1. Amiet C, Gourfinkel-An I, Laurent C, Bodeau N, Genin B, Leguern E, Tordjman S, Cohen D. {{Does epilepsy in multiplex autism pedigrees define a different subgroup in terms of clinical characteristics and genetic risk?}}. {Mol Autism};2013 (Dec 1);4(1):47.
BACKGROUND: Autism spectrum disorders (ASD) and epilepsy frequently occur together. Prevalence rates are variable, and have been attributed to age, gender, comorbidity, subtype of pervasive developmental disorder (PDD) and risk factors. Recent studies have suggested disparate clinical and genetic settings depending on simplex or multiplex autism. The aim of this study was to assess: 1) the prevalence of epilepsy in multiplex autism and its association with genetic and non-genetic risk factors of major effect, intellectual disability and gender; and 2) whether autism and epilepsy cosegregate within multiplex autism families. METHODS: We extracted from the Autism Genetic Resource Exchange (AGRE) database (n = 3,818 children from 1,264 families) all families with relevant medical data (n = 664 children from 290 families). The sample included 478 children with ASD and 186 siblings without ASD. We analyzed the following variables: seizures, genetic and non-genetic risk factors, gender, and cognitive functioning as assessed by Raven’s Colored Progressive Matrices (RCPM) and Vineland Adaptive Behavior Scales (VABS). RESULTS: The prevalence of epilepsy was 12.8% in cases with ASD and 2.2% in siblings without ASD (P <10-5). With each RCPM or VABS measure, the risk of epilepsy in multiplex autism was significantly associated with intellectual disability, but not with gender. Identified risk factors (genetic or non-genetic) of autism tended to be significantly associated with epilepsy (P = 0.052). When children with prematurity, pre- or perinatal insult, or cerebral palsy were excluded, a genetic risk factor was reported for 6/59 (10.2%) of children with epilepsy and 12/395 (3.0%) of children without epilepsy (P = 0.002). Finally, using a permutation test, there was significant evidence that the epilepsy phenotype co-segregated within families (P <10-4). CONCLUSIONS: Epilepsy in multiplex autism may define a different subgroup in terms of clinical characteristics and genetic risk.
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2. Barneveld PS, Swaab H, Fagel S, van Engeland H, de Sonneville LM. {{Quality of life: A case-controlled long-term follow-up study, comparing young high-functioning adults with autism spectrum disorders with adults with other psychiatric disorders diagnosed in childhood}}. {Compr Psychiatry};2013 (Oct 10)
BACKGROUND: Long term outcome in childhood autism spectrum disorders (ASD) was evaluated by studying quality of life (QoL) in young adulthood in comparison to the outcome of other child psychiatric disorders. METHODS: In this follow-up study, objective and subjective QoL of 169 high-functioning (IQ>70) adults with ASD (19 to 30years) was contrasted with QoL data of age matched adults diagnosed with attention deficit/hyperactivity disorder (N=85), disruptive behaviour disorders (N=83), and affective disorders (N=85) during childhood. The mean follow-up period of the ASD patients was 13.9years. Objective QoL included marital status, living arrangements, level of education, employment, and usage of mental health care. Subjective QoL included satisfaction concerning living arrangements, work or education, physical condition, partner relationship, social relationships, state of mind, and future perspective. RESULTS: QoL was more compromised in adults diagnosed with ASD in childhood than in adults with other psychiatric disorders in childhood. A relatively large proportion of the adults with ASD were single, few lived with a partner or a family and many of them were institutionalized. Adults with ASD had lower educational levels, relatively few had paid employment and many were social security recipients, as compared to the other psychiatric patients. In case the adults with ASD used medication, 47% used anti-psychotics. Regarding the subjective QoL, the adults with ASD were less satisfied about their work or education, partner relationship, and future perspective than the other groups. Even when highly educated adults with ASD were compared to highly educated adults diagnosed with other childhood disorders, the QoL appeared to be more disadvantageous in adults with ASD. CONCLUSION: Many studies have shown that QoL is threatened in psychiatric patients, but findings of this study indicate that young high-functioning adults diagnosed with ASD in childhood are at relatively high risk for poor QoL compared to other childhood psychiatric disorders.
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3. Becker EB, Stoodley CJ. {{Autism spectrum disorder and the cerebellum}}. {Int Rev Neurobiol};2013;113:1-34.
The cerebellum has been long known for its importance in motor learning and coordination. Recently, anatomical, clinical, and neuroimaging studies strongly suggest that the cerebellum supports cognitive functions, including language and executive functions, as well as affective regulation. Furthermore, the cerebellum has emerged as one of the key brain regions affected in autism. Here, we discuss our current understanding of the role of the cerebellum in autism, including evidence from genetic, molecular, clinical, behavioral, and neuroimaging studies. Cerebellar findings in autism suggest developmental differences at multiple levels of neural structure and function, indicating that the cerebellum is an important player in the complex neural underpinnings of autism spectrum disorder, with behavioral implications beyond the motor domain.
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4. Bill BR, Lowe JK, Dybuncio CT, Fogel BL. {{Orchestration of Neurodevelopmental Programs by RBFOX1: Implications for Autism Spectrum Disorder}}. {Int Rev Neurobiol};2013;113:251-267.
Neurodevelopmental and neuropsychiatric disorders result from complex interactions between critical genetic factors and as-yet-unknown environmental components. To gain clinical insight, it is critical to develop a comprehensive understanding of these genetic components. RBFOX1, an RNA splicing factor, regulates expression of large genetic networks during early neuronal development, and haploinsufficiency causes severe neurodevelopmental phenotypes including autism spectrum disorder (ASD), intellectual disability, and epilepsy. Genomic testing in individuals and large patient cohorts has identified phenotypically similar cases possessing copy number variations in RBFOX1, implicating the gene as an important cause of neurodevelopmental disease. However, a significant proportion of the observed structural variation is inherited from phenotypically normal individuals, raising questions regarding overall pathogenicity of variation at the RBFOX1 locus. In this chapter, we discuss the molecular, cellular, and clinical evidence supporting the role of RBFOX1 in neurodevelopment and present a comprehensive model for the contribution of structural variation in RBFOX1 to ASD.
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5. Chukoskie L, Townsend J, Westerfield M. {{Motor skill in autism spectrum disorders: a subcortical view}}. {Int Rev Neurobiol};2013;113:207-249.
The earliest observable symptoms of autism spectrum disorders (ASDs) involve motor behavior. There is a growing awareness of the developmental importance of impaired motor function in ASD and its association with social skill. Compromised motor function requires increased attention, leaving fewer resources available for processing environmental stimuli and learning. This knowledge suggests that the motor system-which we know to be trainable-may be a gateway to improving outcomes of individuals living with ASD. In this review, we suggest a framework borrowed from machine learning to examine where, why, and how motor skills are different in individuals with ASD.
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6. Coffman MC, Anderson LC, Naples AJ, McPartland JC. {{Sex Differences in Social Perception in Children with ASD}}. {J Autism Dev Disord};2013 (Nov 30)
Autism spectrum disorder (ASD) is more common in males than females. An underrepresentation of females in the ASD literature has led to limited knowledge of differences in social function across the sexes. Investigations of face perception represent a promising target for understanding variability in social functioning between males and females. The current study analyzed electrophysiological brain recordings during face perception to investigate sex differences in the neural correlates of face perception and their relationship to social function. Event related potentials (ERP) were recorded from children with ASD while viewing faces, inverted faces, and houses. Relative to males, females showed attenuated response at an ERP marker of face perception, the N170. Among females, but not males, atypical face response was associated with symptom severity. Observed sex differences reflect influential differences in social information processing, and impairment in these features correlates with deficits in social information processing in females, but not males, with ASD. These findings hold significance for future treatment protocols, which should account for differences in males and females with ASD in clinical presentation and neural phenotypes.
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7. Doesburg SM, Vidal J, Taylor MJ. {{Reduced Theta Connectivity during Set-Shifting in Children with Autism}}. {Front Hum Neurosci};2013;7:785.
Autism spectrum disorder (ASD) is a characterized by deficits in social cognition and executive function. An area of particular difficulty for children with ASD is cognitive flexibility, such as the ability to shift between attentional or response sets. The biological basis of such deficits remains poorly understood, although atypical development of structural and functional brain connectivity have been reported in ASD, suggesting that disruptions of normal patterns of inter-regional communication may contribute to cognitive problems in this group. The present magnetoencephalography study measured inter-regional phase synchronization while children with ASD and typically developing matched controls (6-14 years of age) performed a set-shifting task. Reduced theta-band phase synchronization was observed in children with ASD during extradimensional set-shifting. This reduction in task-dependent inter-regional connectivity encompassed numerous areas including multiple frontal lobe regions, and indicates that problems with communication among brain areas may contribute to difficulties with executive function in ASD.
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8. Enloe KA, Rapp JT. {{Effects of Noncontingent Social Interaction on Immediate and Subsequent Engagement in Vocal and Motor Stereotypy in Children With Autism}}. {Behav Modif};2013 (Dec 3)
This study evaluated the effects of noncontingent social interaction (SI) on immediate and subsequent engagement in vocal and motor stereotypy in three children with autism. During SI, a therapist delivered continuous interaction in the form of reading aloud from a Kindle e-reader. Results showed that when compared with a no-interaction baseline sequence, SI decreased immediate engagement vocal stereotypy for all three participants without increasing subsequent engagement for any participant. Furthermore, SI also increased immediate engagement in motor stereotypy for one participant, decreased immediate engagement in motor stereotypy for two participants, but did not increase subsequent engagement in motor stereotypy for any participant. Some clinical implications and limitations of the findings are discussed.
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9. Gentile I, Zappulo E, Coppola N, Bonavolta R, Portella G, Cernia DS, Riccio MP, Settimi A, Pascotto A, Borgia G, Bravaccio C. {{Prevalence of HHV-6 and HHV-8 Antibodies in Patients with Autism Spectrum Disorders}}. {In Vivo};2013 (Nov-Dec);27(6):843-849.
Background/Aim: The etiology of autism spectrum disorders (ASD) still eludes investigators. Several viral infections have been associated with ASD etiopathogenesis but few studies have ever focused on the role of HHV-6 and HHV-8, two members of the herpesviridae family. The aim of the present study was to evaluate seropositivity rate and levels of antibodies to HHV6 and HHV-8 in children with ASD compared to controls. PATIENTS AND METHODS: We measured and compared seropositivity rate and levels of antibodies to HHV-6 and HHV-8 in 30 children with ASD (14 with autistic disorder and 16 with non-autistic disorder ASD) and in 28 healthy controls of the same age. RESULTS: Seropositivity rate and levels of the two antibodies were similar in cases and controls. Seropositivity rate and levels of antibodies were not correlated with disease severity in children with ASD. CONCLUSION: Levels and seropositivity rate of antibodies to HHV-6 and HHV-8 do not differ between children with ASD and controls.
10. Gerhardt J, Tomishima MJ, Zaninovic N, Colak D, Yan Z, Zhan Q, Rosenwaks Z, Jaffrey SR, Schildkraut CL. {{The DNA Replication Program Is Altered at the FMR1 Locus in Fragile X Embryonic Stem Cells}}. {Mol Cell};2013 (Nov 26)
Fragile X syndrome (FXS) is caused by a CGG repeat expansion in the FMR1 gene that appears to occur during oogenesis and during early embryogenesis. One model proposes that repeat instability depends on the replication fork direction through the repeats such that (CNG)n hairpin-like structures form, causing DNA polymerase to stall and slip. Examining DNA replication fork progression on single DNA molecules at the endogenous FMR1 locus revealed that replication forks stall at CGG repeats in human cells. Furthermore, replication profiles of FXS human embryonic stem cells (hESCs) compared to nonaffected hESCs showed that fork direction through the repeats is altered at the FMR1 locus in FXS hESCs, such that predominantly the CCG strand serves as the lagging-strand template. This is due to the absence of replication initiation that would typically occur upstream of FMR1, suggesting that altered replication origin usage combined with fork stalling promotes repeat instability during early embryonic development.
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11. Glatt SJ. {{How should we interpret and value the pursuit of blood-based biomarkers for autism spectrum disorders?}}. {J Am Acad Child Adolesc Psychiatry};2013 (Dec);52(12):1248-1250.
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12. Hartley C, Allen ML. {{Symbolic Understanding of Pictures in Low-Functioning Children with Autism: The Effects of Iconicity and Naming}}. {J Autism Dev Disord};2013 (Nov 29)
This research investigated whether symbolic understanding of pictures in low-functioning children with autism is mediated by iconicity and language. In Experiment 1, participants were taught novel words paired with unfamiliar pictures that varied in iconicity (black-and-white line drawings, greyscale photographs, colour line drawings, colour photographs). Unlike mental-age matched typically developing peers, children with autism generally mapped words onto pictures rather than depicted referents, however, they generalised labels more frequently in colour picture conditions. In Experiment 2, children with autism categorised a line drawing with its referent, rather than another picture, regardless of whether it was named. Typically developing children only viewed pictures as symbols when they were labelled. Overall, symbolic understanding of pictures in children with autism is facilitated by iconicity (particularly colour), but not language.
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13. Hsiao EY. {{Immune dysregulation in autism spectrum disorder}}. {Int Rev Neurobiol};2013;113:269-302.
Autism spectrum disorder (ASD) is a highly heterogeneous disorder diagnosed based on the presence and severity of core abnormalities in social communication and repetitive behavior, yet several studies converge on immune dysregulation as a feature of ASD. Widespread alterations in immune molecules and responses are seen in the brains and periphery of ASD individuals, and early life immune disruptions are associated with ASD. This chapter discusses immune-related environmental and genetic risk factors for ASD, emphasizing population-wide studies and animal research that reveal potential mechanistic pathways involved in the development of ASD-related symptoms. It further reviews immunologic pathologies seen in ASD individuals and how such abnormalities can impact neurodevelopment and behavior. Finally, it evaluates emerging evidence for an immune contribution to the pathogenesis of ASD and a potential role for immunomodulatory effects in current treatments for ASD.
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14. Huang Z, Mou L, Shen Q, Lu S, Li C, Liu X, Wang G, Li S, Geng L, Liu Y, Wu J, Chen G, Zhang J. {{ASD v2.0: updated content and novel features focusing on allosteric regulation}}. {Nucleic Acids Res};2013 (Nov 28)
Allostery is the most direct and efficient way for regulation of biological macromolecule function and is induced by the binding of a ligand at an allosteric site topographically distinct from the orthosteric site. AlloSteric Database (ASD, http://mdl.shsmu.edu.cn/ASD) has been developed to provide comprehensive information on allostery. Owing to the inherent high receptor selectivity and lower target-based toxicity, allosteric regulation is expected to assume a more prominent role in drug discovery and bioengineering, leading to the rapid growth of allosteric findings. In this updated version, ASD v2.0 has expanded to 1286 allosteric proteins, 565 allosteric diseases and 22 008 allosteric modulators. A total of 907 allosteric site-modulator structural complexes and >200 structural pairs of orthosteric/allosteric sites in the allosteric proteins were constructed for researchers to develop allosteric site and pathway tools in response to community demands. Up-to-date allosteric pathways were manually curated in the updated version. In addition, both the front-end and the back-end of ASD have been redesigned and enhanced to allow more efficient access. Taken together, these updates are useful for facilitating the investigation of allosteric mechanisms, allosteric target identification and allosteric drug discovery.
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15. Kocourkova J, Dudova I, Koutek J. {{Asperger syndrome related suicidal behavior: two case studies}}. {Neuropsychiatr Dis Treat};2013;9:1815-1819.
Asperger syndrome hinders adaptation to developmental challenges during childhood and adolescence, particularly with regard to interpersonal relationships. Individuals with Asperger syndrome display lack of empathy and limited ability to understand social and emotional exchanges with other people. Individuals with Asperger syndrome are significantly exposed to the risk of suicidal behavior, especially during adolescence. The authors describe cases of suicidal behavior in two adolescent boys with Asperger syndrome.
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16. Konopka G. {{Preface: the neurobiology of autism: integrating genetics, brain development, behavior, and the environment}}. {Int Rev Neurobiol};2013;113:xi-xii.
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17. Kubota T. {{Epigenome: what we learned from Rett syndrome, a neurological disease caused by mutation of a methyl-CpG binding protein}}. {Rinsho Shinkeigaku};2013;53(11):1339-1341.
Epigenome is defined as DNA and histone modification-dependent gene regulation system. Abnormalities in this system are known to cause various neuro-developmental diseases. We recently reported that neurological symptoms of Rett syndrome, which is an autistic disorder caused by mutations in methyl-CpG binding protein 2 (MeCP2), was associated with failure of epigenomic gene regulation in neuronal cells, and that clinical differences in the identical twins with Rett syndrome in the differences in DNA methylation in neuronal genes, but not caused by DNA sequence differences. Since central nervus system requires precise gene regulation, neurological diseases including Alzheimer and Parkinson diseases may be caused by acquired DNA modification (epigenomic) changes that results in aberrant gene regulation as well as DNA sequence changes congenitally occurred (mutation).
18. Kwan KY. {{Transcriptional Dysregulation of Neocortical Circuit Assembly in ASD}}. {Int Rev Neurobiol};2013;113:167-205.
Autism spectrum disorders (ASDs) impair social cognition and communication, key higher-order functions centered in the human neocortex. The assembly of neocortical circuitry is a precisely regulated developmental process susceptible to genetic alterations that can ultimately affect cognitive abilities. Because ASD is an early onset neurodevelopmental disorder that disrupts functions executed by the neocortex, miswiring of neocortical circuits has been hypothesized to be an underlying mechanism of ASD. This possibility is supported by emerging genetic findings and data from imaging studies. Recent research on neocortical development has identified transcription factors as key determinants of neocortical circuit assembly, mediating diverse processes including neuronal specification, migration, and wiring. Many of these TFs (TBR1, SOX5, FEZF2, and SATB2) have been implicated in ASD. Here, I will discuss the functional roles of these transcriptional programs in neocortical circuit development and their neurobiological implications for the emerging etiology of ASD.
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19. Lee SY, Ramirez J, Franco M, Lectez B, Gonzalez M, Barrio R, Mayor U. {{Ube3a, the E3 ubiquitin ligase causing Angelman syndrome and linked to autism, regulates protein homeostasis through the proteasomal shuttle Rpn10}}. {Cell Mol Life Sci};2013 (Dec 1)
Ubiquitination, the covalent attachment of ubiquitin to a target protein, regulates most cellular processes and is involved in several neurological disorders. In particular, Angelman syndrome and one of the most common genomic forms of autism, dup15q, are caused respectively by lack of or excess of UBE3A, a ubiquitin E3 ligase. Its Drosophila orthologue, Ube3a, is also active during brain development. We have now devised a protocol to screen for substrates of this particular ubiquitin ligase. In a neuronal cell system, we find direct ubiquitination by Ube3a of three proteasome-related proteins Rpn10, Uch-L5, and CG8209, as well as of the ribosomal protein Rps10b. Only one of these, Rpn10, is targeted for degradation upon ubiquitination by Ube3a, indicating that degradation might not be the only effect of Ube3a on its substrates. Furthermore, we report the genetic interaction in vivo between Ube3a and the C-terminal part of Rpn10. Overexpression of these proteins leads to an enhanced accumulation of ubiquitinated proteins, further supporting the biochemical evidence of interaction obtained in neuronal cells.
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20. Lehnhardt FG, Gawronski A, Pfeiffer K, Kockler H, Schilbach L, Vogeley K. {{The investigation and differential diagnosis of asperger syndrome in adults}}. {Dtsch Arztebl Int};2013 (Nov 8);110(45):755-763.
BACKGROUND: As a result of the increased public interest in autism spectrum disorders (ASD), certain core manifestations of ASD-impaired social interaction and communication, bizarre interests-are now commonly recognized as being typical of autism, not only in children, but in adults as well. More often than before, general practitioners, neurologists, and psychiatrists find themselves being asked whether a patient is suffering from previously unrecognized Asperger syndrome (AS). The prevalence of ASD is estimated at 1%, and the ratio of diagnosed to undiagnosed cases at about 3:2. Little is known about the diagnostic evaluation of AS in adulthood. METHOD: We selectively searched the Medline database for pertinent literature, paying special attention to diagnostic manuals and to the guideline of the United Kingdom’s National Institute for Health and Care Excellence (NICE). RESULTS: Centrally important aspects of the diagnosis of AS include an assessment of the patient’s ability to assume the emotional perspectives of others, non-verbal modes of expression, repetitive behavior patterns, and childhood social behavioral history. The autism quotient (AQ) is now established as a simple but nonspecific screening test. Up to 70% of all affected adults have comorbid disturbances, most often depression and anxiety disorders. The differential diagnosis includes personality disorders, anxiety disorders, obsessive-compulsive disorder, and attention deficit-hyperactivity disorder. The diagnostic assessment should proceed in stepwise fashion, starting from simple screening in primary care and then moving on to evaluation of the suspected diagnosis by a mental health care specialist, followed by extensive further investigation in an outpatient clinic specifically devoted to patients with autism spectrum disorders. CONCLUSION: The diagnostic assessment of autism in adults requires knowledge of the core and accompanying manifestations of autism and of their differential diagnoses. More research is needed for the development of further screening tests and the precise determination of diagnosis rates, differential diagnoses, nd comorbidities.
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21. Lepp S, Anderson A, Konopka G. {{Connecting Signaling Pathways Underlying Communication to ASD Vulnerability}}. {Int Rev Neurobiol};2013;113:97-133.
Language is a human-specific trait that likely facilitated the rapid increase in higher cognitive function in our species. A consequence of the selective pressures that have permitted language and cognition to flourish in humans is the unique vulnerability of humans to developing cognitive disorders such as autism. Therefore, progress in understanding the genetic and molecular mechanisms of language evolution should provide insight into such disorders. Here, we discuss the few genes that have been identified in both autism-related pathways and language. We also detail the use of animal models to uncover the function of these genes at a mechanistic and circuit level. Finally, we present the use of comparative genomics to identify novel genes and gene networks involved in autism. Together, all of these approaches will allow for a broader and deeper view of the molecular brain mechanisms involved in the evolution of language and the gene disruptions associated with autism.
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22. Levy F. {{The autism spectrum disorder ‘epidemic’: Need for biopsychosocial formulation}}. {Aust N Z J Psychiatry};2013 (Nov 29)
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23. Lockwood PL, Bird G, Bridge M, Viding E. {{Dissecting empathy: high levels of psychopathic and autistic traits are characterized by difficulties in different social information processing domains}}. {Front Hum Neurosci};2013;7:760.
Individuals with psychopathy or autism spectrum disorder (ASD) can behave in ways that suggest lack of empathy towards others. However, many different cognitive and affective processes may lead to unempathic behavior and the social processing profiles of individuals with high psychopathic vs. ASD traits are likely different. Whilst psychopathy appears characterized by problems with resonating with others’ emotions, ASD appears characterized by problems with cognitive perspective-taking. In addition, alexithymia has previously been associated with both disorders, but the contribution of alexithymia needs further exploration. In a community sample (N = 110) we show for the first time that although affective resonance and cognitive perspective-taking are related, high psychopathic traits relate to problems with resonating with others’ emotions, but not cognitive perspective taking. Conversely, high ASD traits relate to problems with cognitive perspective-taking but not resonating with others’ emotions. Alexithymia was associated with problems with affective resonance independently of psychopathic traits, suggesting that different component processes (reduced tendency to feel what others feel and reduced ability to identify and describe feelings) comprise affective resonance. Alexithymia was not associated with the reduced cognitive perspective-taking in high ASD traits. Our data suggest that (1) elevated psychopathic and ASD traits are characterized by difficulties in different social information processing domains and (2) reduced affective resonance in individuals with elevated psychopathic traits and the reduced cognitive perspective taking in individuals with elevated ASD traits are not explained by co-occurring alexithymia. (3) Alexithymia is independently associated with reduced affective resonance. Consequently, our data point to different component processes within the construct of empathy that are suggestive of partially separable cognitive and neural systems.
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24. Maloney SE, Rieger MA, Dougherty JD. {{Identifying essential cell types and circuits in autism spectrum disorders}}. {Int Rev Neurobiol};2013;113:61-96.
Autism spectrum disorder (ASD) is highly genetic in its etiology, with potentially hundreds of genes contributing to risk. Despite this heterogeneity, these disparate genetic lesions may result in the disruption of a limited number of key cell types or circuits-information which could be leveraged for the design of therapeutic interventions. While hypotheses for cellular disruptions can be identified by postmortem anatomical analysis and expression studies of ASD risk genes, testing these hypotheses requires the use of animal models. In this review, we explore the existing evidence supporting the contribution of different cell types to ASD, specifically focusing on rodent studies disrupting serotonergic, GABAergic, cerebellar, and striatal cell types, with particular attention to studies of the sufficiency of specific cellular disruptions to generate ASD-related behavioral abnormalities. This evidence suggests multiple cellular routes can create features of the disorder, though it is currently unclear if these cell types converge on a final common circuit. We hope that in the future, systematic studies of cellular sufficiency and genetic interaction will help to classify patients into groups by type of cellular disruptions which suggest tractable therapeutic targets.
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25. Meinzen-Derr J, Wiley S, Bishop S, Manning-Courtney P, Choo DI, Murray D. {{Autism spectrum disorders in 24 children who are deaf or hard of hearing}}. {Int J Pediatr Otorhinolaryngol};2013 (Nov 14)
OBJECTIVES: Approximately 4% of children who are deaf or hard of hearing have co-occurring autism spectrum disorder (ASD). Making an additional diagnosis of ASD in this population can be challenging, given the complexities of determining whether speech/language and social delays can be accounted for by their hearing loss, or whether these delays might be indicative of a comorbid ASD diagnosis. This exploratory study described a population of 24 children with the dual diagnosis of ASD and hearing loss. METHODS: Children completed a comprehensive ASD evaluation using standardized autism diagnostic instruments (Autism Diagnostic Observation Schedule, language and psychological testing). Children with permanent hearing loss who had a developmental evaluation between 2001 and 2011 and were diagnosed with an ASD based on the results of that evaluation were included. Information on communication modality, language and cognitive abilities was collected. RESULTS: The median age of diagnosis was 14 months (range 1-71) for hearing loss and 66.5 months (range 33-106) for ASD. Only 25% (n=6) children were diagnosed with ASD </=48 months of age and 46% by </=6 years. Twelve (50%) children were diagnosed with ASD, 11 were diagnosed with pervasive developmental disorder not otherwise specified and 1 child had Asperger’s. Most (67%) had profound degree of hearing loss. Fourteen (58%) children had received a cochlear implant, while 3 children had no amplification for hearing loss. Nine (38%) of the 24 children used speech as their mode of communication (oral communicators). CONCLUSIONS: Communication delays in children who are deaf or hard of hearing are a serious matter and should not be assumed to be a direct consequence of the hearing loss. Children who received cochlear implants completed a multidisciplinary evaluation including a developmental pediatrician, which may have provided closer monitoring of speech and language progression and subsequently an earlier ASD diagnosis. Because children who are deaf or hard of hearing with ASD are challenging to evaluate, they may receive a diagnosis of ASD at older ages.
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26. Miyauchi S, Voineagu I. {{Autism susceptibility genes and the transcriptional landscape of the human brain}}. {Int Rev Neurobiol};2013;113:303-318.
Autism is the most severe end of a spectrum of neurodevelopmental conditions, autism spectrum disorders (ASD). ASD are genetically heterogeneous, and hundreds of genes have been implicated in the etiology of the disease. Here, we discuss the contribution of brain transcriptome studies in advancing our understanding of the genetic mechanisms of ASD and review recent work characterizing the spatial and temporal variation of the human brain transcriptome, with a focus on the relevance of these data to autism susceptibility genes.
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27. Noriega DB, Savelkoul HF. {{Immune dysregulation in autism spectrum disorder}}. {Eur J Pediatr};2013 (Dec 3)
Autism spectrum disorder (ASD) is a common and severe neuro-developmental disorder in early childhood which is defined by social and communication deficits and repetitive and stereotypic behaviours. The aetiology of ASD remains poorly understood. Susceptibility to development of ASD has significant environmental components, in addition to the profound genetic heritability. Few genes have been associated to the risk for ASD development. There is substantial evidence implicating chronic neurological inflammation and immune dysregulation leading to upregulation of inflammatory cytokines in the ASD brain, probably due to altered blood-brain barrier function. The immune system is characterized by excessive and skewed cytokine responses, modulated T cell reactivity, decreased regulation and production of immunosuppressive cytokines, modified NK function and increased autoantibody production. Conclusion: The perinatal environment generates vulnerability to chronic neuro-inflammation in the brain associated with profound modulation and dysregulation in the immune system leading to the rapid development of ASD in genetically susceptible children.
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28. Paemka L, Mahajan VB, Skeie JM, Sowers LP, Ehaideb SN, Gonzalez-Alegre P, Sasaoka T, Tao H, Miyagi A, Ueno N, Takao K, Miyakawa T, Wu S, Darbro BW, Ferguson PJ, Pieper AA, Britt JK, Wemmie JA, Rudd DS, Wassink T, El-Shanti H, Mefford HC, Carvill GL, Manak JR, Bassuk AG. {{PRICKLE1 Interaction with SYNAPSIN I Reveals a Role in Autism Spectrum Disorders}}. {PLoS One};2013;8(12):e80737.
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.
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29. Peng Y, Huentelman M, Smith C, Qiu S. {{MET Receptor Tyrosine Kinase as an Autism Genetic Risk Factor}}. {Int Rev Neurobiol};2013;113:135-165.
In this chapter, we will briefly discuss recent literature on the role of MET receptor tyrosine kinase (RTK) in brain development and how perturbation of MET signaling may alter normal neurodevelopmental outcomes. Recent human genetic studies have established MET as a risk factor for autism, and the molecular and cellular underpinnings of this genetic risk are only beginning to emerge from obscurity. Unlike many autism risk genes that encode synaptic proteins, the spatial and temporal expression pattern of MET RTK indicates this signaling system is ideally situated to regulate neuronal growth, functional maturation, and establishment of functional brain circuits, particularly in those brain structures involved in higher levels of cognition, social skills, and executive functions.
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30. Peters B, Williams KC, Gorrindo P, Rosenberg D, Lee EB, Levitt P, Veenstra-Vanderweele J. {{Rigid-Compulsive Behaviors are Associated with Mixed Bowel Symptoms in Autism Spectrum Disorder}}. {J Autism Dev Disord};2013 (Nov 29)
Based on clinical experience, we hypothesized that rigid-compulsive behaviors are associated with severe constipation and co-occurring diarrhea or underwear staining in children with autism spectrum disorder. Using data from the Autism Treatment Network, we evaluated the association between these gastrointestinal symptoms and measures of rigid compulsive behavior in children ages 2-17. Following statistical correction, four of five primary measures were significantly associated with constipation and diarrhea or underwear staining, including parental report of repetitive behavior, parental report of compulsive behavior, clinician diagnosis of obsessive-compulsive disorder, and report of rituals observed on the autism diagnostic observation schedule. This association could point to a causal connection between these symptoms or to a common biological pathway that impacts both gut and brain.
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31. Russell G, Rodgers LR, Ford T. {{The strengths and difficulties questionnaire as a predictor of parent-reported diagnosis of autism spectrum disorder and attention deficit hyperactivity disorder}}. {PLoS One};2013;8(12):e80247.
The Strengths and Difficulties Questionnaire (SDQ) is widely used as an international standardised instrument measuring child behaviour. The primary aim of our study was to examine whether behavioral symptoms measured by SDQ were elevated among children with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) relative to the rest of the population, and to examine the predictive value of the SDQ for outcome of parent-reported clinical diagnosis of ASD/ADHD. A secondary aim was to examine the extent of overlap in symptoms between children diagnosed with these two disorders, as measured by the SDQ subscales. A cross-sectional secondary analysis of data from the Millennium Birth Cohort (n = 19,519), was conducted. Data were weighted to be representative of the UK population as a whole. ADHD or ASD identified by a medical doctor or health professional were reported by parents in 2008 and this was the case definition of diagnosis; (ADHD n = 173, ASD n = 209, excluding twins and triplets). Study children’s ages ranged from 6.3-8.2 years; (mean 7.2 years). Logistic regression was used to examine the association between the parent-reported clinical diagnosis of ASD/ADHD and teacher and parent-reported SDQ subscales. All SDQ subscales were strongly associated with both ASD and ADHD. There was substantial co-occurrence of behavioral difficulties between children diagnosed with ASD and those diagnosed with ADHD. After adjustment for other subscales, the final model for ADHD, contained hyperactivity/inattention and impact symptoms only and had a sensitivity of 91% and specificity of 90%; (AUC) = 0.94 (95% CI, 0.90-0.97). The final model for ASD was composed of all subscales except the ‘peer problems’ scales, indicating of the complexity of behavioural difficulties that may accompany ASD. A threshold of 0.03 produced model sensitivity and specificity of 79% and 93% respectively; AUC = 0.90 (95% CI, 0.86-0.95). The results support changes to DSM-5 removing exclusivity clauses.
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32. Scheid I, Maruani A, Huguet G, Leblond CS, Nygren G, Anckarsater H, Beggiato A, Rastam M, Amsellem F, Gillberg IC, Elmaleh M, Leboyer M, Gillberg C, Betancur C, Coleman M, Hama H, Cook EH, Bourgeron T, Delorme R. {{Heterozygous FA2H mutations in autism spectrum disorders}}. {BMC Med Genet};2013 (Dec 3);14(1):124.
BACKGROUND: Widespread abnormalities in white matter development are frequently reported in cases of autism spectrum disorders (ASD) and could be involved in the disconnectivity suggested in these disorders. Homozygous mutations in the gene coding for fatty-acid 2-hydroxylase (FA2H), an enzyme involved in myelin synthesis, are associated with complex leukodystrophies, but little is known about the functional impact of heterozygous FA2H mutations. We hypothesized that rare deleterious heterozygous mutations of FA2H might constitute risk factors for ASD. METHODS: We searched deleterious mutations affecting FA2H, by genotyping 1256 independent patients with ASD genotyped using Genome Wide SNP arrays, and also by sequencing in independent set of 186 subjects with ASD and 353 controls. We then explored the impact of the identified mutations by measuring FA2H enzymatic activity and expression, in transfected COS7 cells. RESULTS: One heterozygous deletion within 16q22.3-q23.1 including FA2H was observed in two siblings who share symptoms of autism and severe cognitive impairment, axial T2-FLAIR weighted MRI posterior periventricular white matter lesions. Also, two rare non-synonymous mutations (R113W and R113Q) were reported. Although predictive models suggested that R113W should be a deleterious, we did not find that FA2H activity was affected by expression of the R113W mutation in cultured COS cells. CONCLUSIONS: While our results do not support a major role for FA2H coding variants in ASD, a screening of other genes related to myelin synthesis would allow us to better understand the role of non-neuronal elements in ASD susceptibility.
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33. Shrestha M, Shrestha R. {{Symptom Recognition to Diagnosis of Autism in Nepal}}. {J Autism Dev Disord};2013 (Nov 29)
Awareness and knowledge about autism is almost non-existent in Nepal. Children who eventually get the diagnosis often miss their opportunity for early intervention. The current study shows that medical help was seeked at mean age of 27.9 + 14.5 months and most of them were for delayed language and the first preference for parents were pediatricians. The mean age of diagnosis of autism was 55.6 months. The time length between help seeking to diagnosis was 29.4 months with longest time lag of 13 years. Delay in recognition of symptoms, delay in health seeking and lack of awareness even in treating physicians might be the reason for advanced age at diagnosis of autism in Nepal.
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34. Silva L, Schalock M. {{Treatment of Tactile Impairment in Young Children with Autism: Results with Qigong Massage}}. {Int J Ther Massage Bodywork};2013;6(4):12-20.
BACKGROUND: Following the inclusion of sensory abnormalities in the diagnostic criteria for autism, evidence has emerged showing that tactile abnormalities in young children with autism are severe, universally present, and directly related to delay of early self-regulation milestones required for social development. Parent touch is the most effective means of stimulating early self-regulation, yet parents of children with autism avoid touch because their children respond abnormally to it. This suggests that tactile abnormalities pose a barrier to parent touch in autism, and that treatment of tactile abnormalities may improve developmental outcomes. We have developed a qigong massage treatment for tactile abnormalities in young children with autism. Here we evaluate whether tactile abnormalities decrease following treatment, and whether treatment results in improved self-regulatory outcomes. METHODS: We retrospectively analyzed our qigong massage database for treatment effect on tactile abnormalities, self-regulatory delay, and parenting stress. Five-month interval data were available for 129 children with autism aged 3-6 years. Of these 129, 97 received treatment and 32 were in the wait-list control condition. There were no differences between treatment and control groups by age, gender, or severity of tactile impairment. RESULTS: Treatment resulted in significant decreases of tactile impairment, self-regulatory delay, and parenting stress (p < .001 on all paired t-tests); mean decreases were 25.5%, 24.5%, and 35.8%, respectively. Results were significant compared to controls [F(3,122) = 11.27, p < .001]. In the pretreatment data, tactile impairment was directly related to self-regulatory delay; post-treatment, both variables decreased proportionally. CONCLUSION: Results demonstrate that tactile impairment in young children with autism is treatable with a qigong massage protocol. The direct relationship between tactile impairment and self-regulatory delay pretreatment, and the proportional decrease of both following treatment, suggest that tactile impairment is a cause of self-regulatory delay, and that qigong massage is a promising avenue to improve developmental outcomes in autism.
35. Starling J. {{Are we over-diagnosing autism? The case against}}. {Aust N Z J Psychiatry};2013 (Nov 29)
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36. Verma D, Chakraborti B, Karmakar A, Bandyopadhyay T, Singh AS, Sinha S, Chatterjee A, Ghosh S, Mohanakumar KP, Mukhopadhyay K, Rajamma U. {{Sexual Dimorphic Effect in the Genetic Association of MAOA Markers with Autism Spectrum Disorder}}. {Prog Neuropsychopharmacol Biol Psychiatry};2013 (Nov 27)
Autism Spectrum disorders are heritable and behaviorally-defined neurodevelopmental disorders having skewed sex ratio. Serotonin as modulator of behavior and implication of serotonergic dysfunction in ASD etiology corroborate that serotonergic system genes are potential candidates for autism susceptibility. In the current study X-chromosomal gene, MAOA responsible for degradation of serotonin is investigated for possible association with ASD using population-based approach. Study covers analysis of 8 markers in 421 subjects including cases and ethnically-matched controls from West Bengal. MAOA marker, rs6323 and various haplotypes formed between the markers show significant association with the disorder. Stratification on the basis of sex reveals significant genetic effect of rs6323 with low activity T allele posing higher risk in males, but not in females. Haplotypic association results also show differential effect both in males and females. Contrasting linkage disequilibrium pattern between pair of markers involving rs6323 in male cases and controls further supports the sex-bias in genetic association. Bioinformatic analysis shows presence of Y-encoded SRY transcription factor binding sites in the neighborhood of rs1137070. C allele of rs1137070 causes deletion of GATA-2 binding site and GATA-2 is known to interact with SRY. This is the first study highlighting male-specific effect of rs6323 marker and its haplotypes in ASD etiology and it suggests sexual dimorphic effect of MAOA in this disorder. Overall results of this study identify MAOA as a possible ASD susceptibility locus and the differential genetic effect in males and females might contribute to the sex ratio differences and molecular pathology of the disorder.
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37. Vivanti G, Trembath D, Dissanayake C. {{Atypical monitoring and responsiveness to goal-directed gaze in autism spectrum disorder}}. {Exp Brain Res};2013 (Nov 29)
We hypothesized that difficulty in understanding the goals of others’ actions in autism spectrum disorder (ASD) might be linked to a diminished attention and responsivity to relevant social cues. Using an eye-tracking paradigm, we investigated how 24 children with ASD and 24 matched children without ASD responded to the observation of uncompleted actions without a clear target (neutral condition) versus a condition in which the actor’s gaze direction indicated the target of the actions (head-turning condition). Children without ASD significantly increased their attention to the actor’s face and to the action’s target in the head-turning condition compared to the neutral condition, while this was not the case in the ASD group. Overall, our findings suggest a diminished monitoring and responsivity to social cues signalling goal-directedness, which might impact on the ability to understand other’s action goals in young children with ASD.
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38. Vorstman JA, Spooren W, Persico AM, Collier DA, Aigner S, Jagasia R, Glennon JC, Buitelaar JK. {{Using genetic findings in autism for the development of new pharmaceutical compounds}}. {Psychopharmacology (Berl)};2013 (Nov 30)
RATIONALE: The main reason for the current lack of effective treatments for the core symptoms of autism is our limited understanding of the biological mechanisms underlying this heterogeneous group of disorders. A primary value of genetic research is enhancing our insight into the biology of autism through the study of identified autism risk genes. OBJECTIVES: In the current review we discuss (1) the genes and loci that are associated with autism, (2) how these provide us with essential cues as to what neurobiological mechanisms may be involved, and (3) how these mechanisms may be used as targets for novel treatments. Next, we provide an overview of currently ongoing clinical trials registered at clinicaltrials.gov with a variety of compounds. Finally, we review current approaches used to translate knowledge derived from gene discovery into novel pharmaceutical compounds and discuss their pitfalls and problems. CONCLUSIONS: An increasing number of genetic variants associated with autism have been identified. This will generate new ideas about the biological mechanisms involved in autism, which in turn may provide new leads for the development of novel pharmaceutical compounds. To optimize this pipeline of drug discovery, large-scale international collaborations are needed for gene discovery, functional validation of risk genes, and improvement of clinical outcome measures and clinical trial methodology in autism.
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39. Wilkinson B, Campbell DB. {{Contribution of Long Noncoding RNAs to Autism Spectrum Disorder Risk}}. {Int Rev Neurobiol};2013;113:35-59.
Accumulating evidence indicates that long noncoding RNAs (lncRNAs) contribute to autism spectrum disorder (ASD) risk. Although a few lncRNAs have long been recognized to have important functions, the vast majority of this class of molecules remains uncharacterized. Because lncRNAs are more abundant in human brain than protein-coding RNAs, it is likely that they contribute to brain disorders, including ASD. We review here the known functions of lncRNAs and the potential contributions of lncRNAs to ASD.
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40. Ziv Y, Hadad BS, Khateeb Y, Terkel-Dawer R. {{Erratum to: Social Information Processing in Preschool Children Diagnosed with Autism Spectrum Disorder}}. {J Autism Dev Disord};2013 (Nov 29)
