1. Amos P. {{Rhythm and timing in autism: learning to dance}}. {Front Integr Neurosci};2013;7:27.
In recent years, a significant body of research has focused on challenges to neural connectivity as a key to understanding autism. In contrast to attempts to identify a single static, primarily brain-based deficit, children and adults diagnosed with autism are increasingly perceived as out of sync with their internal and external environments in dynamic ways that must also involve operations of the peripheral nervous systems. The noisiness that seems to occur in both directions of neural flow may help explain challenges to movement and sensing, and ultimately to entrainment with circadian rhythms and social interactions across the autism spectrum, profound differences in the rhythm and timing of movement have been tracked to infancy. Difficulties with self-synchrony inhibit praxis, and can disrupt the « dance of relationship » through which caregiver and child build meaning. Different sensory aspects of a situation may fail to match up; ultimately, intentions and actions themselves may be uncoupled. This uncoupling may help explain the expressions of alienation from the actions of one’s body which recur in the autobiographical autism literature. Multi-modal/cross-modal coordination of different types of sensory information into coherent events may be difficult to achieve because amodal properties (e.g., rhythm and tempo) that help unite perceptions are unreliable. One question posed to the connectivity research concerns the role of rhythm and timing in this operation, and whether these can be mobilized to reduce overload and enhance performance. A case is made for developmental research addressing how people with autism actively explore and make sense of their environments. The parent/author recommends investigating approaches such as scaffolding interactions via rhythm, following the person’s lead, slowing the pace, discriminating between intentional communication and « stray » motor patterns, and organizing information through one sensory mode at a time.
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2. Bahi-Buisson N. {{Genetically determined encephalopathy: Rett syndrome}}. {Handb Clin Neurol};2013;111:281-286.
Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily affecting females that has an incidence of 1:10000 female births, one of the most common genetic causes of severe mental retardation in females. Development is apparently normal for the first 6-18 months until fine and gross motor skills and social interaction are lost, and stereotypic hand movements develop. Progression and severity of the classical form of RTT are most variable, and there are a number of atypical variants, including congenital, early onset seizure, preserved speech variant, and « forme fruste. » Mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2) involve most of the classical RTT patients. Mutations in cyclin-dependent kinase like 5 (CDKL5) and FoxG1 genes have been identified in the early onset seizure and the congenital variants respectively. Management of RTT is mainly symptomatic and individualized. It focuses on optimizing each patient’s abilities. A dynamic multidisciplinary approach is most effective, with specific attention given to epileptic and nonepileptic paroxysmal events, as well as scoliosis, osteoporosis, and the development of spasticity, which can have a major impact on mobility, and to the development of effective communication strategies for these severely disabled individuals.
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3. Bozdagi O, Tavassoli T, Buxbaum JD. {{Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay}}. {Mol Autism};2013 (Apr 27);4(1):9.
BACKGROUND: Haploinsufficiency of SHANK3, due to either hemizygous gene deletion (termed 22q13 deletion syndrome or Phelan-McDermid syndrome) or to gene mutation, accounts for about 0.5% of the cases of autism spectrum disorder (ASD) and/or developmental delay, and there is evidence for a wider role for SHANK3 and glutamate signaling abnormalities in ASD and related conditions. Therapeutic approaches that reverse deficits in SHANK3-haploinsufficiency may therefore be broadly beneficial in ASD and in developmental delay. FINDINGS: We observed that daily intraperitoneal injections of human insulin-like growth factor 1 (IGF-1) over a 2-week period reversed deficits in hippocampal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) signaling, long-term potentiation (LTP), and motor performance that we had previously reported in Shank3-deficient mice. Positive effects were observed with an IGF-1 peptide derivative as well. CONCLUSIONS: We observed significant beneficial effects of IGF-1 in a mouse model of ASD and of developmental delay. Studies in mouse and human neuronal models of Rett syndrome also show benefits with IGF-1, raising the possibility that this compound may have benefits broadly in ASD and related conditions, even with differing molecular etiology. Given the extensive safety data for IGF-1 in children with short stature due to primary IGF-1 deficiency, IGF-1 is an attractive candidate for controlled clinical trials in SHANK3-deficiency and in ASD.
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4. Burgdorf J, Moskal JR, Brudzynski SM, Panksepp J. {{Rats selectively bred for low levels of play-induced 50 kHz vocalizations as a model for Autism Spectrum Disorders: A role for NMDA receptors}}. {Behav Brain Res};2013 (Apr 23)
Early childhood autism is characterized by deficits in social approach and play behaviors, socio-emotional relatedness, and communication/speech abnormalities, as well as repetitive behaviors. These core neuropsychological features of autism can be modeled in laboratory rats, and the results may be useful for drug discovery and therapeutic development. We review data that show that rats selectively bred for low rates of play-related pro-social ultrasonic vocalizations (USVs) can be used to model social deficit symptoms of autism. Low-line animals engage in less social contact time with conspecifics, show lower rates of play induced pro-social USVs, and show an increased proportion of non-frequency modulated (i.e. monotonous) ultrasonic vocalizations compared to non-selectively bred random-line animals. Gene expression patterns in the low-line animals show significant enrichment in autism-associated genes, and the NMDA receptor family was identified as a significant hub. Treatment of low-line animals with the NMDAR functional glycine site partial agonist, GLYX-13, rescued the deficits in play-induced pro-social 50-kHz USVs and reduced monotonous USVs. Since the NMDA receptor has been implicated in the genesis of autistic symptoms, it is possible that GLYX-13 may be of therapeutic value in the treatment of autism.
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5. Gentile I, Zappulo E, Militerni R, Pascotto A, Borgia G, Bravaccio C. {{Etiopathogenesis of autism spectrum disorders: Fitting the pieces of the puzzle together}}. {Med Hypotheses};2013 (Apr 24)
Autism spectrum disorders (ASD) are disorders of the central nervous system characterized by impairments in communication and social reciprocity. Despite thousands of studies on this topic, the etiopathogenesis of these disorders remains unclear, apart from a general belief that they derive from an interaction between several genes and the environment. Given the mystery surrounding the etiopathogenesis of ASD it is impossible to plan effective preventive and treatment measures. This is of particular concern due to the progressive increase in the prevalence of ASD, which has reached a figure as high as 1:88 children in the USA. Here we present data corroborating a novel unifying hypothesis of the etiopathogenesis of ASD. We suggest that ASD are disorders of the immune system that occur in a very early phase of embryonic development. In a background of genetic predisposition and environmental predisposition (probably vitamin D deficiency), an infection (notably a viral infection) could trigger a deranged immune response which, in turn, results in damage to specific areas of the central nervous system. If proven, this hypothesis would have dramatic consequences for strategies aimed at preventing and treating ASD. To confirm or refute this hypothesis, we need a novel research approach, which unlike former approaches in this field, examine the major factors implicated in ASD (genetic, infections, vitamin D deficiency, immune system deregulation) not separately, but collectively and simultaneously.
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6. Hollway JA, Aman MG, Butter E. {{Correlates and Risk Markers for Sleep Disturbance in Participants of the Autism Treatment Network}}. {J Autism Dev Disord};2013 (Apr 27)
We explored possible cognitive, behavioral, emotional, and physiological risk markers for sleep disturbance in children with autism spectrum disorders. Data from 1,583 children in the Autism Treatment Network were analyzed. Approximately 45 potential predictors were analyzed using hierarchical regression modeling. As medication could confound findings, it was included in the analyses as a covariate. Results revealed that anxiety, autism symptom severity, sensory sensitivities, and GI problems were associated with sleep disturbance. IQ positively predicted sleep disturbance, and children with Asperger’s Disorder were more vulnerable than others. The amount of variance in sleep outcomes explained by predictor variables was modest (i.e., R 2 from .104 to .201). Predictor variables were evaluated in the context of a bidirectional theoretical framework.
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7. Huang A, Seshadri K, Matthews TA, Ostfeld BM. {{Parental Perspectives on Use, Benefits, and Physician Knowledge of Complementary and Alternative Medicine in Children with Autistic Disorder and Attention-Deficit/Hyperactivity Disorder}}. {J Altern Complement Med};2013 (Apr 26)
Abstract Background: Complementary and alternative medicine (CAM) use appears to be increasing in children with developmental disorders. However, it is not clear whether parents perceive their healthcare providers as resources who are knowledgeable about CAM therapies and are interested in further developing their knowledge. Objectives: (1) To establish and compare use of, and perceived satisfaction with, traditional medicine and CAM in children with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASDs) and (2) to assess parental perceptions of physician knowledge of CAM and physician interest in continuing education about CAM for the two groups of parents. Methods: Families of children with a diagnosis of ADHD or ASD were surveyed regarding the frequency of use of traditional treatment and CAM, parental perceptions of the helpfulness of each therapy, parental perceptions regarding physicians’ knowledge level about CAM, and physician interest in continuing education. Results: Thirty-six percent (n=135) of 378 surveys were returned: 41 contained a diagnosis of ADHD and 22 of ASD. Traditional therapies were used by 98% of children with ADHD and 100% of those with ASD. Perceived helpfulness of medication was 92% for children with ADHD and 60% for children with ASD (p<0.05). CAM was used for 19.5% of children with ADHD and 82% of children with ASD. Perceived satisfaction for any form of CAM in the children with ADHD was at an individual patient level. Satisfaction for two of the most commonly used CAM treatments in children with ASD ranged from 50% to 78%. In children with ASD (the diagnostic group with the highest use of and satisfaction with CAM), physician’s perceived knowledge of CAM was lower (14% versus 38%; p<0.05), as was perceptions of the physician’s interest in learning more (p<0.05). Conclusion: CAM use is significant, especially in children with ASD. Physicians are not perceived as a knowledgeable resource.
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8. King BH, Veenstra-Vanderweele J, Lord C. {{DSM-5 and Autism: Kicking the Tires and Making the Grade}}. {J Am Acad Child Adolesc Psychiatry};2013 (May);52(5):454-457.
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9. Kong SW, Shimizu-Motohashi Y, Campbell MG, Lee IH, Collins CD, Brewster SJ, Holm IA, Rappaport L, Kohane IS, Kunkel LM. {{Peripheral blood gene expression signature differentiates children with autism from unaffected siblings}}. {Neurogenetics};2013 (Apr 28)
Autism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental disorders with high heritability, yet a majority of genetic contribution to pathophysiology is not known. Siblings of individuals with ASD are at increased risk for ASD and autistic traits, but the genetic contribution for simplex families is estimated to be less when compared to multiplex families. To explore the genomic (dis-) similarity between proband and unaffected sibling in simplex families, we used genome-wide gene expression profiles of blood from 20 proband-unaffected sibling pairs and 18 unrelated control individuals. The global gene expression profiles of unaffected siblings were more similar to those from probands as they shared genetic and environmental background. A total of 189 genes were significantly differentially expressed between proband-sib pairs (nominal p < 0.01) after controlling for age, sex, and family effects. Probands and siblings were distinguished into two groups by cluster analysis with these genes. Overall, unaffected siblings were equally distant from the centroid of probands and from that of unrelated controls with the differentially expressed genes. Interestingly, five of 20 siblings had gene expression profiles that were more similar to unrelated controls than to their matched probands. In summary, we found a set of genes that distinguished probands from the unaffected siblings, and a subgroup of unaffected siblings who were more similar to probands. The pathways that characterized probands compared to siblings using peripheral blood gene expression profiles were the up-regulation of ribosomal, spliceosomal, and mitochondrial pathways, and the down-regulation of neuroreceptor-ligand, immune response and calcium signaling pathways. Further integrative study with structural genetic variations such as de novo mutations, rare variants, and copy number variations would clarify whether these transcriptomic changes are structural or environmental in origin.
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10. Kopecky K, Broder-Fingert S, Iannuzzi D, Connors S. {{The Needs of Hospitalized Patients With Autism Spectrum Disorders: A Parent Survey}}. {Clin Pediatr (Phila)};2013 (Apr 25)
Objective. This survey assessed the in-hospital needs of patients diagnosed with autism spectrum disorders (ASDs). Methods. Parents were recruited to complete a 21-item survey about the needs of their child with an ASD while in the hospital. ASD diagnosis was reported by parents at the time of the survey. The results of the survey were analyzed and evaluated in 3 distinct categories of need. Results. We documented a range of responses associated with ASD-specific needs during hospitalization. Common concerns included child safety and the importance of acknowledging individual communication methods. Conclusions. In a population of children with ASDs, parents report a diverse range of needs while in the hospital. These data support the concept that a pragmatic assessment of individual communication and sensory differences is likely to be essential in the development of an appropriate inpatient care plan.
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11. Lin Y, Tang C, He H, Duan R. {{Activation of mTOR Ameliorates Fragile X Premutation rCGG Repeat-Mediated Neurodegeneration}}. {PLoS One};2013;8(4):e62572.
Fragile X associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder caused by aberrant expansion of CGG repeats in 5′ UTR of FMR1 gene. The elevated mRNA confers a toxic gain-of-function thought to be the critical event of pathogenesis. Expressing rCGG90 repeats of the human FMR1 5’UTR in Drosophila is sufficient to induce neurodegeneration. Rapamycin has been demonstrated to attenuate neurotoxicity by inducing autophagy in various animal models of neurodegenerative diseases. Surprisingly, we observed rapamycin exacerbated rCGG90-induced neurodegenerative phenotypes through an autophagy-independent mechanism. CGG90 expression levels of FXTAS flies exposed to rapamycin presented no significant differences. We further demonstrated that activation of the mammalian target of rapamycin (mTOR) signaling could suppress neurodegeneration of FXTAS. These findings indicate that rapamycin will exacerbate neurodegeneration, and that enhancing autophagy is insufficient to alleviate neurotoxicity in FXTAS. Moreover, these results suggest mTOR and its downstream molecules as new therapeutic targets for FXTAS by showing significant protection against neurodegeneration.
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12. Maxwell CR, Villalobos ME, Schultz RT, Herpertz-Dahlmann B, Konrad K, Kohls G. {{Atypical Laterality of Resting Gamma Oscillations in Autism Spectrum Disorders}}. {J Autism Dev Disord};2013 (Apr 30)
Abnormal brain oscillatory activity has been found in autism spectrum disorders (ASD) and proposed as a potential biomarker. While several studies have investigated gamma oscillations in ASD, none have examined resting gamma power across multiple brain regions. This study investigated resting gamma power using EEG in 15 boys with ASD and 18 age and intelligence quotient matched typically developing controls. We found a decrease in resting gamma power at right lateral electrodes in ASD. We further explored associations between gamma and ASD severity as measured by the Social Responsiveness Scale (SRS) and found a negative correlation between SRS and gamma power. We believe that our findings give further support of gamma oscillations as a potential biomarker for ASD.
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13. Mottron L, Dawson M. {{The autistic spectrum}}. {Handb Clin Neurol};2013;111:263-271.
The autistic spectrum currently encompasses common precocious behaviourally identified constellations of social and communication atypicalities associated with restricted interests and repetitive behavior, together with uneven ability profiles. It is associated with multiple but heterogeneous genetic, functional, and structural variations whose established links with an autistic behavioral phenotype are as yet minimal. Strong evidence of high heritability contrasts with limited determination of genes and modes of transmission involved. Adaptation and outcomes vary widely according to opportunities, accommodation, and co-occurring conditions. With current diagnostic practices, multiple genetic conditions overlap with the autistic spectrum, with potential for confusion arising from phenocopies. Recent advances question the often presumed association between autism and intellectual disability and/or epilepsy. Autism is currently understood as a final common phenotypical pathway resulting from an indefinite number of genetic variations, possibly involving the same information processing pathways, and producing a variant in the way humans perceive, memorize, manipulate, and attribute emotional value to available information. Findings plausibly converge on more optional, rather than typically mandatory, hierarchies of information processing as fundamental to autism. Adaptation of education and employment according to individual strengths and needs, as well as attention to co-occurring conditions as necessary, remains today the best way to assist autistic individuals.
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14. Oranje B, Lahuis B, van Engeland H, Jan van der Gaag R, Kemner C. {{Sensory and sensorimotor gating in children with multiple complex developmental disorders (MCDD) and autism}}. {Psychiatry Res};2013 (Apr 30);206(2-3):287-292.
Multiple Complex Developmental Disorder (MCDD) is a well-defined and validated behavioral subtype of autism with a proposed elevated risk of developing a schizophrenic spectrum disorder. The current study investigated whether children with MCDD show the same deficits in sensory gating that are commonly reported in schizophrenia, or whether they are indistinguishable from children with autism in this respect. P50 suppression and prepulse inhibition (PPI) of the startle reflex were assessed in children with MCDD (n=14) or autism (n=13), and healthy controls (n=12), matched on age and IQ. All subjects showed high levels of PPI and P50 suppression. However, no group differences were found. No abnormalities in sensory filtering could be detected in children with autism or MCDD. Since sensory gating deficits are commonly regarded as possible endophenotypic markers for schizophrenia, the current results do not support a high level of similarity between schizophrenia and MCDD.
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15. Verhoeven EW, Smeekens I, Didden R. {{Brief Report: Suitability of the Social Skills Performance Assessment (SSPA) for the Assessment of Social Skills in Adults with Autism Spectrum Disorders}}. {J Autism Dev Disord};2013 (Apr 28)
The present study aims at examining whether the ‘Social Skills Performance Assessment’ (SSPA; Patterson et al. in Schizophr Res 48(2-3):351-360, 2001) is a suitable performance-based measure to assess social skills in adults with autism spectrum disorders (ASD). For this purpose, social skills of individuals with ASD and non-ASD participants were assessed through the SSPA role plays. Results of this study suggest that the SSPA is suitable for the assessment of social skills in adults with ASD. The SSPA discriminates between individuals with ASD and non-ASD individuals, with the ASD group scoring significantly lower. Although no evidence was found for convergent validity of the SSPA in participants with ASD, divergent validity of the SSPA and interrater reliability among adults with ASD were good.
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16. Walker CK, Anderson KW, Milano KM, Ye S, Tancredi DJ, Pessah IN, Hertz-Picciotto I, Kliman HJ. {{Trophoblast Inclusions Are Significantly Increased in the Placentas of Children in Families at Risk for Autism}}. {Biol Psychiatry};2013 (Apr 22)
BACKGROUND: Gestation is a critical window for neurodevelopmental vulnerability. This study examined whether the presence of trophoblast inclusions (TIs) in the placenta could serve as a predictor for children at elevated risk for autism spectrum disorder (ASD). METHODS: Placentas were obtained from 117 births in the MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) cohort of families who have one or more previous biological children with ASD, placing their newborn at elevated risk for neurodevelopmental compromise. Control samples were obtained from 100 uncomplicated term pregnancies of multiparous women with one or more typically developing biological children. Frequency of TIs was compared across the two groups. RESULTS: Placentas from at-risk pregnancies had an eightfold increased odds of having two or more TIs compared with control samples (odds ratio: 8.0, 95% confidence interval: 3.6-18.0). The presence of>/=2 TIs yielded a sensitivity of 41% and a specificity of 92% for predicting ASD risk status, whereas>/=4 TIs yielded a sensitivity of 19%, a specificity of 99.9%, and a positive likelihood ratio of 242 and conservatively predicted an infant with a 74% probability of being at risk for ASD. CONCLUSIONS: Our findings suggest that the placentas from women whose fetuses are at elevated risk for autism are markedly different from control placentas. These differences are manifested histologically as TIs. Their identification has the possibility of identifying newborns at risk for ASD who might benefit from targeted early interventions aimed at preventing or ameliorating behavioral symptoms and optimizing developmental outcomes.
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17. Woynaroski TG, Kwakye LD, Foss-Feig JH, Stevenson RA, Stone WL, Wallace MT. {{Multisensory Speech Perception in Children with Autism Spectrum Disorders}}. {J Autism Dev Disord};2013 (Apr 27)
This study examined unisensory and multisensory speech perception in 8-17 year old children with autism spectrum disorders (ASD) and typically developing controls matched on chronological age, sex, and IQ. Consonant-vowel syllables were presented in visual only, auditory only, matched audiovisual, and mismatched audiovisual (« McGurk ») conditions. Participants with ASD displayed deficits in visual only and matched audiovisual speech perception. Additionally, children with ASD reported a visual influence on heard speech in response to mismatched audiovisual syllables over a wider window of time relative to controls. Correlational analyses revealed associations between multisensory speech perception, communicative characteristics, and responses to sensory stimuli in ASD. Results suggest atypical speech perception is linked to broader behavioral characteristics of ASD.
