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.     

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。     

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。     

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.     

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.     

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.     

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.     

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.     

Obsessive-Compulsive Disorder and Autism Spectrum Disorders: Longitudinal and Offspring Risk

Background

Despite substantial similarities and overlaps in the pathophysiology of obsessive-compulsive disorders (OCD) and autism spectrum disorders, little is known about the clinical and etiologic cohesion of these two disorders. We therefore aimed to determine the patterns of comorbidity, longitudinal risks, and shared familial risks between these disorders.

Methods

In a prospective study design we explored the effect of a prior diagnosis of OCD in patients and parents on the susceptibility to autism spectrum disorders and vice versa. Analyses were adjusted for sex, age, calendar year, parental age and place at residence at time of birth. As measures of relative risk incidence rate ratios (IRR) and accompanying 95% confidence intervals (CIs) were employed.

Results

The risk of a comorbid diagnosis of OCD in individuals with autism spectrum disorder and aggregation of autism spectrum disorders in offspring of parents with OCD were increased. Individuals first diagnosed with autism spectrum disorders had a 2-fold higher risk of a later diagnosis of OCD (IRR = 2.18, 95% CI = 1.91–2.48), whereas individuals diagnosed with OCD displayed a nearly 4-fold higher risk to be diagnosed with autism spectrum disorders (IRR = 3.91, 95% CI = 3.46–4.40) later in life. The observed associations were somewhat stronger for less severe types of autism spectrum disorders without a comorbid diagnosis of mental disabilities.

Conclusions

The high comorbidity, sequential risk, and shared familial risks between OCD and autism spectrum disorders are suggestive of partially shared etiological mechanisms. The results have implications for current gene-searching efforts and for clinical practice.     

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...     

Stronger Neural Modulation by Visual Motion Intensity in Autism Spectrum Disorders

Theories of autism spectrum disorders (ASD) have focused on altered perceptual integration of sensory features as a possible core deficit. Yet, there is little understanding of the neuronal processing of elementary sensory features in ASD. For typically developed individuals, we previously established a direct link between frequency-specific neural activity and the intensity of a specific sensory feature: Gamma-band activity in the visual cortex increased approximately linearly with the strength of visual motion. Using magnetoencephalography (MEG), we investigated whether in individuals with ASD neural activity reflect the coherence, and thus intensity, of visual motion in a similar fashion. Thirteen adult participants with ASD and 14 control participants performed a motion direction discrimination task with increasing levels of motion coherence. A polynomial regression analysis revealed that gamma-band power increased significantly stronger with motion coherence in ASD compared to controls, suggesting excessive visual activation with increasing stimulus intensity originating from motion-responsive visual areas V3, V6 and hMT/V5. Enhanced neural responses with increasing stimulus intensity suggest an enhanced response gain in ASD. Response gain is controlled by excitatory-inhibitory interactions, which also drive high-frequency oscillations in the gamma-band. Thus, our data suggest that a disturbed excitatory-inhibitory balance underlies enhanced neural responses to coherent motion in ASD.     

Behavioral Effects of Afobazole in an Experimental Model of Autism Spectrum Disorders

Journal of Evolutionary Biochemistry and Physiology - The study was conducted on a model of fetal valproate syndrome (FVS) induced by a single subcutaneous administration of sodium valproate (VPA,...     

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.     

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.     

Investigation of Rare Single-Nucleotide PCDH15 Variants in Schizophrenia and Autism Spectrum Disorders

Both schizophrenia (SCZ) and autism spectrum disorders (ASD) are neuropsychiatric disorders with overlapping genetic etiology. Protocadherin 15 (PCDH15), which encodes a member of the cadherin super family that contributes to neural development and function, has been cited as a risk gene for neuropsychiatric disorders. Recently, rare variants of large effect have been paid attention to understand the etiopathology of these complex disorders. Thus, we evaluated the impacts of rare, single-nucleotide variants (SNVs) in PCDH15 on SCZ or ASD. First, we conducted coding exon-targeted resequencing of PCDH15 with next-generation sequencing technology in 562 Japanese patients (370 SCZ and 192 ASD) and detected 16 heterozygous SNVs. We then performed association analyses on 2,096 cases (1,714 SCZ and 382 ASD) and 1,917 controls with six novel variants of these 16 SNVs. Of these six variants, four (p.R219K, p.T281A, p.D642N, c.3010-1G>C) were ultra-rare variants (minor allele frequency < 0.0005) that may increase disease susceptibility. Finally, no statistically significant association between any of these rare, heterozygous PCDH15 point variants and SCZ or ASD was found. Our results suggest that a larger sample size of resequencing subjects is necessary to detect associations between rare PCDH15 variants and neuropsychiatric disorders.