1. Alaerts K, Woolley DG, Steyaert J, Di Martino A, Swinnen SP, Wenderoth N. {{Underconnectivity of the Superior Temporal Sulcus predicts Emotion recognition deficits in Autism}}. {Soc Cogn Affect Neurosci};2013 (Sep 26)
Neurodevelopmental disconnections have been assumed to cause behavioral alterations in autism spectrum disorders (ASD). Here, we combined measurements of intrinsic functional connectivity (iFC) from resting-state fMRI with task-based fMRI to explore whether altered activity and/or iFC of the right posterior superior temporal sulcus (pSTS) mediates deficits in emotion recognition in ASD. Fifteen adults with ASD and fifteen matched-controls underwent resting-state and task-based fMRI, during which participants discriminated emotional states from point light displays (PLDs). Intrinsic FC of the right pSTS was further examined using 584 (278 ASD/306 controls) resting-state data of the Autism Brain Imaging Data Exchange (ABIDE).Participants with ASD were less accurate than controls in recognizing emotional states from PLDs. Analyses revealed pronounced ASD-related reductions both in task-based activity and resting-state iFC of the right pSTS with fronto-parietal areas typically encompassing the action observation network. Notably, pSTS-hypo-activity was related to pSTS-hypo-connectivity and both measures were predictive of emotion recognition performance with each measure explaining a unique part of the variance. Analyses with the large independent ABIDE-dataset replicated reductions in pSTS-iFC to fronto-parietal regions.These findings provide novel evidence that pSTS hypo-activity and hypo-connectivity with the fronto-parietal action observation network are linked to the social deficits characteristic of ASD.
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2. Camacho-Garcia RJ, Hervas A, Toma C, Balmana N, Cormand B, Martinez-Mir A, Scholl FG. {{Rare variants analysis of neurexin-1beta in autism reveals a novel start codon mutation affecting protein levels at synapses}}. {Psychiatr Genet};2013 (Sep 23)
Neurexins are synaptic plasma membrane proteins encoded by three genes (NRXN1, -2, -3) with alternative promoters. Mutations in neurexin genes have been identified in different neurodevelopmental disorders, including autism. Recently, two point mutations altering the translation initiation site of NRXN1beta (c.-3G>T and c.3G>T) have been described in patients with autism and mental retardation. In this study, we analyzed the NRXN1beta gene in a sample of 153 patients with autism. We report the identification of a novel mutation, c.3G>A (p.Met1), affecting the translation initiation site. Expression analysis showed that the c.3G>A mutation switches the translation start site of NRXN1beta to an in-frame downstream methionine and decreases synaptic levels of the mutant protein in cultured neurons. These data reinforce a role for synaptic defects of NRXN1beta in neurodevelopmental disorders.
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3. Campbell MG, Kohane IS, Kong SW. {{Pathway-based outlier method reveals heterogeneous genomic structure of autism in blood transcriptome}}. {BMC Med Genomics};2013 (Sep 24);6(1):34.
BACKGROUND: Decades of research strongly suggest that the genetic etiology of autism spectrum disorders (ASDs) is heterogeneous. However, most published studies focus on group differences between cases and controls. In contrast, we hypothesized that the heterogeneity of the disorder could be characterized by identifying pathways for which individuals are outliers rather than pathways representative of shared group differences of the ASD diagnosis. METHODS: Two previously published blood gene expression data sets — the Translational Genetics Research Institute (TGen) dataset (70 cases and 60 unrelated controls) and the Simons Simplex Consortium (Simons) dataset (221 probands and 191 unaffected family members) — were analyzed. All individuals of each dataset were projected to biological pathways, and each sample’s Mahalanobis distance from a pulled centroid was calculated to compare the number of case and control outliers for each pathway. RESULTS: Analysis of a set of blood gene expression profiles from 70 ASD and 60 unrelated controls revealed three pathways whose outliers were significantly overrepresented in the ASD cases: neuron development including axonogenesis and neurite development (29% of ASD, 3% of control), nitric oxide signaling (29%, 3%), and skeletal development (27%, 3%). Overall, 50% of cases and 8% of controls were outliers in one of these three pathways, which could not be identified using group comparison or gene-level outlier methods. In an independently collected data set consisting of 221 ASD and 191 unaffected family members, outliers in the neurogenesis pathway were heavily biased towards cases (20.8% of ASD, 12.0% of control). Interestingly, neurogenesis outliers were more common among unaffected family members (Simons) than unrelated controls (TGen), but the statistical significance of this effect was marginal (Chi squared P < 0.09). CONCLUSIONS: Unlike group difference approaches, our analysis identified the samples within the case and control groups that manifested each expression signal, and showed that outlier groups were distinct for each implicated pathway. Moreover, our results suggest that by seeking heterogeneity, pathway-based outlier analysis can reveal expression signals that are not apparent when considering only shared group differences.
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4. Carmo JC, Rumiati RI, Siugzdaite R, Brambilla P. {{Preserved imitation of known gestures in children with high-functioning autism}}. {ISRN Neurol};2013;2013:751516.
It has been suggested that children with autism are particularly deficient at imitating novel gestures or gestures without goals. In the present study, we asked high-functioning autistic children and age-matched typically developing children to imitate several types of gestures that could be either already known or novel to them. Known gestures either conveyed a communicative meaning (i.e., intransitive) or involved the use of objects (i.e., transitive). We observed a significant interaction between gesture type and group of participants, with children with autism performing known gestures better than novel gestures. However, imitation of intransitive and transitive gestures did not differ across groups. These findings are discussed in light of a dual-route model for action imitation.
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5. Chandler F, Dissanayake C. {{An investigation of the security of caregiver attachment during middle childhood in children with high-functioning autistic disorder}}. {Autism};2013 (Sep 26)
Previous research has investigated caregiver attachment relationships in children with autism during early childhood, with few differences found from matched control groups. However, little is known of this relationship during middle childhood (ages 8-12 years). In this study, the aim was to establish whether there are differences in the security of attachment in children with high-functioning autism compared to typically developing children. A secondary aim was to establish whether caregivers’ perceptions of their child’s attachment to them accorded with the children’s own reports. Twenty-one children with high-functioning autism and 17 typically developing children were administered the Kerns Security Scale and the Inventory of Parent and Peer Attachment-Revised, and caregivers completed the same questionnaires from the viewpoint of their child. There were no differences between the groups in the children’s and parents’ reports of attachment security. Parents’ and children’s reports were moderately correlated on the Kerns Security Scale but were not correlated on the Inventory of Parent and Peer Attachment-Revised. The results indicate that levels of attachment security in children with high-functioning autism are not different from those in typically developing children.
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6. Domes G, Kumbier E, Heinrichs M, Herpertz SC. {{Oxytocin Promotes Facial Emotion Recognition and Amygdala Reactivity in Adults With Asperger Syndrome}}. {Neuropsychopharmacology};2013 (Sep 26)
The neuropeptide oxytocin has recently been shown to enhance eye gaze and emotion recognition in healthy men. Here, we report a randomized double-blind, placebo-controlled trial that examined the neural and behavioral effects of a single dose of intranasal oxytocin on emotion recognition in individuals with Asperger syndrome (AS), a clinical condition characterized by impaired eye gaze and facial emotion recognition. Using functional magnetic resonance imaging, we examined whether oxytocin would enhance emotion recognition from facial sections of the eye vs. the mouth region and modulate regional activity in brain areas associated with face perception in both adults with AS, and a neurotypical control group. Intranasal administration of the neuropeptide oxytocin improved performance in a facial emotion recognition task in individuals with AS. This was linked to increased left amygdala reactivity in response to facial stimuli and increased activity in the neural network involved in social cognition. Our data suggest that the amygdala, together with functionally associated cortical areas mediate the positive effect of oxytocin on social cognitive functioning in AS.Neuropsychopharmacology accepted article preview online, 26 September 2013. doi:10.1038/npp.2013.254.
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7. Eapen V, Crncec R, Walter A. {{Exploring Links between Genotypes, Phenotypes, and Clinical Predictors of Response to Early Intensive Behavioral Intervention in Autism Spectrum Disorder}}. {Front Hum Neurosci};2013;7:567.
Autism spectrum disorder (ASD) is amongst the most familial of psychiatric disorders. Twin and family studies have demonstrated a monozygotic concordance rate of 70-90%, dizygotic concordance of around 10%, and more than a 20-fold increase in risk for first-degree relatives. Despite major advances in the genetics of autism, the relationship between different aspects of the behavioral and cognitive phenotype and their underlying genetic liability is still unclear. This is complicated by the heterogeneity of autism, which exists at both genetic and phenotypic levels. Given this heterogeneity, one method to find homogeneous entities and link these with specific genotypes would be to pursue endophenotypes. Evidence from neuroimaging, eye tracking, and electrophysiology studies supports the hypothesis that, building on genetic vulnerability, ASD emerges from a developmental cascade in which a deficit in attention to social stimuli leads to impaired interactions with primary caregivers. This results in abnormal development of the neurocircuitry responsible for social cognition, which in turn adversely affects later behavioral and functional domains dependent on these early processes, such as language development. Such a model begets a heterogeneous clinical phenotype, and is also supported by studies demonstrating better clinical outcomes with earlier treatment. Treatment response following intensive early behavioral intervention in ASD is also distinctly variable; however, relatively little is known about specific elements of the clinical phenotype that may predict response to current behavioral treatments. This paper overviews the literature regarding genotypes, phenotypes, and predictors of response to behavioral intervention in ASD and presents suggestions for future research to explore linkages between these that would enable better identification of, and increased treatment efficacy for, ASD.
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8. Falck-Ytter T, Bolte S, Gredeback G. {{Eye tracking in early autism research}}. {J Neurodev Disord};2013 (Sep 26);5(1):28.
Eye tracking has the potential to characterize autism at a unique intermediate level, with links ‘down’ to underlying neurocognitive networks, as well as ‘up’ to everyday function and dysfunction. Because it is non-invasive and does not require advanced motor responses or language, eye tracking is particularly important for the study of young children and infants. In this article, we review eye tracking studies of young children with autism spectrum disorder (ASD) and children at risk for ASD. Reduced looking time at people and faces, as well as problems with disengagement of attention, appear to be among the earliest signs of ASD, emerging during the first year of life. In toddlers with ASD, altered looking patterns across facial parts such as the eyes and mouth have been found, together with limited orienting to biological motion. We provide a detailed discussion of these and other key findings and highlight methodological opportunities and challenges for eye tracking research of young children with ASD. We conclude that eye tracking can reveal important features of the complex picture of autism.
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9. Ference J, Curtin S. {{Attention to lexical stress and early vocabulary growth in 5-month-olds at risk for autism spectrum disorder}}. {J Exp Child Psychol};2013 (Sep 26);116(4):891-903.
Typically developing infants differentiate strong-weak (trochaic) and weak-strong (iambic) stress patterns by 2months of age. The ability to discriminate rhythmical patterns, such as lexical stress, has been argued to facilitate language development, suggesting that a difficulty in discriminating stress might affect early word learning as reflected in vocabulary size. Children with autism spectrum disorder (ASD) often have difficulty in correctly producing lexical stress, yet little is known about how they perceive it. The current study tested 5-month-old infants with typically developing older siblings (SIBS-TD) and infants with an older sibling diagnosed with ASD (SIBS-A) on their ability to differentiate the trochaic and iambic stress patterns of the word form gaba. SIBS-TD infants showed an increased interest in attention to the trochaic stress pattern, which was also positively correlated with vocabulary comprehension at 12months of age. In contrast, SIBS-A infants attended equally to these stress patterns, although this was unrelated to later vocabulary size.
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10. Geurts HM, de Wit S. {{Goal-directed action control in children with autism spectrum disorders}}. {Autism};2013 (Sep 26)
Repetitive behavior is a key characteristic of autism spectrum disorders. Our aim was to investigate the hypothesis that this abnormal behavioral repetition results from a tendency to over-rely on habits at the expense of flexible, goal-directed action. Twenty-four children with autism spectrum disorders and 24 age- and gender-matched controls (8-12 years) initially learned to give specific responses to different pictorial stimuli in order to gain valuable outcomes. Subsequently, in the « slips-of-action » test, some of these outcomes were no longer valuable. Children needed to refrain from responding when stimuli were shown that signaled the availability of those outcomes while continuing to respond for the still-valuable outcomes. Reliance on habits should lead to « slips of action » toward no longer valuable outcomes. Therefore, the children’s ability to respond selectively for still-valuable outcomes provides a measure of relative habitual versus goal-directed control. Two additional tasks were included to control for general task characteristics (i.e. working memory and inhibition). Children with autism spectrum disorders learned equally well as controls and were not impaired at flexibly adjusting their behavior to devaluation of the outcomes or stimuli. We found no evidence for a disruption in the balance between goal-directed and habitual behavioral control in children with autism spectrum disorders.
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11. Gogolinska A, Nowak W. {{Molecular basis of lateral force spectroscopy nano-diagnostics: computational unbinding of autism related chemokine MCP-1 from IgG antibody}}. {J Mol Model};2013 (Sep 6)
Monocyte-chemoattractant protein-1 (MCP-1), also known as CCL2, is a potent chemoattractant of T cells and monocytes, involved in inflammatory and angio-proliferative brain and retinal diseases. Higher expression of MCP-1 is observed in metastatic tumors. Unusual levels of MCP-1 in the brain may be correlated with autism. Immunochemistry where atomic force microscope (AFM) tips functionalized with appropriate antibodies against MCP-1 are used could in principle support medical diagnostics. Useful signals from single molecule experiments may be generated if interaction forces are large enough. The chemokine-antibody unbinding force depends on a relative motion of the interacting fragments of the complex. In this paper the stability of the medically important MCP-1- immunoglobulin G antibody Fab fragment complex has been studied using steered molecular dynamics (SMD) computer simulations with the aim to model possible arrangements of nano-diagnostics experiments. Using SMD we confirm that molecular recognition in MCP1-IgG is based mainly on six pairs of residues: Glu39A – Arg98H, Lys56A – Asp52H, Asp65A – Arg32L, Asp68A – Arg32L, Thr32A – Glu55L, Gln61A – Tyr33H. The minimum external force required for mechanical dissociation of the complex depends on a direction of the force. The pulling of the MCP-1 antigen in the directions parallel to the antigen-antibody contact plane requires forces about 20 %-40 % lower than in the perpendicular one. Fortunately, these values are large enough that the fast lateral force spectroscopy may be used for effective nano-diagnostics purposes. We show that molecular modeling is a useful tool in planning AFM force spectroscopy experiments.
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12. Haven EL, Manangan CN, Sparrow JK, Wilson BJ. {{The relation of parent-child interaction qualities to social skills in children with and without autism spectrum disorders}}. {Autism};2013 (Sep 26)
This study examined associations between parent-child interactions and the development of social skills in 42 children (21 typically developing and 21 with autism spectrum disorders) between the ages of 3 years, 0 months and 6 years, 11 months. We expected that positive parent-child interaction qualities would be related to children’s social skills and would mediate the negative relation between children’s developmental status (typical development vs autism spectrum disorders) and social skills. Videotapes of parents and children during a 5-min wordless book task were coded for parent positive affect and emotional support as well as parent-child cohesiveness. Emotional support and cohesiveness were significantly related to children’s social skills, such that higher emotional support and cohesiveness were associated with higher social skills, R2 = .29, p = .02, and R2 = .38, p = .002, respectively. Additionally, cohesiveness mediated the relation between children’s developmental status and social skills. These findings suggest that parent emotional support and cohesiveness between parents and children positively influence children’s social skills. Parent positive affect was unrelated to social skills. Implications of these findings for social skills interventions are discussed, particularly for young children with autism spectrum disorders.
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13. Humphreys JS, Gringras P, Blair PS, Scott N, Henderson J, Fleming PJ, Emond AM. {{Sleep patterns in children with autistic spectrum disorders: a prospective cohort study}}. {Arch Dis Child};2013 (Sep 23)
OBJECTIVE: To investigate longitudinal sleep patterns in children with autistic spectrum disorders (ASDs). STUDY DESIGN: Prospective longitudinal study using Avon Longitudinal Study of Parents and Children, an English cohort born in 1991-1992. Parental reports of sleep duration were collected by questionnaires at 8 time points from 6 months to 11 years. Children with an ASD diagnosis at age 11 years (n=73) were identified from health and education records. RESULTS: From aged 30 months to 11 years old, children with ASD slept for 17-43 min less each day than contemporary controls. No significant difference in total sleep duration was found in infancy, but from 30 months of age children with ASD slept less than their peers, a difference that remained significant after adjusting for sex, ethnicity, high parity and epilepsy. The reduction in total sleep was wholly due to changes in night rather than daytime sleep duration. Night-time sleep duration was shortened by later bedtimes and earlier waking times. Frequent waking (3 or more times a night) was also evident among the children with ASD from 30 months of age. Age-specific decreases of >1SD within individuals in sleep duration across adjacent time points was a predictor of ASD between 18 months and 30 months of age (p=0.04) and from 30 months to 42 months (p=0.02). CONCLUSIONS: Sleep duration in children with ASD is reduced from 30 months of age and persists until adolescence.
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14. Kancherla V, Van Naarden Braun K, Yeargin-Allsopp M. {{Childhood vision impairment, hearing loss and co-occurring autism spectrum disorder}}. {Disabil Health J};2013 (Oct);6(4):333-342.
BACKGROUND: Limited population-based data on prevalence of childhood vision impairment (VI) and hearing loss (HL), and their co-occurrence with autism spectrum disorder (ASD) exists. OBJECTIVE: To examine prevalence and characteristics of VI, HL and co-occurring ASD among 8-year-olds in metropolitan Atlanta 2000-2008. METHODS: We used data from the population-based Metropolitan Atlanta Developmental Disabilities Surveillance Program. Prevalence, birth and parental characteristics, presence and severity of other co-occurring developmental disabilities, and age of earliest identification of ASD, were examined for children with VI and HL, by co-occurring ASD. RESULTS: VI and HL prevalences were 1.2 and 1.3 per 1000 8-year-olds, respectively. Approximately 6-7% of children with VI or HL had co-occurring ASD. Children with VI or HL with co-occurring ASD differed from those without co-occurring ASD by select birth characteristics and the presence of other co-occurring DDs. The median age of earliest known ASD diagnosis was significantly later among children with VI and ASD compared to children with ASD without VI (79 vs. 56 months). Children with HL and ASD were first evaluated by a community provider significantly earlier than those with ASD without HL (40 vs. 50 months). CONCLUSIONS: The frequency of co-occurring ASD with VI and HL is higher than the population prevalence of ASD. The significant delays in diagnosis of ASD in children with VI and lack of earlier diagnosis of ASD among children with HL despite earlier evaluation highlight the importance of developing screening tools for early identification of ASD among children with VI and HL.
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15. Kesli R, Gokcen C, Bulug U, Terzi Y. {{Investigation of the relation between anaerobic bacteria genus clostridium and late-onset autism etiology in children}}. {J Immunoassay Immunochem};2014 (Jan 2);35(1):101-109.
The aim of this study was to investigate the relation between the etiology of late-onset childhood autism and anaerobic bacteria. Thirty children diagnosed with autistic disorder and control group have been included in the study. 3-(3-hydroxy phenyl)-3-hydroxypropionic acid (HPHPA) excretion rates which is a metabolic product of the genus Clostridium, were measured via mass spectrometry-gas chromatography (MS-GC) method from urine samples. When the assayed average HPHPA values compared with each group, a statistically significant difference was found (p < 0.05). Data obtained from this study support the existence of a significant correlation between autism etiology and anaerobic bacteria.
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16. King BH, Dukes K, Donnelly CL, Sikich L, McCracken JT, Scahill L, Hollander E, Bregman JD, Anagnostou E, Robinson F, Sullivan L, Hirtz D. {{Baseline Factors Predicting Placebo Response to Treatment in Children and Adolescents With Autism Spectrum Disorders: A Multisite Randomized Clinical Trial}}. {JAMA Pediatr};2013 (Sep 23)
IMPORTANCE The finding of factors that differentially predict the likelihood of response to placebo over that of an active drug could have a significant impact on study design in this population. OBJECTIVE To identify possible nonspecific, baseline predictors of response to intervention in a large randomized clinical trial of children and adolescents with autism spectrum disorders. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of citalopram hydrobromide for children and adolescents with autism spectrum disorders and prominent repetitive behavior. Baseline data at study entry were examined with respect to final outcome to determine if response predictors could be identified. A total of 149 children and adolescents 5 to 17 years of age (mean [SD] age, 9.4 [3.1] years) from 6 academic centers were randomly assigned to citalopram (n = 73) or placebo (n = 76). Participants had autistic disorder, Asperger syndrome, or pervasive developmental disorder, not otherwise specified; had illness severity ratings that were moderate or more than moderate on the Clinical Global Impression-Severity scale; and scored moderate or more than moderate on compulsive behaviors measured with the modified Children’s Yale-Brown Obsessive-Compulsive Scale. INTERVENTIONS Twelve weeks of treatment with citalopram (10 mg/5 mL) or placebo. The mean (SD) maximum dose of citalopram was 16.5 (6.5) mg by mouth daily (maximum dose, 20 mg/d). MAIN OUTCOMES AND MEASURES A positive response was defined as having a score of at least much improved on the Clinical Global Impression-Improvement scale at week 12. Baseline measures included demographic (sex, age, weight, and pubertal status), clinical, and family measures. Clinical variables included baseline illness severity ratings (the Aberrant Behavior Checklist, the Child and Adolescent Symptom Inventory, the Vineland Adaptive Behavior Scales, the Repetitive Behavior Scale-Revised, and the Children’s Yale-Brown Obsessive-Compulsive Scale). Family measures included the Caregiver Strain Questionnaire. RESULTS Several baseline predictors of response were identified, and a principal component analysis yielded 3 composite measures (disruptive behavior, autism/mood, and caregiver strain) that significantly predicted response at week 12. Specifically, participants in the placebo group were significantly less likely than participants in the citalopram group to respond at week 12 if they entered the study more symptomatic on each of the 3 composite measures, and they were at least 2 times less likely to be responders. CONCLUSIONS AND RELEVANCE This analysis suggests strategies that may be useful in anticipating and potentially mitigating the nonspecific response in randomized clinical trials of children and adolescents with autism spectrum disorders. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00086645.
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17. Kondapalli KC, Hack A, Schushan M, Landau M, Ben-Tal N, Rao R. {{Functional evaluation of autism-associated mutations in NHE9}}. {Nat Commun};2013 (Sep 25);4:2510.
NHE9 (SLC9A9) is an endosomal cation/proton antiporter with orthologues in yeast and bacteria. Rare, missense substitutions in NHE9 are genetically linked with autism but have not been functionally evaluated. Here we use evolutionary conservation analysis to build a model structure of NHE9 based on the crystal structure of bacterial NhaA and use it to screen autism-associated variants in the human population first by phenotype complementation in yeast, followed by functional analysis in primary cortical astrocytes from mouse. NHE9-GFP localizes to recycling endosomes, where it significantly alkalinizes luminal pH, elevates uptake of transferrin and the neurotransmitter glutamate, and stabilizes surface expression of transferrin receptor and GLAST transporter. In contrast, autism-associated variants L236S, S438P and V176I lack function in astrocytes. Thus, we establish a neurobiological cell model of a candidate gene in autism. Loss-of-function mutations in NHE9 may contribute to autistic phenotype by modulating synaptic membrane protein expression and neurotransmitter clearance.
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18. Koshimizu E, Miyatake S, Okamoto N, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Matsumoto N. {{Performance Comparison of Bench-Top Next Generation Sequencers Using Microdroplet PCR-Based Enrichment for Targeted Sequencing in Patients with Autism Spectrum Disorder}}. {PLoS One};2013;8(9):e74167.
Next-generation sequencing (NGS) combined with enrichment of target genes enables highly efficient and low-cost sequencing of multiple genes for genetic diseases. The aim of this study was to validate the accuracy and sensitivity of our method for comprehensive mutation detection in autism spectrum disorder (ASD). We assessed the performance of the bench-top Ion Torrent PGM and Illumina MiSeq platforms as optimized solutions for mutation detection, using microdroplet PCR-based enrichment of 62 ASD associated genes. Ten patients with known mutations were sequenced using NGS to validate the sensitivity of our method. The overall read quality was better with MiSeq, largely because of the increased indel-related error associated with PGM. The sensitivity of SNV detection was similar between the two platforms, suggesting they are both suitable for SNV detection in the human genome. Next, we used these methods to analyze 28 patients with ASD, and identified 22 novel variants in genes associated with ASD, with one mutation detected by MiSeq only. Thus, our results support the combination of target gene enrichment and NGS as a valuable molecular method for investigating rare variants in ASD.
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19. Kubota T, Miyake K, Hirasawa T. {{Role of epigenetics in Rett syndrome}}. {Epigenomics};2013 (Oct);5(5):583-592.
Rett syndrome (RTT) is an X-linked neurodevelopmental disease caused by MECP2 mutations. The MeCP2 protein was originally thought to function as a transcription repressor by binding to methylated CpG dinucleotides, but is now also thought to be a transcription activator. Recent studies suggest that MeCP2 is not only being expressed in neurons, but also in glial cells, which suggests a new paradigm for understanding the pathogenesis of RTT. It has also been demonstrated that reintroduction of MeCP2 into behaviorally affected Mecp2-null mice after birth rescues neurological symptoms, which indicates that epigenetic failures in RTT are reversible. Therefore, RTT may well be seen as a model disease that can be potentially treated by taking advantage of the reversibility of epigenetic phenomena in various congenital neurodevelopmental diseases that were previously thought to be untreatable.
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20. Mire SS, Nowell KP, Kubiszyn T, Goin-Kochel RP. {{Psychotropic medication use among children with autism spectrum disorders within the Simons Simplex Collection: Are core features of autism spectrum disorder related?}}. {Autism};2013 (Sep 26)
Psychotropic medication use and its relationship to autism spectrum core features were examined in a well-characterized but nonstratified North American sample (N = 1605) of children/adolescents diagnosed with autism spectrum disorders utilizing the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised, from the multisite Simons Simplex Collection. Analyses included (a) prevalence of psychotropic use (overall, and by classes), (b) correlations between prevalence of use and autism spectrum core features, age, and cognitive functioning, and (c) logistic regression to identify whether these factors were predictive of psychotropic use. Results indicated 41.7% ever used one or more classes of psychotropic medications, with attention deficit hyperactivity disorder medications used most. Small but significant correlations between psychotropic medication use and (a) social impairment (p < .001) and (b) repetitive behaviors (p < .001) were found. Overall, however, autism spectrum disorder core features are weakly related to medication use. Older children used more psychotropics (p < .001), and higher cognitive functioning was associated with less overall psychotropic use (p < .001). Logistic regression indicated that use of psychotropics was predicted by repetitive behaviors (both clinician-observed and parent-reported), age, and cognitive ability level. Limitations inherent to the Simons Simplex Collection sample, methodology, and the correlational analyses are discussed. Directions for future research include investigation of factors more influential than core symptoms on psychotropic treatment (e.g. parent perceptions, comorbid symptoms).
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21. Nayot D, Chung JT, Son WY, Ao A, Hughes M, Dahan MH. {{Live birth following serial vitrification of embryos and PGD for fragile X syndrome in a patient with the premutation and decreased ovarian reserve}}. {J Assist Reprod Genet};2013 (Sep 6)
PURPOSE: To present a live birth resulting from serial vitrification of embryos and pre-implantation genetic diagnosis (PGD). METHODS: A 31-year-old with primary infertility, fragile-X premutation, and decreased ovarian reserve (DOR) (baseline FSH level 33 IU/L), presented after failing to stimulate to follicle diameters >10 mm with three cycles of invitro fertilization (IVF). After counseling, the couple opted for serial in-vitro maturation (IVM), embryo vitrification, and genetic testing using array comparative genomic hybridization (aCGH) and PGD. Embryos were vitrified 2 days after intra-cytoplasmic sperm injection (ICSI). Thawed embryos were biopsied on day-three and transferred on day-five. RESULTS: The couple underwent 20 cycles of assisted reproductive technology. A total of 23 in-vivo mature and five immature oocytes were retrieved, of which one matured in-vitro. Of 24 embryos, 17/24 (71 %) developed to day two and 11/24 (46 %) survived to blastocyst stage with a biopsy result available. Four blastocysts had normal PGD and aCGH results. Both single embryo transfers resulted in a successful implantation, one a blighted ovum and the other in a live birth. CONCLUSIONS: Young patients with DOR have potential for live birth as long as oocytes can be obtained and embryos created. Serial vitrification may be the mechanism of choice in these patients when PGD is needed.
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22. Redcay E, Moran JM, Mavros PL, Tager-Flusberg H, Gabrieli JD, Whitfield-Gabrieli S. {{Intrinsic functional network organization in high-functioning adolescents with autism spectrum disorder}}. {Front Hum Neurosci};2013;7:573.
Converging theories and data suggest that atypical patterns of functional and structural connectivity are a hallmark neurobiological feature of autism. However, empirical studies of functional connectivity, or, the correlation of MRI signal between brain regions, have largely been conducted during task performance and/or focused on group differences within one network [e.g., the default mode network (DMN)]. This narrow focus on task-based connectivity and single network analyses precludes investigation of whole-brain intrinsic network organization in autism. To assess whole-brain network properties in adolescents with autism, we collected resting-state functional connectivity MRI (rs-fcMRI) data from neurotypical (NT) adolescents and adolescents with autism spectrum disorder (ASD). We used graph theory metrics on rs-fcMRI data with 34 regions of interest (i.e., nodes) that encompass four different functionally defined networks: cingulo-opercular, cerebellar, fronto-parietal, and DMN (Fair etal., 2009). Contrary to our hypotheses, network analyses revealed minimal differences between groups with one exception. Betweenness centrality, which indicates the degree to which a seed (or node) functions as a hub within and between networks, was greater for participants with autism for the right lateral parietal (RLatP) region of the DMN. Follow-up seed-based analyses demonstrated greater functional connectivity in ASD than NT groups between the RLatP seed and another region of the DMN, the anterior medial prefrontal cortex. Greater connectivity between these regions was related to lower ADOS (Autism Diagnostic Observation Schedule) scores (i.e., lower impairment) in autism. These findings do not support current theories of underconnectivity in autism, but, rather, underscore the need for future studies to systematically examine factors that can influence patterns of intrinsic connectivity such as autism severity, age, and head motion.
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23. Sappok T, Budczies J, Bolte S, Dziobek I, Dosen A, Diefenbacher A. {{Emotional development in adults with autism and intellectual disabilities: a retrospective, clinical analysis}}. {PLoS One};2013;8(9):e74036.
Individuals with intellectual disability (ID) are at risk for additional autism spectrum disorders (ASD). A large amount of research reveals deficits in emotion-related processes that are relevant to social cognition in ASD. However, studies on the structure and level of emotional development (ED) assessing emotional maturity according to the normative trajectory in typically developing children are scares. The level of ED can be evaluated by the ‘Scheme of Appraisal of Emotional Development’ (SAED), a semi-structured interview with a close caregiver. The SAED assesses the level of emotional developmental based on a five stage system in 10 domains, for example, ‘interaction with peers’ or ‘object permanence’, which are conducive to the overall emotional developmental level. This study examined the ED as measured by the SAED in 289 adults (mean age: 36 years) with ID with and without additional ASD. A lower level in ED was observed in ASD/ID combined that corresponded to the ED of typically developing children aged 1.5-3 years versus an ED with a corresponding age of 3-7 years in ID individuals without ASD. Moreover, distinct strengths in ‘object permanence’, and weaknesses in ‘interaction’, ‘verbal communication’, ‘experience of self’, ‘affect differentiation’, ‘anxiety’, and ‘handling of material objects’ led to a characteristic pattern of ED in ASD. SAED domains with highest discriminative power between ID individuals with and without ASD (5/10) were used to predict ASD group membership. The classification using a selection of SAED domains revealed a sensitivity of 77.5% and a specificity of 76.4%. ASD risk increased 2.7-fold with every SAED level. The recognition of delayed and uneven pattern of ED contributes to our understanding of the emotion-related impairments in adults with ID and ASD these individuals. Assessment of intra-individual ED could add value to the standard diagnostic procedures in ID, a population at risk for underdiagnosed ASD.
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24. Sharma A, Gokulchandran N, Sane H, Nagrajan A, Paranjape A, Kulkarni P, Shetty A, Mishra P, Kali M, Biju H, Badhe P. {{Autologous bone marrow mononuclear cell therapy for autism: an open label proof of concept study}}. {Stem Cells Int};2013;2013:623875.
Cellular therapy is an emerging therapeutic modality with a great potential for the treatment of autism. Recent findings show that the major underlying pathogenetic mechanisms of autism are hypoperfusion and immune alterations in the brain. So conceptually, cellular therapy which facilitates counteractive processes of improving perfusion by angiogenesis and balancing inflammation by immune regulation would exhibit beneficial clinical effects in patients with autism. This is an open label proof of concept study of autologous bone marrow mononuclear cells (BMMNCs) intrathecal transplantation in 32 patients with autism followed by multidisciplinary therapies. All patients were followed up for 26 months (mean 12.7). Outcome measures used were ISAA, CGI, and FIM/Wee-FIM scales. Positron Emission Tomography-Computed Tomography (PET-CT) scan recorded objective changes. Out of 32 patients, a total of 29 (91%) patients improved on total ISAA scores and 20 patients (62%) showed decreased severity on CGI-I. The difference between pre- and postscores was statistically significant (P < 0.001) on Wilcoxon matched-pairs signed rank test. On CGI-II 96% of patients showed global improvement. The efficacy was measured on CGI-III efficacy index. Few adverse events including seizures in three patients were controlled with medications. The encouraging results of this leading clinical study provide future directions for application of cellular therapy in autism.
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25. Smeekens I, Didden R, Verhoeven EW. {{Exploring the Relationship of Autonomic and Endocrine Activity with Social Functioning in Adults with Autism Spectrum Disorders}}. {J Autism Dev Disord};2013 (Sep 24)
Several studies indicate that autonomic and endocrine activity may be related to social functioning in individuals with autism spectrum disorder (ASD), although the number of studies in adults is limited. The present study explored the relationship of autonomic and endocrine activity with social functioning in young adult males with ASD compared to young adult males without ASD. Autonomic and endocrine activity (i.e. heart rate, heart rate variability and salivary cortisol) were measured during rest and social interaction. No differences in heart rate, heart rate variability and cortisol between both groups were found during rest and social interaction. Repeated measures ANOVA’s indicate a main effect of time for heart rate and cortisol, indicating an increase in these measures for both groups. An interaction effect between time and group was found for heart rate, with the ASD group showing a blunted increase in heart rate from rest to social interaction as compared to those without ASD. Future research should focus on replicating the present findings with larger sample sizes which also enables assessing inter-individual variability in autonomic and endocrine activity in relation to social functioning.
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26. Sullivan JC, Miller LJ, Nielsen DM, Schoen SA. {{The presence of migraines and its association with sensory hyperreactivity and anxiety symptomatology in children with autism spectrum disorder}}. {Autism};2013 (Sep 26)
Migraine headaches are associated with sensory hyperreactivity and anxiety in the general population, but it is unknown whether this is also the case in autism spectrum disorders. This pilot study asked parents of 81 children (aged 7-17 years) with autism spectrum disorders to report their child’s migraine occurrence, sensory hyperreactivity (Sensory Over-Responsivity Inventory), and anxiety symptoms (Spence Child Anxiety Scale). Children with autism spectrum disorders who experienced migraine headaches showed greater sensory hyperreactivity and anxiety symptomatology (p < 0.01; medium effect size for both) than those without migraines. Sensory hyperreactivity and anxiety symptomatology were additionally correlated (rho = 0.31, p = 0.005). This study provides preliminary evidence for a link between migraine headaches, sensory hyperreactivity, and anxiety symptomatology in autism spectrum disorders, which may suggest strategies for subtyping and exploring a common pathogenesis.
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27. Unwin LM, Maybery MT, Wray JA, Whitehouse AJ. {{A « bottom-up » approach to aetiological research in autism spectrum disorders}}. {Front Hum Neurosci};2013;7:606.
Autism spectrum disorders (ASD) are currently diagnosed in the presence of impairments in social interaction and communication, and a restricted range of activities and interests. However, there is considerable variability in the behaviors of different individuals with an ASD diagnosis. The heterogeneity spans the entire range of IQ and language abilities, as well as other behavioral, communicative, and social functions. While any psychiatric condition is likely to incorporate a degree of heterogeneity, the variability in the nature and severity of behaviors observed in ASD is thought to exceed that of other disorders. The current paper aims to provide a model for future research into ASD subgroups. In doing so, we examined whether two proposed risk factors – low birth weight (LBW), and in utero exposure to selective serotonin reuptake inhibitors (SSRIs) – are associated with greater behavioral homogeneity. Using data from the Western Australian Autism Biological Registry, this study found that LBW and maternal SSRI use during pregnancy were associated with greater sleep disturbances and a greater number of gastrointestinal complaints in children with ASD, respectively. The findings from this « proof of principle » paper provide support for this « bottom-up » approach as a feasible method for creating homogenous groups.
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28. Vacek JL, Hunt SL, Shireman T. {{Hypertension medication use and adherence among adults with developmental disability}}. {Disabil Health J};2013 (Oct);6(4):297-302.
BACKGROUND/OBJECTIVE: Adults with developmental disability (DD) have high prevalence of coronary artery disease risk factors, as well as impediments to optimal diagnosis and management. We analyzed antihypertensive medication (AM) use and adherence patterns in a Kansas Medicaid cohort. METHODS: We studied adults (18-64 years) with DD and claims for HT from 7/1/05 to 8/31/06, with review of prescription records of AM use and adherence from 9/1/06 to 8/31/07. Adherence was calculated as proportion of days covered (PDC). RESULTS: Of 3079 eligible people, 280 (9%) had claims for HT: 51% male, mean age 42 +/- 13, and 81% Caucasian. Of these, 280 (72%) had claims for at least 1 AM; 57% received >/=2 AM. Angiotensin converting enzyme inhibitor/angiotensin receptor blockers were most commonly prescribed (65%) followed by diuretics (50%), beta blockers (34%), and calcium channel blockers (26%). Mean PDCs by class ranged from 0.622 to 0.693: 55% had a PDC >/=0.80, a common goal for adherence. Younger individuals were more likely to be adherent (p <0.05), but adherence was not significantly associated with comorbid conditions, gender, or race. CONCLUSIONS: Of our cohort of adults with DD, 9% had HT of whom 72% submitted claims for AMs. A substantial proportion of subjects had inconsistent AM use suggesting suboptimal therapy. The association between younger ages and higher adherence may reflect better community-based support for younger adults. Further work is needed to identify barriers to optimal care for this vulnerable population.
