1. {{Generation and analysis of the Rett syndrome-associated MeCP2- null rat model}}. {Yi Chuan};2016 (Nov 20);38(11):1004-1011.
MeCP2 mutations are associated with the Rett syndrome (RTT). Currently, there is an urgent need for new animal models for RTT as the existing MeCP2 knockout mouse models fail to fully mimic the pathogenesis and symptoms of RTT patients. In order to investigate the role of MeCP2 in brain development and RTT pathogenesis, we aimed to set up the MeCP2-null rat model using the CRISPR/Cas9 technology. Firstly we constructed the MeCP2 targeting vector and then microinjected Cas9 mRNA and sgRNA mixtures into fertilized ova of SD rats. The sgRNA was designed to target the exon 2 of MeCP2. Next, knockout rats were confirmed using DNA sequencing and Western blotting. Lastly, phenotypes including growth and behaviors of MeCP2 knockout rats were analyzed. The results indicated that the MeCP2 knockout rats showed body weight loss, anxiety tendency and cognitive deficits. The MeCP2-null rat model established in this study recapitulates the major symptoms of RTT patients and provides an alternative tool for future studies of MeCP2 functions.
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2. {{New Fragile X tests may improve research on the disorder: Tests’ ability to provide detailed information about genetic mutations and lower cost raise hope for clinical use and newborn screening}}. {Am J Med Genet A};2016 (Dec);170(12):3064-3065.
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3. {{An effective treatment for autism}}. {Arch Dis Child};2016 (Nov 17)
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4. Berding K, Donovan SM. {{Microbiome and nutrition in autism spectrum disorder: current knowledge and research needs}}. {Nutr Rev};2016 (Dec);74(12):723-736.
Autism spectrum disorder (ASD) is the fastest growing neurodevelopmental disorder in the United States. Besides genetic risks, environmental factors have been suggested to contribute to the increase in ASD diagnosis over the past decade. Several studies have reported abnormalities in microbiota composition and differences in microbial metabolites in children with ASD. Gastrointestinal discomfort is commonly reported in children with ASD. Additionally, food selectivity and picky eating patterns are commonly reported. A number of mechanisms underlying the interaction between nutrition, the gut microbiota, and ASD symptoms via the microbiota-gut-brain axis have been proposed, including immune, hormonal, or neuronal pathways. Here, the current evidence base regarding the gut environment and nutritional status of children with ASD is reviewed. Potential underlying mechanisms of the microbiota-gut-brain axis in ASD and the interplay between nutrition, microbiota, and ASD symptoms are also reviewed. Future studies investigating the microbiota in the context of dietary intake are needed to increase understanding of the interplay between diet and the gut microbiota in ASD and to identify potential dietary, probiotic, or prebiotic intervention strategies.
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5. Burrows CA, Usher LV, Mundy PC, Henderson HA. {{The salience of the self: Self-referential processing and internalizing problems in children and adolescents with autism spectrum disorder}}. {Autism Res};2016 (Nov 20)
Children and adolescents with autism spectrum disorder (ASD) demonstrate atypical processing of, and memory for, self-referenced information, which may contribute to the heightened rates of co-occurring internalizing problems. We assessed affective and cognitive aspects of self-referential processing in verbally-fluent children with ASD (N = 79), and an age-matched comparison sample (COM, N = 73) of children without an autism diagnosis. We examined group differences in these two aspects of the self-system, and their joint contributions to individual differnces in internalizing problems. Using a self-referenced memory (SRM) task, participants indicated whether a series of positive and negative trait adjectives described themselves and a well-known fictional character. Participants were then surprised with a recognition memory test on the same adjectives. Overall, individuals with ASD showed a reduction in the extent to which they preferentially endorsed positive over negative trait adjectives about themselves, and a reduction in their preferential memory for self- over other-referenced information. Across the full sample, these two aspects of self-referential processing jointly predicted self-reported internalizing problems. Specifically, self-evaluations were strongly and inversely associated with internalizing problems but only for children with relatively high SRM. These findings suggest that the salience of the self influences the extent to which affective self-evaluations impact emotional functioning for youth both with and without ASD. Implications for basic (e.g., developmental) and translational (e.g., intervention) research are discussed. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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6. Christensen J, Overgaard M, Parner ET, Vestergaard M, Schendel D. {{Risk of epilepsy and autism in full and half siblings-A population-based cohort study}}. {Epilepsia};2016 (Nov 8)
OBJECTIVE: Epilepsy and autism spectrum disorder (ASD) often occur together in the same individual. However, it remains unknown whether siblings of children with ASD have an increased risk of epilepsy and vice versa. This study determines the risk of ASD and epilepsy among younger siblings of children with ASD and epilepsy. DESIGN: The study included all children born in Denmark between January 1, 1980 and 31 December 2006 who participated in follow-up until December 31, 2012 (1,663,302 children). We used Cox regression to calculate the adjusted hazard ratio (aHR) and the Kaplan-Meier method to calculate the cumulative incidence. RESULTS: The overall aHR of epilepsy in younger siblings increased by 70% (aHR 1.70, 95% confidence interval [CI] 1.34-2.16%) if the older sibling had ASD compared with siblings where the older sibling did not have ASD. The cumulative incidence of epilepsy at 20 years of age was 2.54% (95% CI 1.97-3.26%) if the older sibling had ASD, whereas the cumulative incidence of epilepsy at 20 years of age was 1.63% (95% CI 1.60-1.66%) if the older sibling did not have ASD. The overall aHR of ASD in younger siblings increased by 54% if the older sibling had epilepsy (aHR 1.54, 95% CI 1.32-1.80) compared with siblings where the older sibling did not have epilepsy. The cumulative incidence of ASD at 20 years of age was 2.06% (95% CI 1.84-2.32%) if the older sibling had epilepsy, whereas the cumulative incidence of ASD at 20 years of age was 1.27% (95% CI 1.25-1.29%) if the older sibling did not have epilepsy. SIGNIFICANCE: The cross-disorder sibling risk of epilepsy and ASD was increased for the two disorders, which suggests that genes or environmental factors shared by family members may play a causal role in the co-occurrence of ASD and epilepsy.
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7. Curran C, Debbarma S, Sedky K. {{Fragile X and Obstructive Sleep Apnea Syndrome: Case Presentation and Management Challenges}}. {J Clin Sleep Med};2016 (Nov 14)
ABSTRACT: A high prevalence of obstructive sleep apnea (OSA) has been reported in individuals with fragile X syndrome (FXS). Untreated OSA can further complicate both medical and cognitive sequel. Thus, identifying the diagnostic and treatment challenges that arise in these individuals is essential. We describe an adolescent with FXS who presented with significant OSA symptoms, and the challenges associated with management in this case.
8. Degroote S, Hunting D, Takser L. {{Improved assessment of sensorimotor gating in animal models relevant to ASD: A data modelling approach to quantify PrePulse Inhibition of the acoustic startle reflex}}. {J Neurosci Methods};2016 (Nov 14)
BACKGROUND: The PrePulse Inhibition (PPI) of the acoustic startle reflex is a neurobehavioral test frequently used in neurodevelopmental studies. Most PPI studies have used rodent models of schizophrenia; however, the currently used data analysis method does not take into account the variability present in autistic preclinical models. NEW METHOD: We propose a new data modelling approach for PPI data obtained from animals exposed to valproic acid or endocrine disruptors, using mixed modeling; and a new calculation of inhibition of the acoustic startle, which takes into account the habituation phenomenon. RESULTS: Habituation, or possibly exhaustion, occurred in all groups. The classic method of calculation of inhibition analysed with ANOVA indicated no group or sex effect for the overall inhibition of startle. In contrast, when analysed using mixed models, group and sex effects were observed. In addition, using the new method of calculation, both statistical analyses showed a sex effect, with females having decreased global inhibition but no group effect. ANOVA generated more false positive results for PPI in relation to prepulse intensities. COMPARISON WITH EXISTING METHOD: The current classic method of analysis of PPI test is a calculation of inhibition based on average startle amplitude throughout the test session and a statistical ANOVA analysis. This method does not take into account habituation/exhaustion and within-subject and -group variability. CONCLUSIONS: The results of this study demonstrate that use of ANOVA analysis leads to misinterpretation of PPI data in autistic preclinical models and we propose a new data analysis adapted to these models.
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9. Dima D, Lazari O, Schmeck K, Spiegel R, Bronnimann A, Goth K, Herbrecht E. {{Assessing symptoms during comprehensive interventions for young children with autism spectrum disorder: Development and preliminary analysis of the Autism Behaviour Coding System (ABCS)}}. {Psychiatry Res};2016 (Nov 10);247:63-67.
The aims of this paper are to present the Autism Behaviour Coding System (ABCS), a novel, video-based observational instrument for assessing core autism symptoms during intensive early interventions in autism spectrum disorder (ASD), to provide preliminary data on its psychometric characteristics and to discuss its clinical utility. Video recordings of child-therapist interactions during the ‘Fruhintervention bei autistischen Storungen’ (FIAS) were coded by treatment-independent raters who were blind with respect to the temporal order of the sequences. We assessed inter-rater reliability using intra-class correlations (ICCs). Mean ICCs ranged from 0.85 to 0.90. We analysed the sensitivity of the ABCS to change by comparing the change in ABCS scores with the change in a validated external measure of level of functioning (Developmental Disorder-Child-Global Assessment of functioning Scale, DD-C-GAS) in a sample of 15 children who received intensive treatment. Both the ABCS and DD-C-GAS indicated that the intervention improved symptoms. The ABCS has promise as a research instrument and has good to excellent inter-rater agreement and sensitivity to intervention-related changes. This pilot study suggests that the ABCS may be useful as an objective method of assessing the proximal effects of therapy in young children with ASD.
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10. Finucane B, Lincoln S, Bailey L, Martin CL. {{Prognostic dilemmas and genetic counseling for prenatally-detected fragile X gene expansions}}. {Prenat Diagn};2016 (Nov 11)
With widespread adoption of fragile X carrier screening in pregnant women, the number of expectant couples receiving news of an unanticipated Fragile X Mental Retardation 1 (FMR1) gene expansion has increased. The most common abnormal result from maternal FMR1 testing involves an intermediate allele, also known as a gray zone result, which requires genetic counseling but poses minimal risk for an adverse developmental outcome. By contrast, the finding of a maternal FMR1 pre- or full mutation during pregnancy has important implications for the woman herself, her unborn child, and her extended family. These multiple levels of impact, in addition to the complex inheritance pattern and variable expressivity of fragile X-associated disorders, cause significant stress for newly-identified expectant couples and pose unique challenges for genetic counselors in the prenatal setting.
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11. Fox F, Aabe N, Turner K, Redwood S, Rai D. {{« It was like walking without knowing where I was going »: A Qualitative Study of Autism in a UK Somali Migrant Community}}. {J Autism Dev Disord};2016 (Nov 17)
Increasing recognition of autism in Somali migrant communities means that appropriate support services are needed. Attitudes to autism and barriers related to help-seeking in these communities are poorly understood. We aimed to assess what families affected by autism need, and how health, education and social care services can support them. In partnership with the local Somali community the research team conducted 15 in-depth interviews with parents affected by autism. Two themes are reported; ‘Perceptions of Autism’ and ‘Navigating the System’. Our research shows the importance of understanding cultural views of autism and the need to raise awareness, reduce stigma and provide support to encourage families not to delay seeking help for their children.
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12. Grimaldi R, Cela D, Swann JR, Vulevic J, Gibson GR, Tzortzis G, Costabile A. {{In vitro fermentation of B-GOS: Impact on faecal bacterial populations and metabolic activity in autistic and non-autistic children}}. {FEMS Microbiol Ecol};2016 (Nov 16)
Children with autism spectrum disorders (ASD) often suffer gastrointestinal problems consistent with imbalances in the gut microbial population. Treatment with antibiotics or pro/prebiotics has been postulated to regulate microbiota and improve gut symptoms, but there is a lack of evidence for such approaches, especially for prebiotics. This study assessed the influence of a prebiotic galactooligosaccharide (B-GOS) on gut microbial ecology and metabolic function using faecal samples from autistic and non-autistic children in an in vitro gut model system. Bacteriology was analysed using flow cytometry combined with fluorescence in situ hybridization and metabolic activity by HPLC and 1H-NMR. Consistent with previous studies, the microbiota of ASD children contained a higher number of Clostridium spp. and a lower number of bifidobacteria compared to non-autistic children. B-GOS administration significantly increased bifidobacterial populations in each compartment of the models, both with autistic and non-autistic derived samples, and lactobacilli in the final vessel of non-autistic models. In addition, changes in other bacterial population have been seen in particular for Clostridium, Rosburia, Bacteroides, Atopobium, F. prausnitzii, Sutterella spp. and Veillonellaceae. Furthermore, the addition of B-GOS to the models significantly altered short chain fatty acid production in both groups, and increased ethanol and lactate in autistic children.
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13. Jones EJ, Venema K, Earl RK, Lowy R, Webb SJ. {{Infant social attention: an endophenotype of ASD-related traits?}}. {J Child Psychol Psychiatry};2016 (Nov 8)
BACKGROUND: As a neurodevelopmental disorder, symptoms of ASD likely emerge from a complex interaction between preexisting genetic vulnerabilities and the child’s environment. One way to understand causal paths to ASD is to identify dimensional ASD-related traits that vary in the general population and that predispose individuals with other risk factors toward ASD. Moving beyond behavioral traits to explore underlying neurocognitive processes may further constrain the underlying genetics. Endophenotypes are quantitative, heritable, trait-related differences that are generally assessed with laboratory-based methods, can be identified in the general population, and may be more closely tied to particular causal chains that have a more restricted set of genetic roots. The most fruitful endophenotypes may be those observed in infancy, prior to the emergence of behavioral symptoms that they are hypothesized to cause. Social motivation is an ASD-related trait that is highly heritable. In this study, we investigate whether infant endophenotypes of social attention relate to familial risk for lower social motivation in the general population. METHODS: We examined whether infant social attention (measured using habituation, EEG power, and event-related potential tasks previously used in infants/toddlers with ASD) varies quantitatively with parental social motivation in 117 six-month-old and 106 twelve-month-old typically developing infants assessed cross-sectionally. To assess heritable aspects of social motivation, primary caregiver biological parents completed two self-report measures of social avoidance and discomfort that have shown high heritability in previous work. RESULTS: Parents with higher social discomfort and avoidance had infants who showed shorter looks to faces but not objects; reduced theta power during naturalistic social attention; and smaller P400 responses to faces versus objects. CONCLUSIONS: Early reductions in social attention are continuously related to lower parental social motivation. Alterations in social attention may be infant endophenotypes of social motivation traits related to ASD.
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14. Kim E, Kyeong S, Cheon KA, Park B, Oh MK, Chun JW, Park HJ, Kim JJ, Song DH. {{Corrigendum to « Neural responses to affective and cognitive theory of mind in children and adolescents with autism spectrum disorder » [Neurosci. Lett. 621 (2016) 117-125]}}. {Neurosci Lett};2016 (Nov 14)
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15. Li C, Schaefer M, Gray C, Yang Y, Furmanski O, Liu S, Worley P, Mintz CD, Tao F, Johns RA. {{Sensitivity to isoflurane anesthesia increases in autism spectrum disorder Shank3+/c mutant mouse model}}. {Neurotoxicol Teratol};2016 (Nov 14)
Autism is a heterogeneous developmental disorder characterized by impaired social interaction, impaired communication skills, and restricted and repetitive behavior. The abnormal behaviors of these patients can make their anesthetic and perioperative management difficult. Evidence in the literature suggests that some patients with autism or specific autism spectrum disorders (ASD) exhibit altered responses to pain and to anesthesia or sedation. A genetic mouse model of one particular ASD, Phelan McDermid Syndrome, has been developed that has a Shank3 haplotype truncation (Shank3+/Deltac). These mice exhibit important characteristics of autism that mimic human autistic behavior. Our study demonstrates that a Shank3+/DeltaC mutation in mice is associated with a reduction in both the MAC and RREC50 of isoflurane and down regulation of NR1 in vestibular nuclei and PSD95 in spinal cord. Decreased expression of NR1 and PSD95 in the central nervous system of Shank3+/DeltaC mice could help reduce the MAC and RREC50 of isoflurane, which would warrant confirmation in a clinical study. If Shank3 mutations are found to affect anesthetic sensitivity in patients with ASD, better communication and stricter monitoring of anesthetic depth may be necessary.
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16. Lindsay S, Hounsell KG, Cassiani C. {{A scoping review of the role of LEGO(R) therapy for improving inclusion and social skills among children and youth with autism}}. {Disabil Health J};2016 (Nov 10)
BACKGROUND: LEGO(R) therapy uses children’s natural interest in play to help motivate behavioural change and may be an effective teaching tool to increase social competency and communication skills. Although the literature is growing it has not been synthesized. OBJECTIVES: To review the literature on the role of LEGO(R) therapy on social skills and inclusion among children and youth with Autism Spectrum Disorder (ASD). METHODS: A scoping review was conducted, involving comprehensive searches of international databases. Eligible articles included: (a) youth aged 19 or younger, with ASD; (b) empirical research on LEGO(R) therapy interventions; (c) published from 1996 to 2016 in a peer-reviewed journal, conference proceedings, or dissertation. RESULTS: Of the 6964 studies identified, 15 articles-involving 293 participants, aged 5-16 (mean age 8.7 years), across five countries-met the inclusion criteria. Although the outcomes of the LEGO(R) therapy varied across the studies, 14 studies reported at least one improvement in social and communication skills (e.g., building friendships, improved social interactions and social competence), ASD-specific behaviors, belonging, family relationships, coping, and reductions in playing alone. CONCLUSIONS: Although LEGO(R) therapy shows promise as an intervention for children and youth with ASD, more rigorously designed studies are needed to fully understand its impact.
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17. Mechler K, Hoffmann GF, Dittmann RW, Ries M. {{Defining the hidden evidence in autism research. Forty per cent of rigorously designed clinical trials remain unpublished – a cross-sectional analysis}}. {Int J Methods Psychiatr Res};2016 (Nov 9)
Autism spectrum disorders (ASD) have a prevalence of up to 2.7% and show significant rates of comorbidities. Pharmacological treatment can be difficult. New treatment options are needed, several are currently under investigation. Publication bias presents a major problem in current clinical research. This study was designed to quantify publication bias in rigorously designed ASD research. The database at ClinicalTrials.gov was searched for all completed randomized controlled clinical trials investigating interventions in ASD and their results made public. If results could neither be retrieved through search of the database, nor of scientific databases nor by enquiries of the responsible parties or sponsors listed, a trial was defined as not published. The search delivered N = 30 (60%) trials were published, N = 20 (40%) remained unpublished, N = 2,421 (59%) patients were enrolled in the published trials, N = 1,664 (41%) patients in the unpublished trials, time to publication was 21.4 months [standard deviation (SD) = 18.48; range = -5 to 80 months]. Results of N = 22 trials were available through ClinicalTrials.gov. Characteristics of published compared to unpublished trials did not show apparent differences. The majority of trials investigated drugs. The results emphasize the serious issue of publication bias. The large proportion of unpublished results precludes valuable information and has the potential to distort evidence for treatment approaches in ASD.
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18. Moriuchi JM, Klin A, Jones W. {{Mechanisms of Diminished Attention to Eyes in Autism}}. {Am J Psychiatry};2016 (Nov 18):appiajp201615091222.
OBJECTIVE: Two hypotheses, gaze aversion and gaze indifference, are commonly cited to explain a diagnostic hallmark of autism: reduced attention to others’ eyes. The two posit different areas of atypical brain function, different pathogenic models of disability, and different possible treatments. Evidence for and against each hypothesis is mixed but has thus far focused on older children and adults. The authors evaluated both mechanistic hypotheses in two sets of experiments at the time of initial diagnosis. METHOD: Eye-tracking data were collected in 86 2-year-olds: 26 with autism, tested at initial diagnosis; 38 matched typically developing children; and 22 matched developmentally delayed children. In two experiments, the authors measured response to direct and implicit cueing to look at the eyes. RESULTS: When directly cued to look at the eyes, 2-year-olds with autism did not look away faster than did typically developing children; their latency varied neither categorically nor dimensionally by degree of eye cueing. Moreover, direct cueing had a stronger sustained effect on their amount of eye-looking than on that of typically developing children. When presented with implicit social cues for eye-looking, 2-year-olds with autism neither shifted their gaze away nor more subtly averted their gaze to peripheral locations. CONCLUSIONS: The results falsify the gaze aversion hypothesis; instead, at the time of initial diagnosis, diminished eye-looking in autism is consistent with passive insensitivity to the social signals in others’ eyes.
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19. Motavalli Mukaddes N, Mutluer T, Ayik B, Umut A. {{What Happens to Children Who Move off the Autism Spectrum? A Clinical Follow-Up Study}}. {Pediatr Int};2016 (Nov 12)
OBJECTIVES: There is controversial information on school age outcome of individuals who lose the diagnosis of autism and achieve « optimal outcome » (OO). The present study aimed to assess the autism symptoms and other psychiatric disorders in a group of children with a past history of autism. METHODS: The study includes individuals (n=26) who lost the diagnosis of autism two to eight years previously. Clinical assessment was done with both parents and children. DSM-V criteria were used for diagnosis of ASD. In addition, Childhood Autism Rating Scale (CARS) and Social Communication Questionnaire (SCQ, current version) were used. Psychiatric disorders were assessed using Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime Version (K-SADS -PL). RESULTS: None of the participants met criteria for an autism diagnosis. Ninety-two percent had a lifetime diagnosis and 81% had a present psychiatric disorder based on the K-SADS. ADHD, specific phobia and Obsessive Compulsive Disorder (OCD) were the most common disorders. CONCLUSIONS: Our results indicate that the improved status with regard to autism symptomatology is maintained over time. However, these individuals were vulnerable to developing other psychiatric disorders. It is crucial to maintain psychiatric follow up of children who move-off ASD. This article is protected by copyright. All rights reserved.
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20. Naerland T, Bakke KA, Storvik S, Warner G, Howlin P. {{Age and gender-related differences in emotional and behavioural problems and autistic features in children and adolescents with Down syndrome: a survey-based study of 674 individuals}}. {J Intellect Disabil Res};2016 (Nov 13)
BACKGROUND: Recent studies have indicated an increased risk of autism, behavioural and emotional problems and attention-deficit/hyperactivity disorder in individuals with Down syndrome. METHOD: In a large-scale survey-based study, we examined the rates of these problems and their relationship to age and gender, in a sample of 674 individuals (4-18 years) with Down syndrome. The relationship with IQ level was also explored in a subsample (n = 175). The Strengths and Difficulties Questionnaire and the Social Communication Questionnaire were used to assess behavioural and emotional problems and autism traits. RESULTS: On the Strengths and Difficulties Questionnaire, peer problems were the most frequently reported difficulty (48% > cut-off), followed by hyperactivity/inattention (34% > cut-off). On the Social Communication Questionnaire, 37% scored at or above cut-off (>/=15) for autism spectrum disorder; 17% were at or above the suggested cut-off (>/=22) for autism. Little association between age and behavioural or emotional problems or with severity of autistic symptomatology was found. However, peer problems were more common in adolescents than in junior school children (P < 0.001); Hyperactivity/inattention was less prevalent among adolescents (P < 0.001). CONCLUSIONS: High rates of autistic features, emotional and behavioural problems are documented. These problems are related to age, gender and degree of intellectual disability. Lien vers le texte intégral (Open Access ou abonnement)
21. Parente DJ, Garriga C, Baskin B, Douglas G, Cho MT, Araujo GC, Shinawi M. {{Neuroligin 2 nonsense variant associated with anxiety, autism, intellectual disability, hyperphagia, and obesity}}. {Am J Med Genet A};2016 (Nov 16)
Neuroligins are post-synaptic, cellular adhesion molecules implicated in synaptic formation and function. NLGN2 is strongly linked to inhibitory, GABAergic signaling and is crucial for maintaining the excitation-inhibition balance in the brain. Disruption of the excitation-inhibition balance is associated with neuropsychiatric disease. In animal models, altered NLGN2 expression causes anxiety, developmental delay, motor discoordination, social impairment, aggression, and sensory processing defects. In humans, mutations in NLGN3 and NLGN4 are linked to autism and schizophrenia; NLGN2 missense variants are implicated in schizophrenia. Copy number variants encompassing NLGN2 on 17p13.1 are associated with autism, intellectual disability, metabolic syndrome, diabetes, and dysmorphic features, but an isolated NLGN2 nonsense variant has not yet been described in humans. Here, we describe a 15-year-old male with severe anxiety, obsessive-compulsive behaviors, developmental delay, autism, obesity, macrocephaly, and some dysmorphic features. Exome sequencing identified a heterozygous, de novo, c.441C>A p.(Tyr147Ter) variant in NLGN2 that is predicted to cause loss of normal protein function. This is the first report of an NLGN2 nonsense variant in humans, adding to the accumulating evidence that links synaptic proteins with a spectrum of neurodevelopmental phenotypes. (c) 2016 Wiley Periodicals, Inc.
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22. Posar A, Visconti P. {{Omega-3 supplementation in autism spectrum disorders: A still open question?}}. {J Pediatr Neurosci};2016 (Jul-Sep);11(3):225-227.
One of the most commonly used complementary and alternative practices in children with autism spectrum disorder (ASD) is the supplementation of omega-3. We describe the case of a child with ASD who seemed to respond to omega-3 supplementation in a relevant and lasting manner. So far, based on the results of randomized clinical trials, evidence-based medicine negates the effectiveness of omega-3 in ASD children. Nevertheless, considering anecdotal experiences, including that of our patient, and nonrandomized trials, the presence of a subgroup of ASD patients who are really responders to omega-3 cannot be excluded. These responders might not appear when evaluating the omega-3 effects in a sample taken as a whole. Studies that check for the possible presence of this subgroup of ASD individuals responders to omega-3 are necessary.
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23. Rachubinski AL, Hepburn S, Elias ER, Gardiner K, Shaikh TH. {{The co-occurrence of Down syndrome and autism spectrum disorder: is it due to additional genetic variations?}}. {Prenat Diagn};2016 (Nov 17)
Individuals with Down syndrome (DS) are diagnosed with Autism Spectrum Disorder (ASD) at a significantly higher frequency than the typical population. The differentiation of ASD symptoms from those of severe intellectual disability presents diagnostic challenges, which have led to more refined methods in the clinical evaluation of ASD in DS. These improved phenotypic characterization methods not only provide better diagnosis of ASD in DS, but may also be useful in elucidating the etiology of the increased prevalence of ASD in DS. Since all individuals with the classic presentation of DS have trisomy 21, it is possible that those with co-occurring DS and ASD may have additional genetic variants which can act as modifiers of the phenotype, leading to the development of ASD.
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24. Rinaldi A. {{Piecing together a different picture: A host of new studies on autism have begun decoding the longstanding puzzle of its causes}}. {EMBO Rep};2016 (Nov 17)
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25. Rose S, Bennuri SC, Wynne R, Melnyk S, James SJ, Frye RE. {{Mitochondrial and redox abnormalities in autism lymphoblastoid cells: a sibling control study}}. {Faseb j};2016 (Nov 18)
Autism spectrum disorder (ASD) is associated with physiological abnormalities including abnormal redox and mitochondrial metabolism. Lymphoblastoid cell lines (LCLs) from some children with ASD exhibit increased oxidative stress, decreased glutathione redox capacity, and highly active mitochondria with increased vulnerability to reactive oxygen species (ROS). Because unaffected siblings (Sibs) of individuals with ASD share some redox abnormalities, we sought to determine whether LCLs from Sibs share ASD-associated mitochondrial abnormalities. We evaluated mitochondrial bioenergetics in 10 sets of LCLs from children with ASD, Sib, and unrelated/unaffected controls (Cons) after acute increases in ROS. Additionally, intracellular glutathione and uncoupling protein 2 (UCP2) gene expressions were quantified. Compared to sib, ASD LCLs exhibited significantly higher ATP-linked respiration, higher maximal and reserve respiratory capacity, and greater glycolysis and glycolytic reserve. ASD LCLs exhibited a significantly greater change in these parameters, with acute increases in ROS compared to both Sib and Con LCLs. Compared to Con, both ASD and Sib LCLs exhibited significantly higher proton leak respiration. Consistent with this, intracellular glutathione redox capacity was decreased and UCP2 gene expression was increased in both ASD and Sib compared to Con LCLs. These data indicate that mitochondrial respiratory function, not abnormal redox homeostasis, distinguishes ASD from unaffected LCLs.-Rose, S., Bennuri, S. C., Wynne, R., Melnyk, S., James, S. J., Frye, R. E. Mitochondrial and redox abnormalities in autism lymphoblastoid cells: a sibling control study.
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26. Russell M, Baldwin C, McClain D, Matthews N, Smith C, Quan SF. {{Symptoms of Restless Legs Syndrome in Biological Caregivers of Children with Autism Spectrum Disorders}}. {J Clin Sleep Med};2016 (Oct 28)
STUDY OBJECTIVES: In this study, we investigated the prevalence of symptoms of restless legs syndrome (RLS) in biological caregivers of children with a diagnosis of autism spectrum disorder (ASD).The relationship of RLS symptoms to caregiver health-related quality of life (HRQoL) was also examined. Finally, we compared the sleep quality and daytime behaviors of children with ASD in caregivers with and without symptoms of RLS. METHODS: Biological caregivers (N = 50) of children ages 6 to 11 y with a diagnosis of ASD completed a Sleep Habits Questionnaire (SHQ) that included RLS as determined by four questions. HRQoL was assessed using the Medical Outcomes Survey (MOS) 12-Item Short Form (SF-12). Caregivers also completed the Children’s Sleep Habits Questionnaire (CSHQ) and Child Behavior Checklist (CBCL6/18). RESULTS: Eleven caregivers (22%) fit the criteria for RLS symptomatology and caregivers with RLS reported poorer mental health. Caregivers with RLS described more night waking and greater internalized behavior problems in their children with ASD than the caregivers without RLS. CONCLUSIONS: Biological caregivers of children with ASD demonstrated a high prevalence of RLS symptoms and poorer mental health. RLS is known as a sleep disorder that has strong heritability, and it is possible that many of the children with ASD also have symptoms of RLS. RLS as a possible disruptor of sleep should be considered in caregivers and in their children with ASD.
27. Setoh P, Marschik PB, Einspieler C, Esposito G. {{Autism spectrum disorder and early motor abnormalities: Connected or coincidental companions?}}. {Res Dev Disabil};2016 (Nov 15);60:13-15.
Research in the past decade has produced a growing body of evidence showing that motor abnormalities in individuals with autism spectrum disorder (ASD) are the rule rather than the exception. The paper by Chinello and colleagues furthers our understanding of the importance of studying motor functions in ASD by testing a non-clinical population of parents-infant triads. Chinello and colleagues’ findings seem to suggest that subclinical motor impairments may exist in the typical population with inherited non-clinical ASD traits. Chinello and colleagues’ discovery also urges us to ask why motor abnormalities exist in typically developing infants when their parents present some subclinical ASD traits. We believe that there are at least two possibilities. In the first possible scenario, motor impairments and ASD traits form a single cluster of symptoms unique to a subgroup of individuals with autism. A second possible scenario is that motor atypicalities are the first warning signs of vulnerability often associated with atypical development. In conclusion, Chinello et al.’s findings inform us that subclinical atypical phenotypes such as sociocommunicative anomalies may be related to subclinical motor performances in the next generation. This adds to our knowledge by shedding some light on the relation of vulnerability in one domain with vulnerability in another domain.
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28. Shebani SO, Rehman R, Taliotis D, Magee A, Hayes NJ, Baspinar O, Martinez Z, Haas N, Duke C. {{Techniques for transcatheter retrieval of the occlutech ASD device United Kingdom-European multicenter report}}. {Catheter Cardiovasc Interv};2016 (Nov 10)
AIMS: To gather current experience in Occlutech ASD device retrieval, to determine whether snaring is an effective technique and to highlight alternative retrieval techniques; METHODS AND RESULTS: United Kingdom and European Occlutech ASD device implanters reported their experience in dealing with device embolization and retrieval. Six operators reported 12 retrieval cases. Retrieval was successful in 92% (11/12), although in most cases it was not straightforward and required multiple attempts using different techniques and equipment. When each different technique or equipment combination was considered separately, there were a total of 23 retrieval attempts. Fifteen attempts involved snaring the ball on the right atrial disc of the device (« the RA pin »). In 12/15 of these attempts the snare slipped off the RA pin. In 8/15 attempts snaring eventually failed. In two cases retrieval was facilitated by elongating the device in a blood vessel. In three cases retrieval was achieved by grasping the RA pin with the jaws of the Occlutech Flex II delivery cable; CONCLUSIONS: Snares do not grip the RA pin sufficiently to reliably retrieve the device. Funnelling the device into a blood vessel or grasping the RA pin with the jaws of the delivery cable may be successful alternatives. (c) 2016 Wiley Periodicals, Inc.
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29. Sun W, Poschmann J, Cruz-Herrera Del Rosario R, Parikshak NN, Hajan HS, Kumar V, Ramasamy R, Belgard TG, Elanggovan B, Wong CC, Mill J, Geschwind DH, Prabhakar S. {{Histone Acetylome-wide Association Study of Autism Spectrum Disorder}}. {Cell};2016 (Nov 17);167(5):1385-1397.e1311.
The association of histone modification changes with autism spectrum disorder (ASD) has not been systematically examined. We conducted a histone acetylome-wide association study (HAWAS) by performing H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) on 257 postmortem samples from ASD and matched control brains. Despite etiological heterogeneity, >/=68% of syndromic and idiopathic ASD cases shared a common acetylome signature at >5,000 cis-regulatory elements in prefrontal and temporal cortex. Similarly, multiple genes associated with rare genetic mutations in ASD showed common « epimutations. » Acetylome aberrations in ASD were not attributable to genetic differentiation at cis-SNPs and highlighted genes involved in synaptic transmission, ion transport, epilepsy, behavioral abnormality, chemokinesis, histone deacetylation, and immunity. By correlating histone acetylation with genotype, we discovered >2,000 histone acetylation quantitative trait loci (haQTLs) in human brain regions, including four candidate causal variants for psychiatric diseases. Due to the relative stability of histone modifications postmortem, we anticipate that the HAWAS approach will be applicable to multiple diseases.
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30. Tylee DS, Hess JL, Quinn TP, Barve R, Huang H, Zhang-James Y, Chang J, Stamova BS, Sharp FR, Hertz-Picciotto I, Faraone SV, Kong SW, Glatt SJ. {{Blood transcriptomic comparison of individuals with and without autism spectrum disorder: A combined-samples mega-analysis}}. {Am J Med Genet B Neuropsychiatr Genet};2016 (Nov 11)
Blood-based microarray studies comparing individuals affected with autism spectrum disorder (ASD) and typically developing individuals help characterize differences in circulating immune cell functions and offer potential biomarker signal. We sought to combine the subject-level data from previously published studies by mega-analysis to increase the statistical power. We identified studies that compared ex vivo blood or lymphocytes from ASD-affected individuals and unrelated comparison subjects using Affymetrix or Illumina array platforms. Raw microarray data and clinical meta-data were obtained from seven studies, totaling 626 affected and 447 comparison subjects. Microarray data were processed using uniform methods. Covariate-controlled mixed-effect linear models were used to identify gene transcripts and co-expression network modules that were significantly associated with diagnostic status. Permutation-based gene-set analysis was used to identify functionally related sets of genes that were over- and under-expressed among ASD samples. Our results were consistent with diminished interferon-, EGF-, PDGF-, PI3K-AKT-mTOR-, and RAS-MAPK-signaling cascades, and increased ribosomal translation and NK-cell related activity in ASD. We explored evidence for sex-differences in the ASD-related transcriptomic signature. We also demonstrated that machine-learning classifiers using blood transcriptome data perform with moderate accuracy when data are combined across studies. Comparing our results with those from blood-based studies of protein biomarkers (e.g., cytokines and trophic factors), we propose that ASD may feature decoupling between certain circulating signaling proteins (higher in ASD samples) and the transcriptional cascades which they typically elicit within circulating immune cells (lower in ASD samples). These findings provide insight into ASD-related transcriptional differences in circulating immune cells. (c) 2016 Wiley Periodicals, Inc.
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31. van Heumen L. {{Illuminating the « Black Hole »: Aging with Autism Spectrum Disorder}}. {Gerontologist};2016 (Dec);56(6):1180-1181.
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32. Whitehouse AJ. {{Commentary: Are we expecting too much from the extreme male brain theory of autism? A reflection on Kung et al. (2016)}}. {J Child Psychol Psychiatry};2016 (Dec);57(12):1463-1464.
Kung et al. (2016) contribute further evidence demonstrating no clear link between prenatal androgen exposure and the autism phenotype. Do these findings represent a nail in the coffin for the extreme male brain (EMB) theory of autism, or are we simply asking too much of the hypothesis? This commentary highlights the inconsistent findings that have appeared to undermine the EMB theory, but presents an argument that the data may not present an adequate test of the hypothesis. A research agenda is then outlined – the investigation of simple behavioural traits rather than the full combination of ASD behaviours – which may provide greater clarity as to how prenatal androgen exposure relates to developmental psychopathology.
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33. Wu S, Wu F, Ding Y, Hou J, Bi J, Zhang Z. {{Advanced parental age and autism risk in children: a systematic review and meta-analysis}}. {Acta Psychiatr Scand};2016 (Nov 14)
OBJECTIVE: Advanced parental age has raised additional concern as a risk factor of autism. We conducted a meta-analysis of observational studies investigating the association between advanced parental age and risk of autism. METHOD: PubMed, EMBASE, and Web of Science were searched for reports published up to November 11, 2015. Risk estimates from individual studies were pooled using random-effects models. RESULTS: Twenty-seven studies were included in the meta-analysis. Compared with the reference points, the lowest parental age category was associated with a reduced risk of autism in the offspring, with adjusted odds ratios (ORs) 0.89 (95% confidence intervals [CIs] 0.75-1.06) and 0.81 (95% CI 0.73-0.89) for mother and father, respectively, and the highest parental age category was associated with an increased risk of autism in the offspring, with adjusted ORs 1.41 (95% CI 1.29-1.55) and 1.55 (95% CI 1.39-1.73) for mother and father respectively. Dose-response meta-analysis indicated that an increase of 10 years in maternal and paternal age was associated with an 18% and 21% higher risk of autism. CONCLUSION: Advanced parental age was associated with an increased risk of autism in the offspring. More mechanistic studies are needed to further explain this positive association.
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34. Zhang C, Shen Y. {{A Cell Type-Specific Expression Signature Predicts Haploinsufficient Autism-Susceptibility Genes}}. {Hum Mutat};2016 (Nov 16)
Recent studies have identified many genes with rare de novo mutations in autism, but a limited number of these have been conclusively established as disease-susceptibility genes due to lack of recurrence and confounding background mutations. Such extreme genetic heterogeneity severely limits recurrence-based statistical power even in studies with a large sample size. Here we use cell-type specific expression profiles to differentiate mutations in autism patients from those in unaffected siblings. We report a gene expression signature in different neuronal cell types shared by genes with likely gene disrupting (LGD) mutations in autism cases. The signature reflects haploinsufficiency of risk genes enriched in transcriptional and post-transcriptional regulators, with the strongest positive associations with specific types of neurons in different brain regions, including cortical neurons, cerebellar granule cells, and striatal medium spiny neurons. When used to prioritize genes with a single LGD mutation in cases, a D-score derived from the signature achieved a precision of 40% as compared to the 15% baseline with a minimal loss in sensitivity. An ensemble model combining D-score with mutation intolerance metrics from Exome Aggregation Consortium further improved the precision to 60%, resulting in 117 high-priority candidates. These prioritized lists can facilitate identification of additional autism-susceptibility genes. This article is protected by copyright. All rights reserved.
