1. Chandler S, Howlin P, Simonoff E, O’Sullivan T, Tseng E, Kennedy J, Charman T, Baird G. {{Emotional and behavioural problems in young children with autism spectrum disorder}}. {Dev Med Child Neurol};2015 (Jun 16)
AIM: To assess the frequency, pervasiveness, associated features, and persistence of emotional and behavioural problems in a community sample of young children with autism spectrum disorder (ASD). METHOD: Parents (n=277) and teachers (n=228) of 4- to 8-year-olds completed the Developmental Behaviour Checklist (DBC). Intellectual ability and autism symptomatology were also assessed. A subsample repeated the DBC. RESULTS: Three-quarters of the cohort scored above the clinical cut-off on the Developmental Behaviour Checklist Primary Carer Version (DBC-P) questionnaire; almost two-thirds of these scored above cut-off on the Developmental Behaviour Checklist Teacher Version (DBC-T) questionnaire. In 81%, problems persisted above threshold 14 months later. Higher DBC-P scores were associated with greater autism symptomatology, higher deprivation index, parental unemployment, and more children in the home but not with parental education or ethnicity, or child’s age or sex. Children with IQ>70 scored higher for disruptive behaviour, depression, and anxiety symptoms; those with IQ<70 scored higher for self-absorption and hyperactivity. INTERPRETATION: The DBC identifies a range of additional behaviour problems that are common in ASD and which could be the focus for specific intervention. The results highlight the potential benefit of systematic screening for co-existing problems.
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2. de la Hoz AB, Maortua H, Garcia-Rives A, Martinez-Gonzalez MJ, Ezquerra M, Tejada MI. {{3p14 De Novo Interstitial Microdeletion in a Patient with Intellectual Disability and Autistic Features with Language Impairment: A Comparison with Similar Cases}}. {Case Rep Genet};2015;2015:876348.
To date, few cases of 3p proximal interstitial deletions have been reported and the phenotype and genotype correlation is not well understood. Here, we report a new case of a 3p proximal interstitial deletion. The patient is an 11-year-old female with speech and social interaction difficulties, learning disability, and slight facial dysmorphism, but no other major malformations. An 8 Mb de novo interstitial deletion at 3p14.2-p14.1, from position 60.461.316 to 68.515.453, was revealed by means of array comparative genomic hybridization and confirmed using quantitative reverse-transcription polymerase chain reaction assays. This region includes six genes: FEZF2, CADPS, SYNPR, ATXN7, PRICKLE, and MAGI1, that are known to have a role in neurodevelopment. These genes are located on the proximal side of the deletion. We compare our case with previously well-defined patients reported in the literature and databases.
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3. Deutsch SI, Burket JA, Urbano MR, Benson AD. {{The alpha Nicotinic Acetylcholine Receptor: a Mediator of Pathogenesis and Therapeutic Target in Autism Spectrum Disorders and Down Syndrome}}. {Biochem Pharmacol};2015 (Jun 11)
Currently, there are no medications that target core deficits of social communication and restrictive, repetitive patterns of behavior in persons with autism spectrum disorders (ASDs). Adults with Down syndrome (DS) display a progressive worsening of adaptive functioning, which is associated with Alzheimer’s disease (AD)-like histopathological changes in brain. Similar to persons with ASDs, there are no effective medication strategies to prevent or retard the progressive worsening of adaptive functions in adults with DS. Data suggest that the alpha7-subunit containing nicotinic acetylcholine receptor (alpha7nAChR) is implicated in the pathophysiology and serves as a promising therapeutic target of these disorders. In DS, production of the amyloidogenic Abeta1-42 peptide is increased and binds to the alpha7nAChR or the lipid milieu associated with this receptor, causing a cascade that results in cytotoxicity and deposition of amyloid plaques. Independently of their ability to inhibit the complexing of Abeta1-42 with the alpha7nAChR, alpha7nAChR agonists and positive allosteric modulators (PAMs) also possess procognitive and neuroprotective effects in relevant invivo and invitro models. The procognitive and neuroprotective effects of alpha7nAChR agonist interventions may be due, at least in part, to stimulation of the PI3K/Akt signaling cascade, cross-talk with the Wnt/beta-catenin signaling cascade and both transcriptional and non-transcriptional effects of beta-catenin, and effects of transiently increased intraneuronal concentrations of Ca2+ on metabolism and the membrane potential. Importantly, alpha7nAChR PAMs are particularly attractive medication candidates because they lack intrinsic efficacy and act only when and where endogenous acetylcholine is released or choline is generated.
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4. Gliga T, Bedford R, Charman T, Johnson MH. {{Enhanced Visual Search in Infancy Predicts Emerging Autism Symptoms}}. {Curr Biol};2015 (Jun 9)
In addition to core symptoms, i.e., social interaction and communication difficulties and restricted and repetitive behaviors, autism is also characterized by aspects of superior perception [1]. One well-replicated finding is that of superior performance in visual search tasks, in which participants have to indicate the presence of an odd-one-out element among a number of foils [2-5]. Whether these aspects of superior perception contribute to the emergence of core autism symptoms remains debated [4, 6]. Perceptual and social interaction atypicalities could reflect co-expressed but biologically independent pathologies, as suggested by a « fractionable » phenotype model of autism [7]. A developmental test of this hypothesis is now made possible by longitudinal cohorts of infants at high risk, such as of younger siblings of children with autism spectrum disorder (ASD). Around 20% of younger siblings are diagnosed with autism themselves [8], and up to another 30% manifest elevated levels of autism symptoms [9]. We used eye tracking to measure spontaneous orienting to letter targets (O, S, V, and +) presented among distractors (the letter X; Figure 1). At 9 and 15 months, emerging autism symptoms were assessed using the Autism Observation Scale for Infants (AOSI; [10]), and at 2 years of age, they were assessed using the Autism Diagnostic Observation Schedule (ADOS; [11]). Enhanced visual search performance at 9 months predicted a higher level of autism symptoms at 15 months and at 2 years. Infant perceptual atypicalities are thus intrinsically linked to the emerging autism phenotype.
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5. Grange P, Menashe I, Hawrylycz M. {{Cell-type-specific neuroanatomy of cliques of autism-related genes in the mouse brain}}. {Front Comput Neurosci};2015;9:55.
Two cliques of genes identified computationally for their high co-expression in the mouse brain according to the Allen Brain Atlas, and for their enrichment in genes related to autism spectrum disorder (ASD), have recently been shown to be highly co-expressed in the cerebellar cortex, compared to what could be expected by chance. Moreover, the expression of these cliques of genes is not homogeneous across the cerebellar cortex, and it has been noted that their expression pattern seems to highlight the granular layer. However, this observation was only made by eye, and recent advances in computational neuroanatomy allow to rank cell types in the mouse brain (characterized by their transcriptome profiles) according to the similarity between their spatial density profiles and the spatial expression profiles of the cliques. We establish by Monte Carlo simulation that with probability at least 99%, the expression profiles of the two cliques are more similar to the density profile of granule cells than 99% of the expression of cliques containing the same number of genes (Purkinje cells also score above 99% in one of the cliques). Thresholding the expression profiles shows that the signal is more intense in the granular layer. Finally, we work out pairs of cell types whose combined expression profiles are more similar to the expression profiles of the cliques than any single cell type. These pairs predominantly consist of one cortical pyramidal cell and one cerebellar cell (which can be either a granule cell or a Purkinje cell).
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6. Gronborg TK, Hansen SN, Nielsen SV, Skytthe A, Parner ET. {{Stoppage in Autism Spectrum Disorders}}. {J Autism Dev Disord};2015 (Jun 16)
Stoppage refers to changes in reproductive behavior following the birth of a child with a severe disease. The presence of stoppage can bias estimates of sibling recurrence risk if not properly addressed. If stoppage occurs non-randomly (differential stoppage), it is possibly an additional source of bias in sibling recurrence risk estimation. This study investigated whether stoppage occurs in Danish families with a firstborn child diagnosed with autism spectrum disorders, and if stoppage was differential. We found that stoppage occurs moderately in Danish families affected by autism spectrum disorders, and that stoppage is differential. However, differential stoppage is a minor source of estimation bias in Danish sibling recurrence risk studies of autism spectrum disorders.
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7. Hall SS, Frank MC, Pusiol GT, Farzin F, Lightbody AA, Reiss AL. {{Quantifying naturalistic social gaze in fragile X syndrome using a novel eye tracking paradigm}}. {Am J Med Genet B Neuropsychiatr Genet};2015 (Jun 16)
A hallmark behavioral feature of fragile X syndrome (FXS) is the propensity for individuals with the syndrome to exhibit significant impairments in social gaze during interactions with others. However, previous studies employing eye tracking methodology to investigate this phenomenon have been limited to presenting static photographs or videos of social interactions rather than employing a real-life social partner. To improve upon previous studies, we used a customized eye tracking configuration to quantify the social gaze of 51 individuals with FXS and 19 controls, aged 14-28 years, while they engaged in a naturalistic face-to-face social interaction with a female experimenter. Importantly, our control group was matched to the FXS group on age, developmental functioning, and degree of autistic symptomatology. Results showed that participants with FXS spent significantly less time looking at the face and had shorter episodes (and longer inter-episodes) of social gaze than controls. Regression analyses indicated that communication ability predicted higher levels of social gaze in individuals with FXS, but not in controls. Conversely, degree of autistic symptoms predicted lower levels of social gaze in controls, but not in individuals with FXS. Taken together, these data indicate that naturalistic social gaze in FXS can be measured objectively using existing eye tracking technology during face-to-face social interactions. Given that impairments in social gaze were specific to FXS, this paradigm could be employed as an objective and ecologically valid outcome measure in ongoing Phase II/Phase III clinical trials of FXS-specific interventions. (c) 2015 Wiley Periodicals, Inc.
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8. Halladay AK, Bishop S, Constantino JN, Daniels AM, Koenig K, Palmer K, Messinger D, Pelphrey K, Sanders SJ, Singer AT, Taylor JL, Szatmari P. {{Sex and gender differences in autism spectrum disorder: summarizing evidence gaps and identifying emerging areas of priority}}. {Mol Autism};2015;6:36.
One of the most consistent findings in autism spectrum disorder (ASD) research is a higher rate of ASD diagnosis in males than females. Despite this, remarkably little research has focused on the reasons for this disparity. Better understanding of this sex difference could lead to major advancements in the prevention or treatment of ASD in both males and females. In October of 2014, Autism Speaks and the Autism Science Foundation co-organized a meeting that brought together almost 60 clinicians, researchers, parents, and self-identified autistic individuals. Discussion at the meeting is summarized here with recommendations on directions of future research endeavors.
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9. Loke YJ, Hannan AJ, Craig JM. {{The Role of Epigenetic Change in Autism Spectrum Disorders}}. {Front Neurol};2015;6:107.
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders characterized by problems with social communication, social interaction, and repetitive or restricted behaviors. ASD are comorbid with other disorders including attention deficit hyperactivity disorder, epilepsy, Rett syndrome, and Fragile X syndrome. Neither the genetic nor the environmental components have been characterized well enough to aid diagnosis or treatment of non-syndromic ASD. However, genome-wide association studies have amassed evidence suggesting involvement of hundreds of genes and a variety of associated genetic pathways. Recently, investigators have turned to epigenetics, a prime mediator of environmental effects on genomes and phenotype, to characterize changes in ASD that constitute a molecular level on top of DNA sequence. Though in their infancy, such studies have the potential to increase our understanding of the etiology of ASD and may assist in the development of biomarkers for its prediction, diagnosis, prognosis, and eventually in its prevention and intervention. This review focuses on the first few epigenome-wide association studies of ASD and discusses future directions.
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10. McMahon CM, Solomon M. {{Brief Report: Parent-Adolescent Informant Discrepancies of Social Skill Importance and Social Skill Engagement for Higher-Functioning Adolescents with Autism Spectrum Disorder}}. {J Autism Dev Disord};2015 (Jun 16)
Parent- and adolescent-report of social skill importance and social skill engagement on the Social Skills Rating System (Gresham and Elliott in The social skills rating system, American Guidance Service, Circle Pines, 1990) were assessed in higher-functioning adolescents with Autism Spectrum Disorder (ASD). Compared to parents, adolescents reported that social skills were less important. Additionally, adolescents reported that they engaged in social skills more frequently than parents reported them to be engaging in social skills. Parents, but not adolescents, reported a discrepancy between importance and engagement, such that the importance of social skills was rated higher than the frequency of adolescent engagement in social skills. These results suggest that social skills interventions for individuals with ASD may need to target awareness of social skill importance and accurate monitoring of social skill engagement.
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11. Nebel RA, Kirschen J, Cai J, Woo YJ, Cherian K, Abrahams BS. {{Reciprocal Relationship between Head Size, an Autism Endophenotype, and Gene Dosage at 19p13.12 Points to AKAP8 and AKAP8L}}. {PLoS One};2015;10(6):e0129270.
Microcephaly and macrocephaly are overrepresented in individuals with autism and are thought to be disease-related risk factors or endophenotypes. Analysis of DNA microarray results from a family with a low functioning autistic child determined that the proband and two additional unaffected family members who carry a rare inherited 760 kb duplication of unknown clinical significance at 19p13.12 are macrocephalic. Consideration alongside overlapping deletion and duplication events in the literature provides support for a strong relationship between gene dosage at this locus and head size, with losses and gains associated with microcephaly (p=1.11×10-11) and macrocephaly (p=2.47×10-11), respectively. Data support A kinase anchor protein 8 and 8-like (AKAP8 and AKAP8L) as candidate genes involved in regulation of head growth, an interesting finding given previous work implicating the AKAP gene family in autism. Towards determination of which of AKAP8 and AKAP8L may be involved in the modulation of head size and risk for disease, we analyzed exome sequencing data for 693 autism families (2591 individuals) where head circumference data were available. No predicted loss of function variants were observed, precluding insights into relationship to head size, but highlighting strong evolutionary conservation. Taken together, findings support the idea that gene dosage at 19p13.12, and AKAP8 and/or AKAP8L in particular, play an important role in modulation of head size and may contribute to autism risk. Exome sequencing of the family also identified a rare inherited variant predicted to disrupt splicing of TPTE / PTEN2, a PTEN homologue, which may likewise contribute to both macrocephaly and autism risk.
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12. Neul JL, Sahin M. {{Therapeutic Advances in Autism and Other Neurodevelopmental Disorders}}. {Neurotherapeutics};2015 (Jun 16)
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13. Ross LA, Del Bene VA, Molholm S, Frey HP, Foxe JJ. {{Sex differences in multisensory speech processing in both typically developing children and those on the autism spectrum}}. {Front Neurosci};2015;9:185.
BACKGROUND: Previous work has revealed sizeable deficits in the abilities of children with an autism spectrum disorder (ASD) to integrate auditory and visual speech signals, with clear implications for social communication in this population. There is a strong male preponderance in ASD, with approximately four affected males for every female. The presence of sex differences in ASD symptoms suggests a sexual dimorphism in the ASD phenotype, and raises the question of whether this dimorphism extends to ASD traits in the neurotypical population. Here, we investigated possible sexual dimorphism in multisensory speech integration in both ASD and neurotypical individuals. METHODS: We assessed whether males and females differed in their ability to benefit from visual speech when target words were presented under varying levels of signal-to-noise, in samples of neurotypical children and adults, and in children diagnosed with an ASD. RESULTS: In typically developing (TD) children and children with ASD, females (n = 47 and n = 15, respectively) were significantly superior in their ability to recognize words under audiovisual listening conditions compared to males (n = 55 and n = 58, respectively). This sex difference was absent in our sample of neurotypical adults (n = 28 females; n = 28 males). CONCLUSIONS: We propose that the development of audiovisual integration is delayed in male relative to female children, a delay that is also observed in ASD. In neurotypicals, these sex differences disappear in early adulthood when females approach their performance maximum and males « catch up. » Our findings underline the importance of considering sex differences in the search for autism endophenotypes and strongly encourage increased efforts to study the underrepresented population of females within ASD.
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14. Schmidt RJ, Hansen RL, Hartiala J, Allayee H, Sconberg JL, Schmidt LC, Volk HE, Tassone F. {{Selected vitamin D metabolic gene variants and risk for autism spectrum disorder in the CHARGE Study}}. {Early Hum Dev};2015 (Jun 11);91(8):483-489.
BACKGROUND: Vitamin D is essential for proper neurodevelopment and cognitive and behavioral function. We examined associations between autism spectrum disorder (ASD) and common, functional polymorphisms in vitamin D pathways. METHODS: Children aged 24-60months enrolled from 2003 to 2009 in the population-based CHARGE case-control study were evaluated clinically and confirmed to have ASD (n=474) or typical development (TD, n=281). Maternal, paternal, and child DNA samples for 384 (81%) families of children with ASD and 234 (83%) families of TD children were genotyped for: TaqI, BsmI, FokI, and Cdx2 in the vitamin D receptor (VDR) gene, and CYP27B1 rs4646536, GC rs4588, and CYP2R1 rs10741657. Case-control logistic regression, family-based log-linear, and hybrid log-linear analyses were conducted to produce risk estimates and 95% confidence intervals (CI) for each allelic variant. RESULTS: Paternal VDR TaqI homozygous variant genotype was significantly associated with ASD in case-control analysis (odds ratio [OR] [CI]: 6.3 [1.9-20.7]) and there was a trend towards increased risk associated with VDR BsmI (OR [CI]: 4.7 [1.6-13.4]). Log-linear triad analyses detected parental imprinting, with greater effects of paternally-derived VDR alleles. Child GC AA-genotype/A-allele was associated with ASD in log-linear and ETDT analyses. A significant association between decreased ASD risk and child CYP2R1 AA-genotype was found in hybrid log-linear analysis. There were limitations of low statistical power for less common alleles due to missing paternal genotypes. CONCLUSIONS: This study provides preliminary evidence that paternal and child vitamin D metabolism could play a role in the etiology of ASD; further research in larger study populations is warranted.
