Functional Connectivity in the First Year of Life in Infants at Risk for Autism Spectrum Disorder: An EEG Study

In the field of autism research, recent work has been devoted to studying both behavioral and neural markers that may aide in early identification of autism spectrum disorder (ASD). These studies have often tested infants who have a significant family history of autism spectrum disorder, given the increased prevalence observed among such infants. In the present study we tested infants at high- and low-risk for ASD (based on having an older sibling diagnosed with the disorder or not) at 6- and 12-months-of-age. We computed intrahemispheric linear coherence between anterior and posterior sites as a measure of neural functional connectivity derived from electroencephalography while the infants were listening to speech sounds. We found that by 12-months-of-age infants at risk for ASD showed reduced functional connectivity compared to low risk infants. Moreover, by 12-months-of-age infants later diagnosed with ASD showed reduced functional connectivity, compared to both infants at low risk for the disorder and infants at high risk who were not later diagnosed with ASD. Significant differences in functional connectivity were also found between low-risk infants and high-risk infants who did not go onto develop ASD. These results demonstrate that reduced functional connectivity appears to be related to genetic vulnerability for ASD. Moreover, they provide further evidence that ASD is broadly characterized by differences in neural integration that emerge during the first year of life.     

Family history interview of a broad phenotype in specific language impairment and matched controls

The aim was to study a broader phenotype of language‐related diagnoses and problems in three generations of relatives of children with specific language impairment (SLI). Our study is based on a family history interview of the parents of 59 children with SLI and of 100 matched control children, exploring the prevalence of problems related to language, reading, attention, school achievement and social communication as well as diagnoses such as attention‐deficit hyperactivity disorder (ADHD), autism, Asperger syndrome, dyslexia, mental retardation, cleft palate and stuttering. The results show a spectrum of language‐related problems in families of SLI children. In all three generations of SLI relatives, we found significantly higher prevalence rates of language, literacy and social communication problems. The risk of one or both parents having language‐related diagnoses or problems was approximately six times higher for the children with SLI (85%) than for the control children (13%) (odds ratio = 37.2). We did not find a significantly higher prevalence of the diagnoses ADHD, autism or Asperger syndrome in the relatives of the children with SLI. However, significantly more parents of the children with SLI had problems with attention/hyperactivity when compared with the parents of controls. Our findings suggest common underlying mechanisms for problems with language, literacy and social communication, and possibly also for attention/hyperactivity symptoms.     

Mercury as a hapten: A review of the role of toxicant-induced brain autoantibodies in autism and possible treatment considerations

BackgroundMercury has many direct and well-recognized neurotoxic effects. However, its immune effects causing secondary neurotoxicity are less well-recognized. Mercury exposure can induce immunologic changes in the brain indicative of autoimmune dysfunction, including the production of highly specific brain autoantibodies. Mercury, and in particular, Thimerosal, can combine with a larger carrier, such as an endogenous protein, thereby acting as a hapten, and this new molecule can then elicit the production of antibodies.MethodsA comprehensive search using PubMed and Google Scholar for original studies and reviews related to autism, mercury, autoantibodies, autoimmune dysfunction, and haptens was undertaken. All articles providing relevant information from 1985 to date were examined. Twenty-three studies were identified showing autoantibodies in the brains of individuals diagnosed with autism and all were included and discussed in this review.ResultsResearch shows mercury exposure can result in an autoimmune reaction that may be causal or contributory to autism, especially in children with a family history of autoimmunity. The autoimmune pathogenesis in autism is demonstrated by the presence of brain autoantibodies (neuroantibodies), which include autoantibodies to: (1) human neuronal progenitor cells; (2) myelin basic protein (MBP); (3) neuron-axon filament protein (NAFP); (4) brain endothelial cells; (5) serotonin receptors; (6) glial fibrillary acidic protein (GFAP); (7) brain derived neurotrophic factor (BDNF); (8) myelin associated glycoprotein (MAG); and (9) various brain proteins in the cerebellum, hypothalamus, prefrontal cortex, cingulate gyrus, caudate putamen, cerebral cortex and caudate nucleus.ConclusionRecent evidence suggests a relationship between mercury exposure and brain autoantibodies in individuals diagnosed with autism. Moreover, brain autoantibody levels in autism are found to correlate with both autism severity and blood mercury levels. Treatments to reduce mercury levels and/or brain autoantibody formation should be considered in autism.     

Elevated rates of testosterone-related disorders in women with autism spectrum conditions

The androgen theory of autism proposes that autism spectrum conditions (ASC) are in part due to elevated fetal testosterone (FT) levels, which are positively correlated with a number of autistic traits and inversely correlated with social development and empathy. A medical questionnaire was completed by n=54 women with ASC, n=74 mothers of children with ASC, and n=183 mothers of typically developing children to test whether women with ASC have an increased rate of testosterone-related medical conditions, and to see whether mothers of children with ASC show similar abnormalities, as part of the 'broader autism phenotype'. Compared to controls, significantly more women with ASC reported (a) hirsutism, (b) bisexuality or asexuality, (c) irregular menstrual cycle, (d) dysmenorrhea, (e) polycystic ovary syndrome, (f) severe acne, (g) epilepsy, (h) tomboyism, and (i) family history of ovarian, uterine, and prostate cancers, tumors, or growths. Compared to controls, significantly more mothers of ASC children reported (a) severe acne, (b) breast and uterine cancers, tumors, or growths, and (c) family history of ovarian and uterine cancers, tumors, or growths. These results suggest current hormone abnormalities in women with ASC and their mothers. Direct investigations of serum testosterone levels and genetic susceptibility to high testosterone production or sensitivity in women with ASC would illuminate the origin of these conditions. The relationship between FT and current testosterone levels also needs to be clarified. The present results may be relevant to understanding the increased male risk to developing autism.     

Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene

Autism is a genetically complex neurodevelopmental syndrome in which language deficits are a core feature. We describe results from two complimentary approaches used to identify risk variants on chromosome 7 that likely contribute to the etiology of autism. A two-stage association study tested 2758 SNPs across a 10 Mb 7q35 language-related autism QTL in AGRE (Autism Genetic Resource Exchange) trios and found significant association with Contactin Associated Protein-Like 2 (CNTNAP2), a strong a priori candidate. Male-only containing families were identified as primarily responsible for this association signal, consistent with the strong male affection bias in ASD and other language-based disorders. Gene-expression analyses in developing human brain further identified CNTNAP2 as enriched in circuits important for language development. Together, these results provide convergent evidence for involvement of CNTNAP2, a Neurexin family member, in autism, and demonstrate a connection between genetic risk for autism and specific brain structures.     

Autism and carnitine: A possible link

Patients with autism spectrum disorders(ASD) present deficits in social interactions and communication, they also show limited and stereotypical patterns of behaviors and interests. The pathophysiological bases of ASD have not been defined yet. Many factors seem to be involved in the onset of this disorder. These include genetic and environmental factors, but autism is not linked to a single origin, only. Autism onset can be connected with various factors such as metabolic disorders: including carnitine deficiency. Carnitine is a derivative of two amino acid lysine and methionine. Carnitine is a cofactor for a large family of enzymes: the carnitine acyltransferases. Through their action these enzymes(and L-carnitine) are involved in energy production and metabolic homeostasis. Some people with autism(less than 20%) seem to have L-carnitine metabolism disorders and for these patients, a dietary supplementation with Lcarnitine is beneficial. This review summarizes the available information on this topic.     

Reversible autism and intellectual disability in children

Studies on young children with reversible autism and intellectual disability are discussed. Present evidence suggests a clear cause in a minority of cases including early institutionalization, Landau and Kleffner syndrome, and other early onset epilepsies, intrauterine rubella, and blindness. The majority of cases have normal laboratory results and some have early onset Tourette syndrome. Preliminary data of a follow-up study of this last group are reported in 15 patients suggesting the possibility of two subgroups, one represented by early onset Tourette syndrome phenotype, characterized by a positive family history, and by its appearance at the same time as regression and persistence into adolescence while the other of a different nature. Genetic studies could be of help to clarify this issue and support a diagnosis of favorable outcome in young children.     

Shank mutant mice as an animal model of autism

In this review, we focus on the role of the Shank family of proteins in autism. In recent years, autism research has been flourishing. With genetic, molecular, imaging and electrophysiological studies being supported by behavioural studies using animal models, there is real hope that we may soon understand the fundamental pathology of autism. There is also genuine potential to develop a molecular-level pharmacological treatment that may be able to deal with the most severe symptoms of autism, and clinical trials are already underway. The Shank family of proteins has been strongly implicated as a contributing factor in autism in certain individuals and sits at the core of the alleged autistic pathway. Here, we analyse studies that relate Shank to autism and discuss what light this sheds on the possible causes of autism.     

Chromium, Cadmium, and Lead Levels in Urine of Children with Autism and Typically Developing Controls

Although potentially harmful effects of heavy metals are well known, limited numbers of studies exist regarding their relationship with autism. The aim of this study was to investigate urine levels of some heavy metals such as of chromium (Cr), cadmium (Cd), and lead (Pb) in children with autism and healthy subjects. Urine levels of Cr, Cd, and Pb were measured by atomic absorption spectrometry in 30 children with autism and compared with 20 healthy controls. Urine Cd and Pb levels were found as significantly decreased in children with autism compared to healthy subjects (p?<?0.05). On the other hand, urine Cr levels were significantly higher in children with autism than healthy subjects (p?<?0.05). This study suggested that autism may be associated with significant decrease in excretion rate of Cd and Pb and a significant increase excretion rate in the levels of Cr in the urine. These results have indicated that further studies are warranted for investigation of possible roles of heavy metals in autism.     

Reduced activity of protein kinase C in the frontal cortex of subjects with regressive autism: relationship with developmental abnormalities

Autism is a neurodevelopmental disorder with unknown etiology. In some cases, typically developing children regress into clinical symptoms of autism, a condition known as regressive autism. Protein kinases are essential for G-protein-coupled receptor-mediated signal transduction, and are involved in neuronal functions, gene expression, memory, and cell differentiation. Recently, we reported decreased activity of protein kinase A (PKA) in the frontal cortex of subjects with regressive autism. In the present study, we analyzed the activity of protein kinase C (PKC) in the cerebellum and different regions of cerebral cortex from subjects with regressive autism, autistic subjects without clinical history of regression, and age-matched control subjects. In the frontal cortex of subjects with regressive autism, PKC activity was significantly decreased by 57.1% as compared to age-matched control subjects (p = 0.0085), and by 65.8% as compared to non-regressed autistic subjects (p = 0.0048). PKC activity was unaffected in the temporal, parietal and occipital cortices, and in the cerebellum in both autism groups, i.e., regressive and non-regressed autism as compared to control subjects. These results suggest brain region-specific alteration of PKC activity in the frontal cortex of subjects with regressive autism. Further studies showed a negative correlation between PKC activity and restrictive, repetitive and stereotyped pattern of behavior (r= -0.084, p = 0.0363) in autistic individuals, suggesting involvement of PKC in behavioral abnormalities in autism. These findings suggest that regression in autism may be attributed, in part, to alterations in G-protein-coupled receptor-mediated signal transduction involving PKA and PKC in the frontal cortex.     

突触后致密物基因与孤独症

孤独症是一种病因不明的广泛性发育障碍疾病,它是孤独症谱系障碍的代表疾病,发病年龄早,大多在3岁以内起病,以社会交往障碍,言语交流障碍,动作行为的重复刻板和兴趣范围狭窄为三大临床核心症状。孤独症发病率呈逐年增高趋势,我国患者量已超过一百万。但是迄今为止仍没有特异的方法与手段对孤独症进行彻底有效地诊治,为社会和家庭带来了沉重的负担,因此,其发病机制是迫切需要研究的难题。目前国际上公认为遗传因素在孤独症的发病中起着重要作用,但对于致病基因的确定仍不明确。突触后致密物(PSD)在中枢神经系统神经递质和信息的传递过程中起重要作用,影响学习记忆及认知相关功能,而孤独症患者存在认知相关功能损伤的表现,二者可能存在一定的联系。本文对PSD基因功能以及与孤独症关系的研究加以综述,希望有助于孤独症的病因学研究,以期早日改善该病的诊疗及预防。     

Autistic-like and schizotypal traits in a life history perspective: diametrical associations with impulsivity,sensation seeking,and sociosexual behavior

According to recent theoretical models, autistic-like and schizotypal traits can be regarded as opposite sides of a single continuum of variation in personality and cognition, and may be diametrically associated with individual differences in life history strategies. In this view, schizotypy is a psychological phenotype oriented toward high mating effort and reduced parenting, consistent with a fast life history strategy, whereas autistic-like traits contribute to a slow strategy characterized by reduced mating effort and high parental investment. In this study, we tested the hypothesis that autistic-like and schizotypal traits would be diametrically associated with unrestricted sociosexuality, impulsivity, and sensation seeking (three key behavioral correlates of fast life history strategies in humans) in a sample of 152 young adults (18–38 years). The results were consistent with a diametrical autism–schizotypy axis of individual variation. In line with our hypotheses, autism–schizotypy scores were uniquely associated with individual differences in impulsivity, sensation seeking, and sociosexual behavior, even after controlling for variation in Big Five personality traits. However, we found no significant associations with sociosexual attitude in the present sample. Our findings provide additional support for a life history model of autistic-like and schizotypal traits and demonstrate the heuristic value of this approach in the study of personality and psychopathology.     

Factors affecting behavior and welfare of service dogs for children with autism spectrum disorder

The use of service dogs for children with autism spectrum disorder is a relatively new and growing assistance-dog application. The objectives of this article were to identify and describe the factors influencing an autism service dog's performance and the impact of this type of placement on the dog's welfare. A qualitative approach uses interview and observational data to characterize the dogs' behaviors and welfare with relevancy to the dogs' home environments. Identification of potential physical stressors included lack of rest or recovery time after working, unintentional maltreatment and prodding by children with autism, lack of predictability in daily routines, and insufficient opportunities for recreational activities. Results revealed that these dogs formed social relationships primarily with the parents and second with the children with autism. Failure to recognize and respond to the identified physical, emotional, and social needs can have serious impacts on the behavior, welfare, and performance of these autism service dogs, as well as parental satisfaction. As applications of service dogs expand to new domains, there is a need to assess and understand factors and variables affecting the relationship between family and service dog to ensure continued success of these programs.     

Increased excretion of a lipid peroxidation biomarker in autism

It is thought that autism could result from an interaction between genetic and environmental factors with oxidative stress as a potential mechanism linking the two. One genetic factor may be altered oxidative-reductive capacity. This study tested the hypothesis that children with autism have increased oxidative stress. We evaluated children with autism for the presence of two oxidative stress biomarkers. Urinary excretion of 8-hydroxy-2-deoxyguanosine (8-OHdG) and 8-isoprostane-F2alpha (8-iso-PGF2alpha) were determined in 33 children with autism and 29 healthy controls. 8-iso-PGF2alpha levels were significantly higher in children with autism. The isoprostane levels in autistic subjects were variable with a bimodal distribution. The majority of autistic subjects showed a moderate increase in isoprostane levels while a smaller group of autistic children showed dramatic increases in their isoprostane levels. There was a trend of an increase in 8-OHdG levels in children with autism but it did not reach statistical significance. There was no significant correlation between the levels of the biomarkers and vitamin intake, dietary supplements, medicine, medical disorders, or history of regression. These results suggest that the lipid peroxidation biomarker is increased in this cohort of autistic children, especially in the subgroup of autistic children.     

Preference for,and Responsiveness to,People, Dogs and Objects in Children with Autism

ABSTRACT

Autism strongly affects the ability to establish social interactions. However, there is some suggestion that people with autism establish close social relationships with nonverbal communicating and intentionally acting animals (such as dogs). In this study, 14 children with autism (3 females, 11 males; mean age = 11.4 years) were observed when given the choice to interact with a person, dog (certified therapy dog) or objects (e.g., toys). The children interacted most frequently and for longest with the dog, followed by the person and then the objects. We suggest that animals, specifically dogs, communicate their intentions in a way more readily understandable to people with autism. We also suggest that autism affects predominantly interpersonal interactions.     

Munchausen's syndrome and prophylactic mastectomy

A patient sought bilateral prophylactic mastectomies because of a strongly positive family history of breast cancer. Fortunately, prior to operation, this family history was discovered to be a fabrication by the patient. Few ablative plastic surgical procedures are done without objective criteria. Plastic surgeons relying on a positive family history as sufficient indication for bilateral prophylactic mastectomy need to be aware that such a history may be the contrivance of a patient with Munchausen's syndrome. A high index of suspicion may enable the plastic surgeon to recognize Munchausen's syndrome and thus avoid both contributing to the patient's illness and performing an unwarranted operation.     

Atypicalities in Perceptual Adaptation in Autism Do Not Extend to Perceptual Causality

A recent study showed that adaptation to causal events (collisions) in adults caused subsequent events to be less likely perceived as causal. In this study, we examined if a similar negative adaptation effect for perceptual causality occurs in children, both typically developing and with autism. Previous studies have reported diminished adaptation for face identity, facial configuration and gaze direction in children with autism. To test whether diminished adaptive coding extends beyond high-level social stimuli (such as faces) and could be a general property of autistic perception, we developed a child-friendly paradigm for adaptation of perceptual causality. We compared the performance of 22 children with autism with 22 typically developing children, individually matched on age and ability (IQ scores). We found significant and equally robust adaptation aftereffects for perceptual causality in both groups. There were also no differences between the two groups in their attention, as revealed by reaction times and accuracy in a change-detection task. These findings suggest that adaptation to perceptual causality in autism is largely similar to typical development and, further, that diminished adaptive coding might not be a general characteristic of autism at low levels of the perceptual hierarchy, constraining existing theories of adaptation in autism.     

Plasma fatty acid profiles in autism: A case-control study

Increasing evidence is mounting in support of fatty acid metabolism playing a role in neurodevelopmental disorders such as autism. In order to definitely determine whether fatty acid concentrations were associated with autism, we quantitatively measured 30 fatty acids from seven lipid classes in plasma from a large subset of subjects enrolled in the Childhood Autism Risk from Genetics and the Environment (CHARGE) study. The CHARGE study is a large, population-based case-control study on children aged 2–5 born in California. Our subset consisted of 153 children with autism and 97 developmentally normal controls. Results showed that docosahexaenoic acid (DHA, 22:6n-3) was significantly decreased in phosphatidylethanolamine. Dimethyl acetals were significantly decreased in phosphatidylethanolamine and phosphatidylcholine as well. These results are consistent with the only other study to measure dimethyl acetals in children with autism, and suggest that the function of peroxisomes and the enzymes of the peroxisome involved with fatty acid metabolism may be affected in autism.     

Reciprocal Relationship between Head Size,an Autism Endophenotype,and Gene Dosage at 19p13.12 Points to AKAP8 and AKAP8L

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=1.11x10^-11) and macrocephaly (p=2.47x10^-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.     

Views on Researcher-Community Engagement in Autism Research in the United Kingdom: A Mixed-Methods Study

There has been a substantial increase in research activity on autism during the past decade. Research into effective ways of responding to the immediate needs of autistic people is, however, less advanced, as are efforts at translating basic science research into service provision. Involving community members in research is one potential way of reducing this gap. This study therefore investigated the views of community involvement in autism research both from the perspectives of autism researchers and of community members, including autistic adults, family members and practitioners. Results from a large-scale questionnaire study (n = 1,516) showed that researchers perceive themselves to be engaged with the autism community but that community members, most notably autistic people and their families, did not share this view. Focus groups/interviews with 72 participants further identified the potential benefits and remaining challenges to involvement in research, especially regarding the distinct perspectives of different stakeholders. Researchers were skeptical about the possibilities of dramatically increasing community engagement, while community members themselves spoke about the challenges to fully understanding and influencing the research process. We suggest that the lack of a shared approach to community engagement in UK autism research represents a key roadblock to translational endeavors.