SHANK1 Deletions in Males with Autism Spectrum Disorder

Recent studies have highlighted the involvement of rare (<1% frequency) copy-number variations and point mutations in the genetic etiology of autism spectrum disorder (ASD); these variants particularly affect genes involved in the neuronal synaptic complex. The SHANK gene family consists of three members (SHANK1, SHANK2, and SHANK3), which encode scaffolding proteins required for the proper formation and function of neuronal synapses. Although SHANK2 and SHANK3 mutations have been implicated in ASD and intellectual disability, the involvement of SHANK1 is unknown. Here, we assess microarray data from 1,158 Canadian and 456 European individuals with ASD to discover microdeletions at the SHANK1 locus on chromosome 19. We identify a hemizygous SHANK1 deletion that segregates in a four-generation family in which male carriers--but not female carriers--have ASD with higher functioning. A de novo SHANK1 deletion was also detected in an unrelated male individual with ASD with higher functioning, and no equivalent SHANK1 mutations were found in >15,000 controls (p = 0.009). The discovery of apparent reduced penetrance of ASD in females bearing inherited autosomal SHANK1 deletions provides a possible contributory model for the male gender bias in autism. The data are also informative for clinical-genetics interpretations of both inherited and sporadic forms of ASD involving SHANK1.     

HERVs Expression in Autism Spectrum Disorders

Background

Autistic Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder, resulting from complex interactions among genetic, genomic and environmental factors. Here we have studied the expression of Human Endogenous Retroviruses (HERVs), non-coding DNA elements with potential regulatory functions, and have tested their possible implication in autism.

Methods

The presence of retroviral mRNAs from four HERV families (E, H, K and W), widely implicated in complex diseases, was evaluated in peripheral blood mononuclear cells (PBMCs) from ASD patients and healthy controls (HCs) by qualitative RT-PCR. We also analyzed the expression of the env sequence from HERV-H, HERV-W and HERV-K families in PBMCs at the time of sampling and after stimulation in culture, in both ASD and HC groups, by quantitative Real-time PCR. Differences between groups were evaluated using statistical methods.

Results

The percentage of HERV-H and HERV-W positive samples was higher among ASD patients compared to HCs, while HERV-K was similarly represented and HERV-E virtually absent in both groups. The quantitative evaluation shows that HERV-H and HERV-W are differentially expressed in the two groups, with HERV-H being more abundantly expressed and, conversely, HERV-W, having lower abundance, in PBMCs from ASDs compared to healthy controls. PMBCs from ASDs also showed an increased potential to up-regulate HERV-H expression upon stimulation in culture, unlike HCs. Furthermore we report a negative correlation between expression levels of HERV-H and age among ASD patients and a statistically significant higher expression in ASD patients with Severe score in Communication and Motor Psychoeducational Profile-3.

Conclusions

Specific HERV families have a distinctive expression profile in ASD patients compared to HCs. We propose that HERV-H expression be explored in larger samples of individuals with autism spectrum in order to determine its utility as a novel biological trait of this complex disorder.     

The Cost of Autism Spectrum Disorders

Objective

A diagnosis of an autism spectrum disorders is usually associated with substantial lifetime costs to an individual, their family and the community. However, there remains an elusive factor in any cost-benefit analysis of ASD diagnosis, namely the cost of not obtaining a diagnosis. Given the infeasibility of estimating the costs of a population that, by its nature, is inaccessible, the current study compares expenses between families whose children received a formal ASD diagnosis immediately upon suspecting developmental atypicality and seeking advice, with families that experienced a delay between first suspicion and formal diagnosis.

Design

A register based questionnaire study covering all families with a child with ASD in Western Australia.

Participants

Families with one or more children diagnosed with an ASD, totalling 521 children diagnosed with an ASD; 317 records were able to be included in the final analysis.

Results

The median family cost of ASD was estimated to be AUD $34,900 per annum with almost 90% of the sum ($29,200) due to loss of income from employment. For each additional symptom reported, approximately $1,400 cost for the family per annum was added. While there was little direct influence on costs associated with a delay in the diagnosis, the delay was associated with a modest increase in the number of ASD symptoms, indirectly impacting the cost of ASD.

Conclusions

A delay in diagnosis was associated with an indirect increased financial burden to families. Early and appropriate access to early intervention is known to improve a child''s long-term outcomes and reduce lifetime costs to the individual, family and society. Consequently, a per symptom dollar value may assist in allocation of individualised funding amounts for interventions rather than a nominal amount allocated to all children below a certain age, regardless of symptom presentation, as is the case in Western Australia.     

神经元增殖与孤独症谱系障碍大脑过度生长

在患儿发育早期,某一亚类孤独症谱系障碍（autism spectrum disorders, ASDs）大脑呈过度生长趋势。研究发现,部分伴随有大脑过度增生的患者局部脑区神经元数目异常增多。进一步研究表明,神经元的增殖紊乱与局部脑区神经元数目异常增多密切相关。本综述从ASDs相关信号分子对神经元增殖的调控入手,归纳总结近年来基于神经元增殖调控异常的ASDs大脑过度增生的分子机制研究,为探究ASDs的发病机制提供一个重要的突破口。     

Analysis of Hair Trace Elements in Children with Autism Spectrum Disorders and Communication Disorders

The primary objective of the present study is analysis of hair trace elements content in children with communication disorder (CD) and autism spectrum disorder (ASD). A total of 99 children from control, CD, and ASD groups (n = 33) were examined. All children were additionally divided into two subgroups according to age. Hair levels of trace elements were assessed using inductively coupled plasma mass spectrometry. The difference was considered significant at p < 0.01. The obtained data demonstrate that children with CD are characterized by significantly increased hair lithium (Li) (96 %; p = 0.008), selenium (Se) (66 %; p < 0.001), arsenic (As) (96 %; p = 0.005), beryllium (Be) (150 %; p < 0.001), and cadmium (Cd) (72 %; p = 0.007) content, being higher than the respective control values. In the ASD group, hair copper (Cu), iodine (I), and Be levels tended to be lower than the control values. In turn, the scalp hair content of Se significantly exceeded the control values (33 %; p = 0.004), whereas the level of iron (Fe) and aluminum (Al) tended to increase. After gradation for age, the most prominent differences in children with CD were detected in the elder group (5–8 years), whereas in the case of ASD—in the younger group (3–4 years old). Taking into account the role of hair as excretory mechanism for certain elements including the toxic ones, it can be proposed that children suffering from ASD are characterized by more profound alteration of metal handling and excretion in comparison to CD.     

谷氨酸-谷氨酰胺循环异常与孤独症谱系障碍研究进展

孤独症谱系障碍（autism spectrum disorder,ASD）是一种多病因神经发育性疾病,人群患病率高,病因复杂多样,包括炎症、自身免疫、基因异常等,但具体发病机制尚不清楚。在哺乳动物中枢神经系统（central nervous system,CNS）中,谷氨酸是最主要的兴奋性神经递质,也是一种潜在的神经毒素,其引起的兴奋毒性可能导致神经细胞的死亡。而星形胶质细胞和神经元之间谷氨酸-谷氨酰胺的代谢偶联,防止了过量的谷氨酸扩散到周围神经元上,进而避免了神经元的过度兴奋,对神经元起到保护作用。有研究表明,谷氨酸-谷氨酰胺循环异常可能为ASD发生的核心机制。因此,对炎症、自身免疫、基因异常等孤独症谱系障碍经典病因与谷氨酸-谷氨酰胺循环之间的联系进行综述,以期为孤独症谱系障碍分型和治疗提供一种新思路。     

Animal-assisted Social Skills Training for Children with Autism Spectrum Disorders

Recent research indicates that youth with autism spectrum disorder (ASD) show increases in prosocial behaviors in the presence of animals, yet few studies have examined the effects of incorporating animals into treatments. The current study evaluated the effectiveness of an animal-assisted social skills training group for youth with ASD. It was hypothesized that incorporating dogs into social skills training (SST) would produce a greater effect on improving social skills, theory of mind, and feelings of inclusion than would be obtained from SST without an animal present. We compared social skills groups with therapy dogs to traditional social skills groups without an animal present. Students with ASD attending school at a therapeutic treatment facility (n = 31; ages 8–14) were assigned to either experimental or control groups, which were both provided with 12 weeks of weekly treatment. Following participation in SST, participants in the groups with dogs were rated as significantly less symptomatic than participants in the traditional social skills group on the Social Responsiveness Scale (SRS-2), a teacher-rated measure of autism-related symptoms. Based on self-report ratings using the Children’s Depression Inventory (CDI-2), participants in the groups with dogs experienced significantly greater reductions in symptoms measured by the Interpersonal Problems and Functional Problems subscales, and not on the other subscales of the CDI-2. Both groups showed improvement in theory of mind and decreased feelings of isolation and overall depressive symptoms; however, the effect of group on change over time was not significant. On the Social Language Development Test (SLDT), no significant differences were observed. The current findings indicate animal-assisted social skills training may be more beneficial for improving social skills and reducing related affective symptoms than traditional training models.     

Intestinal Dysbiosis and Yeast Isolation in Stool of Subjects with Autism Spectrum Disorders

High frequency of gastrointestinal yeast presence in ASD subjects was shown through a simple cultural approach (Candida spp. in 57.5 % of ASDs and no controls); the identification of aggressive form (pseudo-hyphae presenting) of Candida spp. at light microscope means that adhesion to intestinal mucosa is facilitated. Dysbiosis appears sustained by lowered Lactobacillus spp. and decreased number of Clostridium spp. Absence of C. difficilis and its toxins in both ASDs and controls is also shown. Low-mild gut inflammation and augmented intestinal permeability were demonstrated together with the presence of GI symptoms. Significant linear correlation was found between disease severity (CARs score) and calprotectin and Clostridium spp. presence. Also GI symptoms, such as constipation and alternating bowel, did correlate (multivariate analyses) with the increased permeability to lactulose. The present data provide rationale basis to a possible specific therapeutic intervention in restoring gut homeostasis in ASDs.     

Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10⁻⁵) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10⁻¹⁵, ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.     

Dopamine and the Development of Executive Dysfunction in Autism Spectrum Disorders

Persons with autism regularly exhibit executive dysfunction (ED), including problems with deliberate goal-directed behavior, planning, and flexible responding in changing environments. Indeed, this array of deficits is sufficiently prominent to have prompted a theory that executive dysfunction is at the heart of these disorders. A more detailed examination of these behaviors reveals, however, that some aspects of executive function remain developmentaly appropriate. In particular, while people with autism often have difficulty with tasks requiring cognitive flexibility, their fundamental cognitive control capabilities, such as those involved in inhibiting an inappropriate but relatively automatic response, show no significant impairment on many tasks. In this article, an existing computational model of the prefrontal cortex and its role in executive control is shown to explain this dichotomous pattern of behavior by positing abnormalities in the dopamine-based modulation of frontal systems in individuals with autism. This model offers excellent qualitative and quantitative fits to performance on standard tests of cognitive control and cognitive flexibility in this clinical population. By simulating the development of the prefrontal cortex, the computational model also offers a potential explanation for an observed lack of executive dysfunction early in life.     

Perception of Social Cues of Danger in Autism Spectrum Disorders

Intuitive grasping of the meaning of subtle social cues is particularly affected in autism spectrum disorders (ASD). Despite their relevance in social communication, the effect of averted gaze in fearful faces in conveying a signal of environmental threat has not been investigated using real face stimuli in adults with ASD. Here, using functional MRI, we show that briefly presented fearful faces with averted gaze, previously shown to be a strong communicative signal of environmental danger, produce different patterns of brain activation than fearful faces with direct gaze in a group of 26 normally intelligent adults with ASD compared with 26 matched controls. While implicit cue of threat produces brain activation in attention, emotion processing and mental state attribution networks in controls, this effect is absent in individuals with ASD. Instead, individuals with ASD show activation in the subcortical face-processing system in response to direct eye contact. An effect of differences in looking behavior was excluded in a separate eye tracking experiment. Our data suggest that individuals with ASD are more sensitive to direct eye contact than to social signals of danger conveyed by averted fearful gaze.     

Wal Mutant Mice Have a Mutation Associated with Autism Spectrum Disorders

Doklady Biological Sciences - The waved alopecia (wal) mutation arose spontaneously in mice. Phenotypically, the wal mutation in a homozygous recessive state is manifested by a wavy coat. Over...     

A Comprehensive Survey of Current and Former College Students with Autism Spectrum Disorders

Background: There is a paucity of research concerning individuals with autism spectrum disorders (ASD) pursuing higher education.Method: This study sought to augment this gap in the literature by surveying individuals with ASD who are currently college students or who have previously attended college.Results: Thirty-five individuals completed an online survey. These individuals reported receiving extensive academic supports that enabled their academic success. Their reported difficulties in the social and emotional domains received less support. In addition, not all areas of campus life were supportive, as study abroad and career service offices were reported to not understand individuals with ASD.Conclusions: Overall, the results of this survey indicate the importance of self-advocacy and the need for institutions of higher education to provide comprehensive supports for individuals with ASD in the academic, social, and emotional domains in order to effectively integrate this group into the campus environment.     

Effect of Familiarity on Reward Anticipation in Children with and without Autism Spectrum Disorders

Background

Previous research on the reward system in autism spectrum disorders (ASD) suggests that children with ASD anticipate and process social rewards differently than typically developing (TD) children—but has focused on the reward value of unfamiliar face stimuli. Children with ASD process faces differently than their TD peers. Previous research has focused on face processing of unfamiliar faces, but less is known about how children with ASD process familiar faces. The current study investigated how children with ASD anticipate rewards accompanied by familiar versus unfamiliar faces.

Methods

The stimulus preceding negativity (SPN) of the event-related potential (ERP) was utilized to measure reward anticipation. Participants were 6- to 10-year-olds with (N = 14) and without (N = 14) ASD. Children were presented with rewards accompanied by incidental face or non-face stimuli that were either familiar (caregivers) or unfamiliar. All non-face stimuli were composed of scrambled face elements in the shape of arrows, controlling for visual properties.

Results

No significant differences between familiar versus unfamiliar faces were found for either group. When collapsing across familiarity, TD children showed larger reward anticipation to face versus non-face stimuli, whereas children with ASD did not show differential responses to these stimulus types. Magnitude of reward anticipation to faces was significantly correlated with behavioral measures of social impairment in the ASD group.

Conclusions

The findings do not provide evidence for differential reward anticipation for familiar versus unfamiliar face stimuli in children with or without ASD. These findings replicate previous work suggesting that TD children anticipate rewards accompanied by social stimuli more than rewards accompanied by non-social stimuli. The results do not support the idea that familiarity normalizes reward anticipation in children with ASD. Our findings also suggest that magnitude of reward anticipation to faces is correlated with levels of social impairment for children with ASD.     

Socioeconomic Disparities and Prevalence of Autism Spectrum Disorders and Intellectual Disability

Background and Objectives

Study of the impact of socioeconomic status on autism spectrum disorders (ASD) and severe intellectual disabilities (ID) has yielded conflicting results. Recent European studies suggested that, unlike reports from the United States, low socioeconomic status is associated with an increased risk of ASD. For intellectual disabilities, the links with socioeconomic status vary according to the severity. We wished to clarify the links between socioeconomic status and the prevalence of ASD (with or without ID) and isolated severe ID.

Methods

500 children with ASD and 245 children with severe ID (IQ <50) aged 8 years, born 1995 to 2004, were recruited from a French population-based registry. Inclusions were based on clinical diagnoses reported in medical records according to the International Classification of Diseases, 10^th Revision. Socioeconomic status was measured by indicators available at block census level which characterize the population of the child’s area of residence. Measures of deprivation, employment, occupation, education, immigration and family structure were used. Prevalences were compared between groups of census units defined by the tertiles of socioeconomic level in the general population.

Results

Prevalence of ASD with associated ID was higher in areas with the highest level of deprivation and the highest percentage of unemployed adults, persons with no diploma, immigrants and single-parent families. No association was found when using occupational class. Regarding ASD without associated ID, a higher prevalence was found in areas with the highest percentage of immigrants. No association was found for other socioeconomic indicators. The prevalence of isolated severe ID was likely to be higher in the most disadvantaged groups defined by all indicators.

Conclusion

The prevalence of ASD with associated ID and of severe isolated ID is more likely to be higher in areas with the highest level of deprivation.     

Individuals with Autism Spectrum Disorders Do Not Use Social Stereotypes in Irony Comprehension

Social and communication impairments are part of the essential diagnostic criteria used to define Autism Spectrum Disorders (ASDs). Difficulties in appreciating non-literal speech, such as irony in ASDs have been explained as due to impairments in social understanding and in recognizing the speaker’s communicative intention. It has been shown that social-interactional factors, such as a listener’s beliefs about the speaker’s attitudinal propensities (e.g., a tendency to use sarcasm, to be mocking, less sincere and more prone to criticism), as conveyed by an occupational stereotype, do influence a listener’s interpretation of potentially ironic remarks. We investigate the effect of occupational stereotype on irony detection in adults with High Functioning Autism or Asperger Syndrome (HFA/AS) and a comparison group of typically developed adults. We used a series of verbally presented stories containing ironic or literal utterances produced by a speaker having either a “sarcastic” or a “non-sarcastic” occupation. Although individuals with HFA/AS were able to recognize ironic intent and occupational stereotypes when the latter are made salient, stereotype information enhanced irony detection and modulated its social meaning (i.e., mockery and politeness) only in comparison participants. We concluded that when stereotype knowledge is not made salient, it does not automatically affect pragmatic communicative processes in individuals with HFA/AS.     

PRICKLE1 Interaction with SYNAPSIN I Reveals a Role in Autism Spectrum Disorders

The frequent comorbidity of Autism Spectrum Disorders (ASDs) with epilepsy suggests a shared underlying genetic susceptibility; several genes, when mutated, can contribute to both disorders. Recently, PRICKLE1 missense mutations were found to segregate with ASD. However, the mechanism by which mutations in this gene might contribute to ASD is unknown. To elucidate the role of PRICKLE1 in ASDs, we carried out studies in Prickle1^+/− mice and Drosophila, yeast, and neuronal cell lines. We show that mice with Prickle1 mutations exhibit ASD-like behaviors. To find proteins that interact with PRICKLE1 in the central nervous system, we performed a yeast two-hybrid screen with a human brain cDNA library and isolated a peptide with homology to SYNAPSIN I (SYN1), a protein involved in synaptogenesis, synaptic vesicle formation, and regulation of neurotransmitter release. Endogenous Prickle1 and Syn1 co-localize in neurons and physically interact via the SYN1 region mutated in ASD and epilepsy. Finally, a mutation in PRICKLE1 disrupts its ability to increase the size of dense-core vesicles in PC12 cells. Taken together, these findings suggest PRICKLE1 mutations contribute to ASD by disrupting the interaction with SYN1 and regulation of synaptic vesicles.     

Screening for Autism Spectrum Disorders with the Brief Infant-Toddler Social and Emotional Assessment

Objective

Using parent-completed questionnaires in (preventive) child health care can facilitate the early detection of psychosocial problems and psychopathology, including autism spectrum disorders (ASD). A promising questionnaire for this purpose is the Brief Infant-Toddler Social and Emotional Assessment (BITSEA). The screening accuracy with regard to ASD of the BITSEA Problem and Competence scales and a newly calculated Autism score were evaluated.

Method

Data, that was collected between April 2010 and April 2011, from a community sample of 2-year-olds (N = 3127), was combined with a sample of preschool children diagnosed with ASD (N = 159). For the total population and for subgroups by child''s gender, area under the Receiver Operating Characteristic (ROC) curve was examined, and across a range of BITSEA Problem, Competence and Autism scores, sensitivity, specificity, positive and negative likelihood ratio''s, diagnostic odds ratio and Youden''s index were reported.

Results

The area under the ROC curve (95% confidence interval, [95%CI]) of the Problem scale was 0.90(0.87–0.92), of the Competence scale 0.93(0.91–0.95), and of the Autism score 0.95(0.93–0.97). For the total population, the screening accuracy of the Autism score was significantly better, compared to the Problem scale. The screening accuracy of the Competence scale was significantly better for girls (AUC = 0.97; 95%CI = 0.95–0.98) than for boys (AUC = 0.91; 95%CI = 0.88–0.94).

Conclusion

The results indicate that the BITSEA scales and newly calculated Autism score have good discriminative power to differentiate children with and without ASD. Therefore, the BITSEA may be helpful in the early detection of ASD, which could have beneficial effects on the child''s development.