2013 (Dec 16)
We used a family-based cluster detection approach designed to localize significant rare disease-risk variants clusters within a region of interest to systematically search for schizophrenia (SCZ) susceptibility genes within 49 genomic loci previously implicated by de novo copy number variants. Using two independent whole-exome sequencing family datasets and a follow-up autism spectrum disorder (ASD) case/control whole-exome sequencing dataset, we identified variants in one gene, Fanconi-associated nuclease 1 (FAN1), as being associated with both SCZ and ASD. FAN1 is located in a region on chromosome 15q13.3 implicated by a recurrent copy number variant, which predisposes to an array of psychiatric and neurodevelopmental phenotypes. In both SCZ and ASD datasets, rare nonsynonymous risk variants cluster significantly in affected individuals within a 20-kb window that spans several key functional domains of the gene. Our finding suggests that FAN1 is a key driver in the 15q13.3 locus for the associated psychiatric and neurodevelopmental phenotypes. FAN1 encodes a DNA repair enzyme, thus implicating abnormalities in DNA repair in the susceptibility to SCZ or ASD.
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20. Khor AS, Gray KM, Reid SC, Melvin GA. {{Feasibility and validity of ecological momentary assessment in adolescents with high-functioning autism and Asperger’s disorder}}. {J Adolesc};2014 (Jan);37(1):37-46.
Ecological Momentary Assessment (EMA) may increase accuracy of data compared with retrospective questionnaires by assessing behaviours as they occur, hence decreasing recall biases and increasing ecological validity. This study examined the feasibility and concurrent validity of an EMA tool for adolescents with High-Functioning Autism Spectrum Disorders (HFASD). Thirty-one adolescents with HFASD completed a mobile phone EMA application that assessed stressors and coping for two weeks. Parents and adolescents also completed retrospective measures of the adolescent’s coping/stressors. Moderate compliance with the EMA tool was achieved and some concurrent validity was established with the retrospective measure of coping. Concordance was found between the types of stressors reported by parents and adolescents but not the quantity. The results suggest adolescents with HFASD are capable of reporting on their stressors and coping via EMA. EMA has the potential to be a valuable research tool in this population.
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21. Klausen TK, Janssens A, Prenen J, Owsianik G, Hoffmann EK, Pedersen SF, Nilius B. {{Single point mutations of aromatic residues in transmembrane helices 5 and -6 differentially affect TRPV4 activation by 4alpha-PDD and hypotonicity: Implications for the role of the pore region in regulating TRPV4 activity}}. {Cell Calcium};2013 (Nov 21)
The importance of the TRPV4 channel for human physiology has been highlighted in recent years with the identification of an increasing number of hereditary diseases associated with mutations of this channel. However, the functional understanding of TRPV4 associated pathologies remains a puzzle due to incomplete understanding of the polymodal regulation of TRPV4 channels and lack of insight into the structure-function relationship of the channel. In this work, we identified a series of highly conserved aromatic residues in transmembrane (TM) helices 5-6 with profound importance for TRPV4 activity. Substituting F617, Y621 or F624 in TM5 with leucine reduced channel sensitivity to the agonist 4alpha-PDD and heat, yet two of these mutants – F617L and Y621L – showed increased activation in response to cell swelling. In TM6, a Y702L mutation significantly reduced sensitivity to all of the above stimuli. In conclusion, we have identified residues in TM5-6 which differentially affect heat and agonist activation, and we have demonstrated distinct activation pathways for 4alpha-PDD and osmolarity.
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22. Koegel LK, Koegel RL, Ashbaugh K, Bradshaw J. {{The importance of early identification and intervention for children with or at risk for autism spectrum disorders}}. {Int J Speech Lang Pathol};2013 (Dec 11)
There has been a dramatic rise in the number of children being diagnosed with autism spectrum disorders (ASD), which has led to increased attention paid to assessment and intervention issues. This manuscript agrees with Camarata (2014) that the evidence base for early assessment and intervention should be expanded. However, it disagrees with Warren et al.’s (2011) assumption that there are not empirically validated early interventions. Reliable diagnosis has been documented during infancy and toddlerhood, and evidence suggests that the earlier the onset of intervention, the greater likelihood of an improved developmental trajectory. It is argued that early intervention is more cost and time efficient than a « wait and see » approach. With regard to published studies, the large amount of heterogeneity in the ASD population supports the use of rigorous single case experimental design research. It is an error to limit empirical evidence for treatments to only randomized clinical trials, which have the weakness of masking individual differences. Single case experimental designs examine the effects of intervention beyond typical maturation by allowing for clear estimations of developmental trajectories prior to the onset of intervention, followed by evaluation of the impact of the intervention. This commentary discusses the short- and long-term benefits of early diagnosis and intervention.
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23. Lance EI, York JM, Lee LC, Zimmerman AW. {{Association between regression and self injury among children with autism}}. {Res Dev Disabil};2013 (Dec 13);35(2):408-413.
Self injurious behaviors (SIBs) are challenging clinical problems in individuals with autism spectrum disorders (ASDs). This study is one of the first and largest to utilize inpatient data to examine the associations between autism, developmental regression, and SIBs. Medical records of 125 neurobehavioral hospitalized patients with diagnoses of ASDs and SIBs between 4 and 17 years of age were reviewed. Data were collected from medical records on the type and frequency of SIBs and a history of language, social, or behavioral regression during development. The children with a history of any type of developmental regression (social, behavioral, or language) were more likely to have a diagnosis of autistic disorder than other ASD diagnoses. There were no significant differences in the occurrence of self injurious or other problem behaviors (such as aggression or disruption) between children with and without regression. Regression may influence the diagnostic considerations in ASDs but does not seem to influence the clinical phenotype with regard to behavioral issues. Additional data analyses explored the frequencies and subtypes of SIBs and other medical diagnoses in ASDs, with intellectual disability and disruptive behavior disorder found most commonly.
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24. Legido A, Jethva R, Goldenthal MJ. {{Mitochondrial dysfunction in autism}}. {Semin Pediatr Neurol};2013 (Sep);20(3):163-175.
Using data of the current prevalence of autism as 200:10,000 and a 1:2000 incidence of definite mitochondrial (mt) disease, if there was no linkage of autism spectrum disorder (ASD) and mt disease, it would be expected that 1 in 110 subjects with mt disease would have ASD and 1 in 2000 individuals with ASD would have mt disease. The co-occurrence of autism and mt disease is much higher than these figures, suggesting a possible pathogenetic relationship. Such hypothesis was initially suggested by the presence of biochemical markers of abnormal mt metabolic function in patients with ASD, including elevation of lactate, pyruvate, or alanine levels in blood, cerebrospinal fluid, or brain; carnitine level in plasma; and level of organic acids in urine, and by demonstrating impaired mt fatty acid beta-oxidation. More recently, mtDNA genetic mutations or deletions or mutations of nuclear genes regulating mt function have been associated with ASD in patients or in neuropathologic studies on the brains of patients with autism. In addition, the presence of dysfunction of the complexes of the mt respiratory chain or electron transport chain, indicating abnormal oxidative phosphorylation, has been reported in patients with ASD and in the autopsy samples of brains. Possible pathogenetic mechanisms linking mt dysfunction and ASD include mt activation of the immune system, abnormal mt Ca(2+) handling, and mt-induced oxidative stress. Genetic and epigenetic regulation of brain development may also be disrupted by mt dysfunction, including mt-induced oxidative stress. The role of the purinergic system linking mt dysfunction and ASD is currently under investigation. In summary, there is genetic and biochemical evidence for a mitochondria (mt) role in the pathogenesis of ASD in a subset of children. To determine the prevalence and type of genetic and biochemical mt defects in ASD, there is a need for further research using the latest genetic technology such as next-generation sequencing, microarrays, bioinformatics, and biochemical assays. Because of the availability of potential therapeutic options for mt disease, successful research results could translate into better treatment and outcome for patients with mt-associated ASD. This requires a high index of suspicion of mt disease in children with autism who are diagnosed early.
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25. Lofkvist U, Almkvist O, Lyxell B, Tallberg IM. {{Lexical and semantic ability in groups of children with cochlear implants, language impairment and autism spectrum disorder}}. {Int J Pediatr Otorhinolaryngol};2013 (Nov 25)
OBJECTIVE: Lexical-semantic ability was investigated among children aged 6-9 years with cochlear implants (CI) and compared to clinical groups of children with language impairment (LI) and autism spectrum disorder (ASD) as well as to age-matched children with normal hearing (NH). In addition, the influence of age at implantation on lexical-semantic ability was investigated among children with CI. METHODS: 97 children divided into four groups participated, CI (n=34), LI (n=12), ASD (n=12), and NH (n=39). A battery of tests, including picture naming, receptive vocabulary and knowledge of semantic features, was used for assessment. A semantic response analysis of the erroneous responses on the picture-naming test was also performed. RESULTS: The group of children with CI exhibited a naming ability comparable to that of the age-matched children with NH, and they also possessed a relevant semantic knowledge of certain words that they were unable to name correctly. Children with CI had a significantly better understanding of words compared to the children with LI and ASD, but a worse understanding than those with NH. The significant differences between groups remained after controlling for age and non-verbal cognitive ability. CONCLUSIONS: The children with CI demonstrated lexical-semantic abilities comparable to age-matched children with NH, while children with LI and ASD had a more atypical lexical-semantic profile and poorer sizes of expressive and receptive vocabularies. Dissimilar causes of neurodevelopmental processes seemingly affected lexical-semantic abilities in different ways in the clinical groups.
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26. Lyall K, Ashwood P, Van de Water J, Hertz-Picciotto I. {{Maternal Immune-Mediated Conditions, Autism Spectrum Disorders, and Developmental Delay}}. {J Autism Dev Disord};2013 (Dec 12)
The maternal immune system may play a role in offspring neurodevelopment. We examined whether maternal autoimmune disease, asthma, and allergy were associated with child autism spectrum disorder (ASD) and developmental delay without autism (DD) using 560 ASD cases, 391 typically developing controls, and 168 DD cases from the CHildhood Autism Risk from Genetics and the Environment (CHARGE) study. Results from conditional logistic regression demonstrated few significant associations overall. Maternal autoimmune disease was significantly associated with a modest increase in odds of developmental disorders (combined ASD + DD; OR = 1.46, 95 % CI 1.01, 2.09) but not of ASD alone. Associations with certain allergens and onset periods were also suggested. These findings suggest maternal autoimmune disease may modestly influence childhood developmental disorders (ASD + DD).
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27. McGinnis WR, Audhya T, Edelson SM. {{Proposed toxic and hypoxic impairment of a brainstem locus in autism}}. {Int J Environ Res Public Health};2013;10(12):6955-7000.
Electrophysiological findings implicate site-specific impairment of the nucleus tractus solitarius (NTS) in autism. This invites hypothetical consideration of a large role for this small brainstem structure as the basis for seemingly disjointed behavioral and somatic features of autism. The NTS is the brain’s point of entry for visceral afference, its relay for vagal reflexes, and its integration center for autonomic control of circulatory, immunological, gastrointestinal, and laryngeal function. The NTS facilitates normal cerebrovascular perfusion, and is the seminal point for an ascending noradrenergic system that modulates many complex behaviors. Microvascular configuration predisposes the NTS to focal hypoxia. A subregion-the « pNTS »-permits exposure to all blood-borne neurotoxins, including those that do not readily transit the blood-brain barrier. Impairment of acetylcholinesterase (mercury and cadmium cations, nitrates/nitrites, organophosphates, monosodium glutamate), competition for hemoglobin (carbon monoxide, nitrates/nitrites), and higher blood viscosity (net systemic oxidative stress) are suggested to potentiate microcirculatory insufficiency of the NTS, and thus autism.
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28. Nishiyama T, Suzuki M, Adachi K, Sumi S, Okada K, Kishino H, Sakai S, Kamio Y, Kojima M, Suzuki S, Kanne SM. {{Comprehensive Comparison of Self-administered Questionnaires for Measuring Quantitative Autistic Traits in Adults}}. {J Autism Dev Disord};2013 (Dec 17)
We comprehensively compared all available questionnaires for measuring quantitative autistic traits (QATs) in terms of reliability and construct validity in 3,147 non-clinical and 60 clinical subjects with normal intelligence. We examined four full-length forms, the Subthreshold Autism Trait Questionnaire (SATQ), the Broader Autism Phenotype Questionnaire, the Social Responsiveness Scale2-Adult Self report (SRS2-AS), and the Autism-Spectrum Quotient (AQ). The SRS2-AS and the AQ each had several short forms that we also examined, bringing the total to 11 forms. Though all QAT questionnaires showed acceptable levels of test-retest reliability, the AQ and SRS2-AS, including their short forms, exhibited poor internal consistency and discriminant validity, respectively. The SATQ excelled in terms of classical test theory and due to its short length.
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29. Padmashri R, Reiner BC, Suresh A, Spartz E, Dunaevsky A. {{Altered structural and functional synaptic plasticity with motor skill learning in a mouse model of fragile x syndrome}}. {J Neurosci};2013 (Dec 11);33(50):19715-19723.
Fragile X syndrome (FXS) is the most common inherited intellectual disability. FXS results from a mutation that causes silencing of the FMR1 gene, which encodes the fragile X mental retardation protein. Patients with FXS exhibit a range of neurological deficits, including motor skill deficits. Here, we have investigated motor skill learning and its synaptic correlates in the fmr1 knock-out (KO) mouse. We find that fmr1 KO mice have impaired motor skill learning of a forelimb-reaching task, compared with their wild-type (WT) littermate controls. Electrophysiological recordings from the forelimb region of the primary motor cortex demonstrated reduced, training-induced synaptic strengthening in the trained hemisphere. Moreover, long-term potentiation (LTP) is impaired in the fmr1 KO mouse, and motor skill training does not occlude LTP as it does in the WT mice. Whereas motor skill training induces an increase of synaptic AMPA-type glutamate receptor subunit 1 (GluA1), there is a delay in GluA1 increase in the trained hemisphere of the fmr1 KO mice. Using transcranial in vivo multiphoton microscopy, we find that fmr1 KO mice have similar spine density but increased dendritic spine turnover compared with WT mice. Finally, we report that motor skill training-induced formation of dendritic spines is impaired in fmr1 KO mice. We conclude that FMRP plays a role in motor skill learning and that reduced functional and structural synaptic plasticity might underlie the behavioral deficit in the fmr1 KO mouse.
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30. Pretto DI, Kumar M, Cao Z, Cunningham CL, Durbin-Johnson B, Qi L, Berman R, Noctor SC, Hagerman RJ, Pessah IN, Tassone F. {{Reduced excitatory amino acid transporter 1 and metabotropic glutamate receptor 5 expression in the cerebellum of fragile X mental retardation gene 1 premutation carriers with fragile X-associated tremor/ataxia syndrome}}. {Neurobiol Aging};2013 (Nov 16)
A premutation (PM) expansion (55-200 CGG) in the fragile X mental retardation gene 1 causes elevated messenger RNA and reduced fragile X mental retardation gene 1 protein. Young PM carriers can develop characteristic physical features and mild cognitive disabilities. In addition, individuals with PM, particularly male carriers, are at high risk to develop fragile X-associated tremor/ataxia syndrome (FXTAS) with aging. Human postmortem FXTAS brains show extensive white matter disease in the cerebellum and the presence of intranuclear inclusions throughout the brain, although their etiologic significance is unknown. In the current work, expression levels of the metabotropic glutamate (Glu) receptor 5 and the Glu transporter excitatory amino acid transporter 1, examined by reverse transcription polymerase chain reaction and western blot analyses, were found to be reduced in the postmortem cerebellum of PM carriers with FXTAS compared with age matched controls, with higher CGG repeat number having greater reductions in both proteins. These data suggests a dysregulation of Glu signaling in PM carriers, which would likely contribute to the development and severity of FXTAS.
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31. Roberts TP, Heiken K, Zarnow D, Dell J, Nagae L, Blaskey L, Solot C, Levy SE, Berman JI, Edgar JC. {{Left Hemisphere Diffusivity of the Arcuate Fasciculus: Influences of Autism Spectrum Disorder and Language Impairment}}. {AJNR Am J Neuroradiol};2013 (Dec 12)
BACKGROUND AND PURPOSE:There has been much discussion whether brain abnormalities associated with specific language impairment and autism with language impairment are shared or are disorder specific. Although white matter tract abnormalities are observed in both specific language impairment and autism spectrum disorders, the similarities and differences in the white matter abnormalities in these 2 disorders have not been fully determined.MATERIALS AND METHODS:Diffusion tensor imaging diffusion parameters of the arcuate fasciculus were measured in 14 children with specific language impairment as well as in 16 children with autism spectrum disorder with language impairment, 18 with autism spectrum disorder without language impairment, and 25 age-matched typically developing control participants.RESULTS:Language impairment and autism spectrum disorder both had (elevating) main effects on mean diffusivity of the left arcuate fasciculus, initially suggesting a shared white matter substrate abnormality. Analysis of axial and radial diffusivity components, however, indicated that autism spectrum disorder and language impairment differentially affect white matter microstructural properties, with a main effect of autism spectrum disorder on axial diffusivity and a main effect of language impairment on radial diffusivity.CONCLUSIONS:Although white matter abnormalities appear similar in language impairment and autism spectrum disorder when examining broad white matter measures, a more detailed analysis indicates different mechanisms for the white matter microstructural anomalies associated with language impairment and autism spectrum disorder.
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32. Routh BN, Johnston D, Brager DH. {{Loss of Functional A-Type Potassium Channels in the Dendrites of CA1 Pyramidal Neurons from a Mouse Model of Fragile X Syndrome}}. {J Neurosci};2013 (Dec 11);33(50):19442-19450.
Despite the critical importance of voltage-gated ion channels in neurons, very little is known about their functional properties in Fragile X syndrome: the most common form of inherited cognitive impairment. Using three complementary approaches, we investigated the physiological role of A-type K(+) currents (IKA) in hippocampal CA1 pyramidal neurons from fmr1-/y mice. Direct measurement of IKA using cell-attached patch-clamp recordings revealed that there was significantly less IKA in the dendrites of CA1 neurons from fmr1-/y mice. Interestingly, the midpoint of activation for A-type K(+) channels was hyperpolarized for fmr1-/y neurons compared with wild-type, which might partially compensate for the lower current density. Because of the rapid time course for recovery from steady-state inactivation, the dendritic A-type K(+) current in CA1 neurons from both wild-type and fmr1-/y mice is likely mediated by KV4 containing channels. The net effect of the differences in IKA was that back-propagating action potentials had larger amplitudes producing greater calcium influx in the distal dendrites of fmr1-/y neurons. Furthermore, CA1 pyramidal neurons from fmr1-/y mice had a lower threshold for LTP induction. These data suggest that loss of IKA in hippocampal neurons may contribute to dendritic pathophysiology in Fragile X syndrome.
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33. Scahill L, Dimitropoulos A, McDougle CJ, Aman MG, Feurer ID, McCracken JT, Tierney E, Pu J, White S, Lecavalier L, Hallett V, Bearss K, King B, Arnold LE, Vitiello B. {{Children’s Yale-Brown Obsessive Compulsive Scale in Autism Spectrum Disorder: Component Structure and Correlates of Symptom Checklist}}. {J Am Acad Child Adolesc Psychiatry};2014 (Jan);53(1):97-107 e101.
OBJECTIVE: Repetitive behaviors in autism spectrum disorders (ASD) range from motor stereotypy to immersion in restricted interests. The modified Children’s Yale-Brown Obsessive Compulsive Scale for children with autism spectrum disorder (CYBOCS-ASD) includes a Symptom Checklist (behavior present or absent) and 5 severity scales (Time Spent, Interference, Distress, Resistance and Control). METHOD: We assembled CYBOCS-ASD data from 3 Research Units on Pediatric Psychopharmacology Autism Network trials to explore the component structure of repetitive behaviors in children with ASD. Raters trained to reliability conducted the CYBOCS-ASD in 272 medication-free subjects. Fifteen Symptom Checklist items were endorsed for less than 5% of the sample and were dropped. Principal component analysis was used to explore the clustering of 23 checklist items. Component scores computed for each subject were correlated with other measures. We also examined the distribution of severity scales. RESULTS: The subjects (229 boys and 43 girls; mean age = 7.8 +/- 2.6 years) met criteria for an ASD; half were intellectually disabled. The PCA resulted in a 5-component solution to classify repetitive behaviors (34.4% of the variance): hoarding and ritualistic behavior; sensory and arranging behavior; sameness and self-injurious behavior; stereotypy; restricted interests. Sensory and arranging and stereotypy components were associated with lower adaptive functioning (Pearson r = 0.2-0.3; p < .003). The resistance scale showed little variation, with more than 60% of the sample with the highest score. CONCLUSIONS: Rarely endorsed items can be dropped from the Checklist. The resistance item does not appear to be relevant for children with ASD.
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34. Sethna F, Moon C, Wang H. {{From FMRP Function to Potential Therapies for Fragile X Syndrome}}. {Neurochem Res};2013 (Dec 18)
Fragile X syndrome (FXS) is caused by mutations in the fragile X mental retardation 1 (FMR1) gene. Most FXS cases occur due to the expansion of the CGG trinucleotide repeats in the 5′ un-translated region of FMR1, which leads to hypermethylation and in turn silences the expression of FMRP (fragile X mental retardation protein). Numerous studies have demonstrated that FMRP interacts with both coding and non-coding RNAs and represses protein synthesis at dendritic and synaptic locations. In the absence of FMRP, the basal protein translation is enhanced and not responsive to neuronal stimulation. The altered protein translation may contribute to functional abnormalities in certain aspects of synaptic plasticity and intracellular signaling triggered by Gq-coupled receptors. This review focuses on the current understanding of FMRP function and potential therapeutic strategies that are mainly based on the manipulation of FMRP targets and knowledge gained from FXS pathophysiology.
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35. Stefansson H, Meyer-Lindenberg A, Steinberg S, Magnusdottir B, Morgen K, Arnarsdottir S, Bjornsdottir G, Walters GB, Jonsdottir G, Doyle OM, Tost H, Grimm O, Kristjansdottir S, Snorrason H, Davidsdottir SR, Gudmundsson LJ, Jonsson GF, Stefansdottir B, Helgadottir I, Haraldsson M, Jonsdottir B, Thygesen JH, Schwarz AJ, Didriksen M, Stensbol TB, Brammer M, Kapur S, Halldorsson JG, Hreidarsson S, Saemundsen E, Sigurdsson E, Stefansson K. {{CNVs conferring risk of autism or schizophrenia affect cognition in controls}}. {Nature};2013 (Dec 18)
In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.
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36. Sun X, Allison C, Auyeung B, Matthews FE, Baron-Cohen S, Brayne C. {{Service provision for autism in mainland China: Preliminary mapping of service pathways}}. {Soc Sci Med};2013 (Dec);98:87-94.
Few data on healthcare services for individuals with Autism Spectrum Conditions (ASC) are available from mainland China. This article is based on findings from 69 semi-structured interviews with parents of children with ASC in three intervention centres. The respondents are from 19 regions in mainland China. A service-mapping questionnaire containing 50 questions is developed and used as an interview schedule for service mapping. The pathway to diagnosis and intervention for children with ASC is presented according to parents’ experience. The findings report considerable delay along the pathway which may be partly due to the under-developed service system. Several cultural issues are identified which may also contribute to the delay, such as the perception of mental illness, folk beliefs equating delayed development of language skills in early childhood with future high intelligence, and the state-imposed one-child policy. Delays in recognising ASC and a lack of support are also considered to be associated with the considerable financial burden placed on parents of children with ASC in mainland China.
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37. Towle PO, Vacanti-Shova K, Shah S, Higgins-D’alessandro A. {{School-Aged Functioning of Children Diagnosed with Autism Spectrum Disorder Before Age Three: Parent-Reported Diagnostic, Adaptive, Medication, and School Placement Outcomes}}. {J Autism Dev Disord};2013 (Dec 18)
Eighty children with early autism spectrum disorder (ASD) diagnoses (under 36 months) were identified using a chart abstraction protocol applied to early intervention charts. Parents filled out questionnaires by mail when the children were school-aged (ages 6-16 years). Similar to previous studies, approximately 20 % no longer had ASD diagnoses; the other participants were assigned to Moderate/Severe versus Mild ASD outcome groups. These three groups were compared across several variables, including diagnostic features and functional features including adaptive behavior, social experiences, medication use, and school placement. The findings expand our knowledge about outcomes in longitudinal studies of children with ASD, as well as provide support for using relatively indirect methods (chart review, parent questionnaire) to gather this type of information.
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38. Trembath D, Vivanti G. {{Problematic but predictive: Individual differences in children with autism spectrum disorders}}. {Int J Speech Lang Pathol};2013 (Dec 18)
Camarata highlights the impact that symptom hetereogeneity, overlap, and individual differences can have on the accurate early diagnosis of children with autism spectrum disorders (ASD) and measurement of treatment outcomes. Nevertheless, these individual differences may provide avenues for predicting individual responses to treatment with the view to prospectively matching children with ASD to treatments best-suited to meeting their individual needs. This commentary suggests that the behavioural characterstics that are critical to accurate early diferential diagnosis of ASD may be poor predictors of outcomes. However, factors that are not unique to ASD may in fact be good predictors of treatment outcomes. This commentary illustrates these points with reference to the results of recent studies demonstrating the problems, and possibilities, that individual differences currently present when it comes to understanding and promoting learning in children with ASD.
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39. Vohra R, Madhavan S, Sambamoorthi U, St Peter C. {{Access to services, quality of care, and family impact for children with autism, other developmental disabilities, and other mental health conditions}}. {Autism};2013 (Dec 18)
This cross-sectional study examined perceived access to services, quality of care, and family impact reported by caregivers of children aged 3-17 years with autism spectrum disorders, as compared to caregivers of children with other developmental disabilities and other mental health conditions. The 2009-2010 National Survey of Children with Special Health Care Needs was utilized to examine the association between child’s special needs condition and three outcomes (N = 18,136): access to services (difficulty using services, difficulty getting referrals, lack of source of care, and inadequate insurance coverage), quality of care (lack of care coordination, lack of shared decision making, and no routine screening), and family impact (financial, employment, and time-related burden). Multivariate logistic regressions were performed to compare caregivers of children with autism spectrum disorders to caregivers of children with developmental disabilities (cerebral palsy, Down syndrome, developmental delay, or intellectual disability), mental health conditions (attention deficit hyperactivity disorder, anxiety, behavioral/conduct problems, or depression), or both developmental disabilities and mental health conditions. Caregivers of children with autism spectrum disorders were significantly more likely to report difficulty using services, lack of source of care, inadequate insurance coverage, lack of shared decision making and care coordination, and adverse family impact as compared to caregivers of children with developmental disabilities, mental health conditions, or both.
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40. Volkmar FR, McPartland JC. {{From Kanner to DSM-5: Autism as an Evolving Diagnostic Concept}}. {Annu Rev Clin Psychol};2013 (Dec 9)
Seven decades have elapsed since Leo Kanner described the syndrome he termed early infantile autism. Over this time, and particularly over the past two decades, noteworthy changes have occurred in how the condition is conceptualized. Here we provide an overview of these changes, beginning with a brief discussion of the significance of classification in general before discussing Kanner’s original paper and subsequent changes. We touch on relevant issues, such as comorbidity, dimensional aspects of diagnosis and screening, and the complex issue of diagnosis relative to eligibility for services. Approaches to diagnosis have tended to swing from emphasizing overarching groups (lumping) to focusing on potentially distinct subgroups (splitting). Autism raises particular problems given the broad range of syndrome expression over age and developmental level. The most recent revision of the American Psychiatric Association’s diagnostic taxonomy marks a significant departure from its predecessor and has been the focus of much debate. It remains unclear which of the currently existing categorical approaches will ultimately be most widely applied. We hope to convey a sense of areas in which consensus has been achieved and areas of continued controversy. Expected final online publication date for the Annual Review of Clinical Psychology Volume 10 is March 20, 2014. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
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41. Volkmar FR, Reichow B. {{Infants and toddlers with autism: The promise and the challenges}}. {Int J Speech Lang Pathol};2013 (Dec 18)
There has been a marked increase in interest in early identification of young children with and at risk for autism. This interest has reflected advances in research as well as an awareness of the potential for major changes in long-term outcome as a result of intervention. Several issues have complicated these efforts. There continue to be challenges to implementation of effective screening and diagnostic approaches in young children. Although the body of evidence-based research on treatment has increased, it remains limited. Despite these issues, important findings have emerged that may assist in fostering better approaches to screening, diagnosis, and documenting treatment impact.
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42. Watanabe T, Abe O, Kuwabara H, Yahata N, Takano Y, Iwashiro N, Natsubori T, Aoki Y, Takao H, Kawakubo Y, Kamio Y, Kato N, Miyashita Y, Kasai K, Yamasue H. {{Mitigation of Sociocommunicational Deficits of Autism Through Oxytocin-Induced Recovery of Medial Prefrontal Activity: A Randomized Trial}}. {JAMA Psychiatry};2013 (Dec 18)
IMPORTANCE Sociocommunicational deficits make it difficult for individuals with autism spectrum disorders (ASD) to understand communication content with conflicting verbal and nonverbal information. Despite growing prospects for oxytocin as a therapeutic agent for ASD, no direct neurobiological evidence exists for oxytocin’s beneficial effects on this core symptom of ASD. This is slowing clinical application of the neuropeptide. OBJECTIVE To directly examine whether oxytocin has beneficial effects on the sociocommunicational deficits of ASD using both behavioral and neural measures. DESIGN, SETTING, AND PARTICIPANTS At the University of Tokyo Hospital, we conducted a randomized, double-blind, placebo-controlled, within-subject-crossover, single-site experimental trial in which intranasal oxytocin and placebo were administered. A total of 40 highly functioning men with ASD participated and were randomized in the trial. INTERVENTIONS Single-dose intranasal administration of oxytocin (24 IU) and placebo. MAIN OUTCOMES AND MEASURES Using functional magnetic resonance imaging, we examined effects of oxytocin on behavioral neural responses of the participants to a social psychological task. In our previous case-control study using the same psychological task, when making decisions about social information with conflicting verbal and nonverbal contents, participants with ASD made judgments based on nonverbal contents less frequently with longer time and could not induce enough activation in the medial prefrontal cortex. Therefore, our main outcomes and measures were the frequency of the nonverbal information-based judgments (NVJs), the response time for NVJs, and brain activity of the medial prefrontal cortex during NVJs. RESULTS Intranasal oxytocin enabled the participants to make NVJs more frequently (P = .03) with shorter response time (P = .02). During the mitigated behavior, oxytocin increased the originally diminished brain activity in the medial prefrontal cortex (P < .001). Moreover, oxytocin enhanced functional coordination in the area (P < .001), and the magnitude of these neural effects was predictive of the behavioral effects (P </= .01). CONCLUSIONS AND RELEVANCE These findings provide the first neurobiological evidence for oxytocin’s beneficial effects on sociocommunicational deficits of ASD and give us the initial account for neurobiological mechanisms underlying any beneficial effects of the neuropeptide. TRIAL REGISTRATION umin.ac.jp/ctr Identifier: UMIN000002241 and UMIN000004393.
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43. Yasui DH, Gonzales ML, Aflatooni JO, Crary FK, Hu DJ, Gavino BJ, Golub MS, Vincent JB, Schanen NC, Olson CO, Rastegar M, Lasalle JM. {{Mice with an isoform-ablating Mecp2-exon 1 mutation recapitulate the neurologic deficits of Rett syndrome}}. {Hum Mol Genet};2013 (Dec 18)
Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT OMIM 312750)_ENREF_1. Alternative inclusion of MECP2/Mecp2 exon 1 with exons 3, and 4 encode MeCP2-e1 orMeCP2-e2 protein isoforms with unique amino termini. While most MECP2 mutations are located in exons 3 and 4 thus affecting both isoforms, MECP2 exon 1 mutations but not exon 2 mutations have been identified in RTT patients, suggesting that MeCP2-e1 deficiency is sufficient to cause RTT. As expected, genetic deletion of Mecp2 exons 3 and/or 4 recapitulate RTT-like neurologic defects in mice. However, Mecp2 exon 2 knockout mice have normal neurologic function. Here a naturally occurring MECP2 exon 1 mutation is recapitulated in a mouse model by genetic engineering. A point mutation in the translational start codon of Mecp2 exon1, transmitted through the germline, ablates MeCP2-e1 translation while preserving MeCP2-e2 production in mouse brain. The resulting MeCP2-e1 deficient mice developed forelimb stereotypy, hind limb clasping, excessive grooming, and hypo-activity prior to death between 7-31 weeks. MeCP2-e1 deficient mice also exhibited abnormal anxiety, sociability, and ambulation. Despite MeCP2-e1 and MeCP2-e2 sharing 96% amino acid identity differences were identified. A fraction of phosphorylated MeCP2-e1 differed from the bulk of MeCP2 in sub-nuclear localization and co-factor interaction. Furthermore, MeCP2-e1 exhibited enhanced stability compared with MeCP2-e2 in neurons. Therefore, MeCP2-e1 deficient mice implicate MeCP2-e1 as the sole genetic contributor to RTT with non-redundant functions.
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44. Zhao XN, Usdin K. {{Gender and Cell-Type Specific Effects of the Transcription Coupled Repair Protein, ERCC6/CSB, on Repeat Expansion in a Mouse Model of the Fragile X-Related Disorders}}. {Hum Mutat};2013 (Dec 18)
The Repeat Expansion Diseases (REDs) are human genetic disorders that arise from expansion of a tandem repeat tract. The Fragile X-related disorders are members of this disease group in which the repeat unit is CGG/CCG and is located in the 5′ untranslated region of the FMR1 gene. Affected individuals often show mosaicism with respect to repeat number resulting from both expansion and contraction of the repeat tract, however, the mechanism responsible for these changes in repeat number are unknown. Work from a variety of model systems suggests that Transcription Coupled Repair (TCR) may contribute to repeat instability in diseases resulting from CAG/CTG-repeat expansion. To test whether TCR could contribute to repeat instability in the Fragile X-related disorders, we tested the effect of mutations in Csb (Cockayne Syndrome group B), a gene essential for TCR, in a knock-in mouse model of these disorders. We found that the loss of CSB affects expansions in a gender and cell type-specific manner. Our data also show an unanticipated gender difference in instability even in Csb+/+ animals that may have implications for our understanding of the mechanism of repeat expansion in the FX mouse model and perhaps for humans as well. This article is protected by copyright. All rights reserved.
