1. Banaschewski T, Poustka L, Holtmann M. {{[Autism and ADHD across the life span : Differential diagnoses or comorbidity?]}}. {Nervenarzt}. 2011 Apr 13.
Exclusion criteria of the DSM-IV-TR and ICD-10 do prevent dual diagnoses of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). However, inattention, impulsivity and hyperactivity are amongst the most frequent associated symptoms of ASD. Psychopathological, neuropsychological, brain imaging and genetic studies suggest possible pathophysiological links between ASD and ADHD. Thus, standard diagnostic procedures for both disorders should assess the presence of potential comorbid symptoms of the other disorder. Treatment strategies for ADHD symptoms in the context of ASD overlap with those for patients with ADHD, but lower dosages and slower titration might be recommendable.
2. Bowers K, Li Q, Bressler J, Avramopoulos D, Newschaffer C, Fallin MD. {{Glutathione pathway gene variation and risk of autism spectrum disorders}}. {J Neurodev Disord}. 2011 Mar 5.
Despite evidence that autism is highly heritable with estimates of 15 or more genes involved, few studies have directly examined associations of multiple gene interactions. Since inability to effectively combat oxidative stress has been suggested as a mechanism of autism, we examined genetic variation 42 genes (308 single-nucleotide polymorphisms (SNPs)) related to glutathione, the most important antioxidant in the brain, for both marginal association and multi-gene interaction among 318 case-parent trios from The Autism Genetic Resource Exchange. Models of multi-SNP interactions were estimated using the trio Logic Regression method. A three-SNP joint effect was observed for genotype combinations of SNPs in glutaredoxin, glutaredoxin 3 (GLRX3), and cystathione gamma lyase (CTH); OR = 3.78, 95% CI: 2.36, 6.04. Marginal associations were observed for four genes including two involved in the three-way interaction: CTH, alcohol dehydrogenase 5, gamma-glutamylcysteine synthetase, catalytic subunit and GLRX3. These results suggest that variation in genes involved in counterbalancing oxidative stress may contribute to autism, though replication is necessary.
3. Campbell DB, Datta D, Jones ST, Batey Lee E, Sutcliffe JS, Hammock EA, et al. {{Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder}}. {J Neurodev Disord}. 2011 Jan 6.
Autism spectrum disorder (ASD) is characterized by core deficits in social behavior, communication, and behavioral flexibility. Several lines of evidence indicate that oxytocin, signaling through its receptor (OXTR), is important in a wide range of social behaviors. In attempts to determine whether genetic variations in the oxytocin signaling system contribute to ASD susceptibility, seven recent reports indicated association of common genetic polymorphisms in the OXTR gene with ASD. Each involved relatively small sample sizes (57 to 436 families) and, where it was examined, failed to identify association of OXTR polymorphisms with measures of social behavior in individuals with ASD. We report genetic association analysis of 25 markers spanning the OXTR locus in 1,238 pedigrees including 2,333 individuals with ASD. Association of three markers previously implicated in ASD susceptibility, rs2268493 (P = 0.043), rs1042778 (P = 0.037), and rs7632287 (P = 0.016), was observed. Further, these genetic markers were associated with multiple core ASD phenotypes, including social domain dysfunction, measured by standardized instruments used to diagnose and describe ASD. The data suggest association of OXTR genetic polymorphisms with ASD, although the results should be interpreted with caution because none of the significant associations would survive appropriate correction for multiple comparisons. However, the current findings of association in a large independent cohort are consistent with previous results, and the biological plausibility of participation of the oxytocin signaling system in modulating social disruptions characteristic of ASD, suggest that functional polymorphisms of OXTR may contribute to ASD risk in a subset of families.
4. Chasson GS, Timpano KR, Greenberg JL, Shaw A, Singer T, Wilhelm S. {{Shared social competence impairment: Another link between the obsessive-compulsive and autism spectrums?}}. {Clin Psychol Rev}. 2011 Jun;31(4):653-62.
Recently, there has been a growing interest in the phenotypic, pathogenic, and pathophysiological overlap between autism spectrum disorders (ASD) and obsessive-compulsive spectrum disorders (OCSD). However, social competence impairment is one domain of overlap that has received less attention. Codified as one of three diagnostic categories in ASD, pathological social processing has also been demonstrated in OCSD. Yet, to date no reviews have synthesized the research literature on social competence impairments in OCSD, especially impairments that may parallel those found in ASD. The current review set out to examine the extant literature in this area in the service of advancing understanding of shared phenomenology between these two spectrums of conditions. Further, delineation of shared social competence impairments between ASD and OCSD might highlight candidate endophenotypes for further investigation. Ultimately, understanding the links between OCSD and ASD may aid in development of better intervention and prevention strategies, some of which may directly target maladaptive social processing.
5. Faja S, Webb SJ, Jones E, Merkle K, Kamara D, Bavaro J, et al. {{The Effects of Face Expertise Training on the Behavioral Performance and Brain Activity of Adults with High Functioning Autism Spectrum Disorders}}. {J Autism Dev Disord}. 2011 Apr 12.
The effect of expertise training with faces was studied in adults with ASD who showed initial impairment in face recognition. Participants were randomly assigned to a computerized training program involving either faces or houses. Pre- and post-testing included standardized and experimental measures of behavior and event-related brain potentials (ERPs), as well as interviews after training. After training, all participants met behavioral criteria for expertise with the specific stimuli on which they received training. Scores on standardized measures improved after training for both groups, but only the face training group showed an increased face inversion effect behaviorally and electrophysiological changes to faces in the P100 component. These findings suggest that individuals with ASD can gain expertise in face processing through training.
6. Gousse V, Galera C, Bouvard M, Michel G. {{[Aggregation of social deficits and psychiatric disorders in parents of children with autism: Toward a temperamental link?]}}. {Encephale}. 2011 Apr;37(2):119-26.
BACKGROUND: Autism is a group of neurodevelopmental disorders with heterogeneous phenotypic expression. Twin and family-based studies have demonstrated the importance of genetic factors in the etiology of these disorders. The pioneering work of Folstein and Rutter (1977) [16], showing concordance – 82 % in non affected monozygotic twins and 10 % in non affected dizygotic twins – for cognitive deficits (mostly affecting language), has directed work towards family-based studies aiming at demonstrating the existence of a « broad autism phenotype » (BAP), corresponding to the extension of the « autistic » phenotype in the relatives of affected children (Bailey et al., 1998 [5]). This notion of a broad phenotype makes it possible to take into account abnormalities in one or more of the three domains of the syndrome: communication, socialization and restrained and obsessive interest in a succession of subjects, with qualitatively similar but quantitatively smaller difficulties observed in the relatives. LITERATURE FINDINGS: We review here previous studies investigating the broad phenotype in the relatives of children with autism. We focus specifically on the hypothesis of a link between the aggregation of social deficits and of psychopathological problems, such problems being more frequently observed in these families than in families with other types of handicap (Abbeduto et al., 2004 [1]). Although the difficulties observed in these families may be partly explained by the stress of having to raise a heavily disabled child, genetic susceptibility factors may play a role in the occurrence of these problems in the families of autistic children. Constantino and Todd (2003) [14] support the hypothesis that a single factor is transmitted in families – social reciprocity – and may be responsible for the overall dysfunction in the various domains of the syndrome in affected individuals. However, this susceptibility factor may be linked to other deficits observed in certain psychiatric disorders (e.g., attention deficit in ADHD), consistent with the hypothesis that there is a link between the broad phenotype and psychopathological problems. CONCLUSION: This paper reviews this issue in the two domains of study described and presents a hypothesis to account for the possible link between the presence of the broad phenotype – or more specifically, of social deficits – and the more frequent occurrence of psychological problems in the families of autistic individuals. The notion of temperament (Garon et al., 2009 [17]) is proposed and considered to present essential characteristics that might account for this relationship: indeed, temperament is associated with notions of IQ, psychopathology and social function and could potentially be used as a predictive variable in affected individuals. Finally, the link between temperament and psychopathology in the relatives of affected individuals may be reflected in the presence of cognitive peculiarities more specifically linked to socioemotional dysfunction (Losh and Piven, 2007 [22]).
7. Hutchins TL, Prelock PA, Bonazinga L. {{Psychometric Evaluation of the Theory of Mind Inventory (ToMI): A Study of Typically Developing Children and Children with Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2011 Apr 12.
Two studies examined the psychometric properties of the Theory of Mind Inventory (ToMI). In Study One, 135 caregivers completed the ToMI for children (ages 3 through 17) with autism spectrum disorder (ASD). Findings revealed excellent test-retest reliability and internal consistency. Principle Components Analysis revealed three subscales related to the complexity of ToM understanding. In Study Two, data were collected for 124 typically developing children (2 through 12 years). Findings again revealed excellent test-retest and internal consistency. The ToMI distinguished groups by age (younger vs. older children) and developmental status (typically developing vs. ASD), and predicted child performance on a ToM task battery. Utility of the ToMI, study limitations and directions for future research are discussed.
8. Miller JS, Gabrielsen T, Villalobos M, Alleman R, Wahmhoff N, Carbone PS, et al. {{The Each Child Study: Systematic Screening for Autism Spectrum Disorders in a Pediatric Setting}}. {Pediatrics}. 2011 Apr 11.
Objective: The goal of this study was to investigate the feasibility and outcome of a systematic autism screening process for all toddlers (aged 14-30 months) in a large, community-based pediatric practice. Methods: All toddlers who presented to the clinic during the 6-month screening period were eligible. We used 2 screening questionnaires and allowed physicians to refer directly to capture as many children as possible. Receptionists and medical assistants distributed and collected screening questionnaires; research staff did all scoring and follow-up, either by telephone or in person when indicated. Results: We obtained a high rate of screening (80% of eligible children). Of the 796 children screened, 3 had already been diagnosed with an autism spectrum disorder (ASD); an additional 10 children who showed signs of early ASD that warranted further evaluation or intervention were identified. Formal screening measures identified more children with ASD than did clinical judgment or caregiver concerns; however, no single method (ie, questionnaire, caregiver concerns, provider concerns) identified all children with signs of early ASD. We had excellent participation from racially and ethnically diverse families, including Spanish-speaking families. Thirty-two percent of the children who were screened did not present for a well-child visit during the study period and were screened at a sick visit, follow-up visit, or injection appointment. Conclusions: A partnership between pediatricians and autism specialists resulted in effective, systematic autism screening. Future studies should examine how to create effective systems of care.
9. Modi ME, Young LJ. {{D-Cycloserine Facilitates Socially Reinforced Learning in an Animal Model Relevant to Autism Spectrum Disorders}}. {Biol Psychiatry}. 2011 Apr 7.
BACKGROUND: There are no drugs that specifically target the social deficits of autism spectrum disorders (ASD). This may be due to a lack of behavioral paradigms in animal models relevant to ASD. Partner preference formation in the prairie vole represents a social cognitive process involving socially reinforced learning. D-cycloserine (DCS) is a cognitive enhancer that acts at the N-methyl-D-aspartate receptor to promote learning. If DCS enhances socially reinforced learning in the partner preference paradigm, it may be useful in combination with behavioral therapies for enhancing social functioning in ASD. METHODS: Female prairie and meadow voles were given DCS either peripherally or directly into one of three brain regions: nucleus accumbens, amygdala, or caudate putamen. Subjects were then cohabited with a male vole under conditions that do not typically yield a partner preference. The development of a preference for that stimulus male vole over a novel male vole was assessed using a partner preference test. RESULTS: A low dose of DCS administered peripherally enhanced preference formation in prairie voles but not meadow voles under conditions in which it would not otherwise occur. These effects were replicated in prairie voles by microinfusions of DCS into the nucleus accumbens, which is involved in reinforcement learning, and the amygdala, which is involved in social information processing. CONCLUSIONS: Partner preference in the prairie vole may provide a behavioral paradigm with face, construct, and predictive validity for identifying prosocial pharmacotherapeutics. D-cycloserine may be a viable treatment strategy for social deficits of ASD when paired with social behavioral therapy.
10. Pagani M, Manouilenko I, Stone-Elander S, Odh R, Salmaso D, Hatherly R, et al. {{Brief Report: Alterations in Cerebral Blood Flow as Assessed by PET/CT in Adults with Autism Spectrum Disorder with Normal IQ}}. {J Autism Dev Disord}. 2011 Apr 13.
Specific biological markers for Autism Spectrum Disorder (ASD) have not yet been established. Functional studies have shown abnormalities in the anatomo-functional connectivity of the limbic-striatal « social » brain. This study aimed to investigate regional cerebral blood flow (rCBF) at rest. Thirteen patients with ASD of normal intelligence and ten IQ-, sex- and age-matched healthy controls (HC) underwent PET/CT using [1-(11)C]butanol, a perfusion tracer. As compared to HC, ASD showed significant CBF increases in the right parahippocampal, posterior cingulate, primary visual and temporal cortex, putamen, caudatus, substantia nigra and cerebellum. No statistically significant correlation between CBF and IQ was found. The limbic, posterior associative and cerebellar cortices showed increased blood flow in ASD, confirming previous findings about the neurobiology of ASD.
11. Pagnamenta AT, Holt R, Yusuf M, Pinto D, Wing K, Betancur C, et al. {{A family with autism and rare copy number variants disrupting the Duchenne/Becker muscular dystrophy gene DMD and TRPM3}}. {J Neurodev Disord}. 2011 Feb 12.
Autism spectrum disorder is a genetically complex and clinically heterogeneous neurodevelopmental disorder. A recent study by the Autism Genome Project (AGP) used 1M single-nucleotide polymorphism arrays to show that rare genic copy number variants (CNVs), possibly acting in tandem, play a significant role in the genetic aetiology of this condition. In this study, we describe the phenotypic and genomic characterisation of a multiplex autism family from the AGP study that was found to harbour a duplication of exons 31-44 of the Duchenne/Becker muscular dystrophy gene DMD and also a rare deletion involving exons 1-9 of TRPM3. Further characterisation of these extremely rare CNVs was carried out using quantitative PCR, fluorescent in situ hybridisation, long-range PCR amplification and sequencing of junction fragments. The maternal chrX:32,097,213-32,321,945 tandem duplication and paternal chr9:72,480,413-73,064,196 deletion (NCBI build 36 coordinates) were transmitted to both affected boys, potentially signifying a multi-hit mechanism. The DMD reading frame rule predicts a Becker phenotype, characterised by later onset and milder symptoms. When last evaluated, neither child had developed signs of muscular dystrophy. These data are consistent with a degree of comorbidity between autism and muscular dystrophy and suggest that genomic background as well as the position of the mutation within the DMD gene may impact on the neurological correlates of Duchenne/Becker muscular dystrophy. Finally, communicating unexpected findings such as these back to families raises a number of ethical questions, which are discussed.
12. Patterson PH. {{Maternal infection and immune involvement in autism}}. {Trends Mol Med}. 2011 Apr 7.
Recent studies have highlighted a connection between infection during pregnancy and the increased risk of autism in the offspring. Parallel studies of cerebral spinal fluid, blood and postmortem brains reveal an ongoing, hyper-responsive inflammatory-like state in many young as well as adult autism subjects. There are also indications of gastrointestinal problems in at least a subset of autistic children. Work on the maternal infection risk factor using animal models indicates that aspects of brain and peripheral immune dysregulation can begin during fetal development and continue through adulthood. The offspring of infected or immune-activated dams also display cardinal behavioral features of autism, as well as neuropathology consistent with that seen in human autism. These rodent models are proving useful for the study of pathogenesis and gene-environment interactions as well as for the exploration of potential therapeutic strategies.
13. Pitskel NB, Bolling DZ, Hudac CM, Lantz SD, Minshew NJ, Vander Wyk BC, et al. {{Brain Mechanisms for Processing Direct and Averted Gaze in Individuals with Autism}}. {J Autism Dev Disord}. 2011 Apr 12.
Prior studies have indicated brain abnormalities underlying social processing in autism, but no fMRI study has specifically addressed the differential processing of direct and averted gaze, a critical social cue. Fifteen adolescents and adults with autism and 14 typically developing comparison participants viewed dynamic virtual-reality videos depicting a simple but realistic social scenario, in which an approaching male figure maintained either direct or averted gaze. Significant group by condition interactions reflecting differential responses to direct versus averted gaze in people with autism relative to typically developing individuals were identified in the right temporoparietal junction, right anterior insula, left lateral occipital cortex, and left dorsolateral prefrontal cortex. Our results provide initial evidence regarding brain mechanisms underlying the processing of gaze direction during simple social encounters, providing new insight into the social deficits in individuals with autism.
14. Poustka L, Banaschewski T, Poustka F. {{[Psychopharmacology of autism spectrum disorders.]}}. {Nervenarzt}. 2011 Apr 13.
Autism spectrum disorders (ASD) are persistent, heterogeneous conditions that display many comorbid problems. Especially maladaptive behaviours like increased irritability, aggression, impulsivity and self-injurious behaviours are perceived as enormously stressful and can interfere with interventions targeting social and communication deficits. Medication treatments focussing on troubling comorbid problems in ASD can be fundamentally ameliorative, although core features of the disorder itself cannot be sufficiently treated. While atypical antipsychotics and stimulant medication have been proven to be effective in large multisite networks of ASD, serotonin reuptake inhibitors are of limited efficacy. Novel pharmacotherapies to improve social impairment are in the early stages of research.
15. Sasson NJ, Pinkham AE, Carpenter KL, Belger A. {{The benefit of directly comparing autism and schizophrenia for revealing mechanisms of social cognitive impairment}}. {J Neurodev Disord}. 2010 Dec 16.
Autism and schizophrenia share a history of diagnostic conflation that was not definitively resolved until the publication of the DSM-III in 1980. Though now recognized as heterogeneous disorders with distinct developmental trajectories and dissociative features, much of the early nosological confusion stemmed from apparent overlap in certain areas of social dysfunction. In more recent years, separate but substantial literatures have accumulated for autism and schizophrenia demonstrating that abnormalities in social cognition directly contribute to the characteristic social deficits of both disorders. The current paper argues that direct comparison of social cognitive impairment can highlight shared and divergent mechanisms underlying pathways to social dysfunction, a process that can provide significant clinical benefit by informing the development of tailored treatment efforts. Thus, while the history of diagnostic conflation between autism and schizophrenia may have originated in similarities in social dysfunction, the goal of direct comparisons is not to conflate them once again but rather to reveal distinctions that illuminate disorder-specific mechanisms and pathways that contribute to social cognitive impairment.
16. Sokol DK, Maloney B, Long JM, Ray B, Lahiri DK. {{Autism, Alzheimer disease, and fragile X: APP, FMRP, and mGluR5 are molecular links}}. {Neurology}. 2011 Apr 12;76(15):1344-52.
The present review highlights an association between autism, Alzheimer disease (AD), and fragile X syndrome (FXS). We propose a conceptual framework involving the amyloid-beta peptide (Abeta), Abeta precursor protein (APP), and fragile X mental retardation protein (FMRP) based on experimental evidence. The anabolic (growth-promoting) effect of the secreted alpha form of the amyloid-beta precursor protein (sAPPalpha) may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPalpha levels associate with more severe symptoms of autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell-cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 (mGluR5). Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPPalpha level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPPalpha and production of insoluble Abeta would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism.
17. Verity CM, Stellitano LS, Winstone AM. {{The PIND study found no association between vaccination and autism in mitochondrial disease – correction}}. {Dev Med Child Neurol}. 2011 May;53(5):477.
18. Vieland VJ, Hallmayer J, Huang Y, Pagnamenta AT, Pinto D, Khan H, et al. {{Novel method for combined linkage and genome-wide association analysis finds evidence of distinct genetic architecture for two subtypes of autism}}. {J Neurodev Disord}. 2011 Jan 19.
The Autism Genome Project has assembled two large datasets originally designed for linkage analysis and genome-wide association analysis, respectively: 1,069 multiplex families genotyped on the Affymetrix 10 K platform, and 1,129 autism trios genotyped on the Illumina 1 M platform. We set out to exploit this unique pair of resources by analyzing the combined data with a novel statistical method, based on the PPL statistical framework, simultaneously searching for linkage and association to loci involved in autism spectrum disorders (ASD). Our analysis also allowed for potential differences in genetic architecture for ASD in the presence or absence of lower IQ, an important clinical indicator of ASD subtypes. We found strong evidence of multiple linked loci; however, association evidence implicating specific genes was low even under the linkage peaks. Distinct loci were found in the lower IQ families, and these families showed stronger and more numerous linkage peaks, while the normal IQ group yielded the strongest association evidence. It appears that presence/absence of lower IQ (LIQ) demarcates more genetically homogeneous subgroups of ASD patients, with not just different sets of loci acting in the two groups, but possibly distinct genetic architecture between them, such that the LIQ group involves more major gene effects (amenable to linkage mapping), while the normal IQ group potentially involves more common alleles with lower penetrances. The possibility of distinct genetic architecture across subtypes of ASD has implications for further research and perhaps for research approaches to other complex disorders as well.
