1. Anderson DK, Maye MP, Lord C. {{Changes in maladaptive behaviors from midchildhood to young adulthood in autism spectrum disorder}}. Am J Intellect Dev Disabil. 2011; 116(5): 381-97.
Abstract The current study prospectively examined trajectories of change in symptoms of irritability, hyperactivity, and social withdrawal, as well as predictors of such behaviors, for ages 9-18 years for youths with autism spectrum disorder and a comparison group with nonspectrum developmental delays. Children with more severe core features of autism had consistently higher irritability and hyperactivity scores over time than those with broader autism spectrum disorder and nonspectrum delays. Across all diagnoses, behaviors related to hyperactivity showed the greatest improvement. Social withdrawal worsened with age for a substantial proportion of youths with autism spectrum disorder but not for the nonspectrum comparison group. Compared with youths without autism spectrum disorder, children with the disorder showed greater heterogeneity in trajectories for maladaptive behaviors.
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2. Bader PL, Faizi M, Kim LH, Owen SF, Tadross MR, Alfa RW, Bett GC, Tsien RW, Rasmusson RL, Shamloo M. {{Mouse model of Timothy syndrome recapitulates triad of autistic traits}}. Proc Natl Acad Sci U S A. 2011; 108(37): 15432-7.
Autism and autism spectrum disorder (ASD) typically arise from a mixture of environmental influences and multiple genetic alterations. In some rare cases, such as Timothy syndrome (TS), a specific mutation in a single gene can be sufficient to generate autism or ASD in most patients, potentially offering insights into the etiology of autism in general. Both variants of TS (the milder TS1 and the more severe TS2) arise from missense mutations in alternatively spliced exons that cause the same G406R replacement in the Ca(V)1.2 L-type calcium channel. We generated a TS2-like mouse but found that heterozygous (and homozygous) animals were not viable. However, heterozygous TS2 mice that were allowed to keep an inverted neomycin cassette (TS2-neo) survived through adulthood. We attribute the survival to lowering of expression of the G406R L-type channel via transcriptional interference, blunting deleterious effects of mutant L-type channel overactivity, and addressed potential effects of altered gene dosage by studying Ca(V)1.2 knockout heterozygotes. Here we present a thorough behavioral phenotyping of the TS2-neo mouse, capitalizing on this unique opportunity to use the TS mutation to model ASD in mice. Along with normal general health, activity, and anxiety level, TS2-neo mice showed markedly restricted, repetitive, and perseverative behavior, altered social behavior, altered ultrasonic vocalization, and enhanced tone-cued and contextual memory following fear conditioning. Our results suggest that when TS mutant channels are expressed at levels low enough to avoid fatality, they are sufficient to cause multiple, distinct behavioral abnormalities, in line with the core aspects of ASD.
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3. Bishop SL, Guthrie W, Coffing M, Lord C. {{Convergent validity of the mullen scales of early learning and the differential ability scales in children with autism spectrum disorders}}. Am J Intellect Dev Disabil. 2011; 116(5): 331-43.
Abstract Despite widespread use of the Mullen Scales of Early Learning (MSEL; E. M. Mullen, 1995 ) as a cognitive test for children with autism spectrum disorders and other developmental disabilities, the instrument has not been independently validated for use in these populations. Convergent validity of the MSEL and the Differential Ability Scales (DAS; C. D. Elliott, 1990 , 2007 ) was examined in 53 children with autism spectrum disorder and 19 children with nonspectrum diagnoses. Results showed good convergent validity with respect to nonverbal IQ (NVIQ), verbal IQ (VIQ), and NVIQ-VIQ profiles. These findings provide preliminary support for the practice of using MSEL age-equivalents to generate NVIQ and VIQ scores. Establishing convergent validity of cognitive tests is needed before IQs derived from different tests can be conceptualized as a uniform construct.
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4. Blanchard KS, Palmer RF, Stein Z. {{The value of ecologic studies: mercury concentration in ambient air and the risk of autism}}. Rev Environ Health. 2011; 26(2): 111-8.
Ecologic studies of the spatial relationship between disease and sources of environmental contamination can help to ascertain the degree of risk to populations from contamination and to inform legislation to ameliorate the risk. Population risks associated with persistent low-level mercury exposure have recently begun to be of concern and current reports implicate environmental mercury as a potential contributor in the etiology of various developmental and neurodegenerative diseases including autism and Alzheimer’s disease. In this demonstration of preliminary findings, we demonstrate for Bexar County Texas and Santa Clara County California, the hypothesis that the spatial structure of the occurrence of autism has a positive co-variation with the spatial structure of the distribution of mercury in ambient air. The relative risk of autism is greater in the geographic areas of higher levels of ambient mercury. We find that the higher levels of ambient mercury are geographically associated with point sources of mercury emission, such as coal-fired power plants and cement plants with coal-fired kilns. Although this does not indicate a cause, these results should not be dismissed, but rather seen as a preliminary step for generating a hypothesis for further investigation.
5. Hiramoto T, Kang G, Suzuki G, Satoh Y, Kucherlapati R, Watanabe Y, Hiroi N. {{Tbx1: identification of a 22q11.2 gene as a risk factor for autism spectrum disorder}}. Hum Mol Genet. 2011.
While twin studies indicate clear genetic bases of autism spectrum disorder (ASD), the precise mechanisms through which genetic variations causally result in ASD are poorly understood. Individuals with 3-Mb and nested 1.5-Mb hemizygosity of the chromosome 22q11.2 represent genetically identifiable cases of ASD. However, because more than 30 genes are deleted in even the minimal deletion cases of 22q11.2 deficiency, the individual 22q11.2 gene(s) responsible for ASD remain elusive. Here, we examined the impact of constitutive heterozygosity of Tbx1, a 22q11.2 gene, on the behavioral phenotypes of ASD and characterized the regional and cellular expression of its mRNA and protein in mice. Congenic Tbx1 heterozygous (HT) mice were impaired in social interaction, ultrasonic vocalization, memory-based behavioral alternation, working memory, and thigmotaxis, compared to wild-type (WT) mice. These phenotypes were not due to non-specific alterations in olfactory function, exploratory behavior, motor movement, or anxiety-related behavior. Tbx1 mRNA and protein were ubiquitously expressed throughout the brains of C57BL/6J mice, but protein expression was enriched in regions that postnatally retain the capacity of neurogenesis and in fact, postnatally proliferating cells expressed Tbx1. In postnatally-derived hippocampal culture cells of C57BL/6J mice, Tbx1 levels were higher during proliferation than during differentiation, and expressed in neural progenitor cells, immature and matured neurons, and glial cells. Taken together, our data demonstrate that Tbx1 is a gene responsible for the phenotypes of 22q11.2 hemizygosity-associated ASD possibly through its role in diverse cell types, including postnatally- and prenatally-generated neurons.
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6. Ji L, Chauhan V, Flory MJ, Chauhan A. {{Brain region-specific decrease in the activity and expression of protein kinase a in the frontal cortex of regressive autism}}. PLoS One. 2011; 6(8): e23751.
Autism is a severe neurodevelopmental disorder that is characterized by impaired language, communication, and social skills. In regressive autism, affected children first show signs of normal social and language development but eventually lose these skills and develop autistic behavior. Protein kinases are essential in G-protein-coupled, receptor-mediated signal transduction and are involved in neuronal functions, gene expression, memory, and cell differentiation. We studied the activity and expression of protein kinase A (PKA), a cyclic AMP-dependent protein kinase, in postmortem brain tissue samples from the frontal, temporal, parietal, and occipital cortices, and the cerebellum of individuals with regressive autism; autistic subjects without a clinical history of regression; and age-matched developmentally normal control subjects. The activity of PKA and the expression of PKA (C-alpha), a catalytic subunit of PKA, were significantly decreased in the frontal cortex of individuals with regressive autism compared to control subjects and individuals with non-regressive autism. Such changes were not observed in the cerebellum, or the cortices from the temporal, parietal, and occipital regions of the brain in subjects with regressive autism. In addition, there was no significant difference in PKA activity or expression of PKA (C-alpha) between non-regressive autism and control groups. These results suggest that regression in autism may be associated, in part, with decreased PKA-mediated phosphorylation of proteins and abnormalities in cellular signaling.
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7. Keita L, Mottron L, Dawson M, Bertone A. {{Atypical Lateral Connectivity: A Neural Basis for Altered Visuospatial Processing in Autism}}. Biol Psychiatry. 2011.
BACKGROUND: Autistic perception encompasses both inferior and superior performance on different types of visuospatial tasks. Influential neurocognitive models relevant to atypical perception (i.e., weak central coherence, enhanced perceptual functioning) can, to differing degrees, account for these findings. However, the neural underpinnings mediating atypical visuospatial autistic perception have yet to be elucidated. METHODS: In the present study, we used a lateral masking paradigm to assess the functional integrity of lateral interactions mediating visuospatial information processing within early visual areas of autistic (n = 18) and nonautistic (n = 15) observers. Detection thresholds were measured for centrally presented Gabor targets flanked collinearly at different distances (experiment 1) and flanked orthogonally at different contrasts (experiment 2). RESULTS: Autistic and nonautistic groups showed increased target sensitivity when the distance between collinear targets and flankers was small (3 lambda) but not large (6 lambda). However, the effect of small-distance facilitation was significantly greater for the autistic group. In addition, we observed a group-specific effect of contrast: in the autistic group, target sensitivity was enhanced by low flanker contrasts of both 5% and 10% luminance difference, whereas for the nonautistic group, this effect occurred at 10% contrast only. CONCLUSIONS: These findings support the idea that atypical visuospatial perception in autism may originate from altered lateral connectivity within primary visual areas, differentially affecting perception at the earliest levels of feature extraction.
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8. Lai B, Milano M, Roberts MW, Hooper SR. {{Unmet Dental Needs and Barriers to Dental Care Among Children with Autism Spectrum Disorders}}. J Autism Dev Disord. 2011.
Mail-in pilot-tested questionnaires were sent to a stratified random sample of 1,500 families from the North Carolina Autism Registry. Multivariate logistic regression analysis was used to determine the significance of unmet dental needs and other predictors. Of 568 surveys returned (Response Rate = 38%), 555 were complete and usable. Sixty-five (12%) children had unmet dental needs. Of 516 children (93%) who had been to a dentist, 11% still reported unmet needs. The main barriers were child’s behavior, cost, and lack of insurance. The significant predictor variables of unmet needs were child’s behavior (p = 0.01), child’s dental health (p < 0.001), and caregiver’s last dental visit greater than 6 months (p = 0.002). Type of ASD did not have an effect on having unmet dental needs.
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9. Lightfoot E, Laliberte T. {{Parental supports for parents with intellectual and developmental disabilities}}. Intellect Dev Disabil. 2011; 49(5): 388-91.
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10. Onore C, Careaga M, Ashwood P. {{The role of immune dysfunction in the pathophysiology of autism}}. Brain Behav Immun. 2011.
Autism spectrum disorders (ASD) are a complex group of neurodevelopmental disorders encompassing impairments in communication, social interactions and restricted stereotypical behaviors. Although a link between altered immune responses and ASD was first recognized nearly 40years ago, only recently has new evidence started to shed light on the complex multifaceted relationship between immune dysfunction and behavior in ASD. Neurobiological research in ASD has highlighted pathways involved in neural development, synapse plasticity, structural brain abnormalities, cognition and behavior. At the same time, several lines of evidence point to altered immune dysfunction in ASD that directly impacts some or all these neurological processes. Extensive alterations in immune function have now been described in both children and adults with ASD, including ongoing inflammation in brain specimens, elevated pro-inflammatory cytokine profiles in the CSF and blood, increased presence of brain-specific auto-antibodies and altered immune cell function. Furthermore, these dysfunctional immune responses are associated with increased impairments in behaviors characteristic of core features of ASD, in particular, deficits in social interactions and communication. This accumulating evidence suggests that immune processes play a key role in the pathophysiology of ASD. This review will discuss the current state of our knowledge of immune dysfunction in ASD, how these findings may impact on underlying neuro-immune mechanisms and implicate potential areas where the manipulation of the immune response could have an impact on behavior and immunity in ASD.
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11. Paparella T, Goods KS, Freeman S, Kasari C. {{The emergence of nonverbal joint attention and requesting skills in young children with autism}}. J Commun Disord. 2011.
Joint attention (JA) skills are deficient in children with autism; however, children with autism seem to vary in the degree to which they display joint attention. Joint attention skills refer to verbal and nonverbal skills used to share experiences with others. They include gestures such as pointing, coordinated looks between objects and people, and showing. Some nonverbal gestures are used to request rather than merely to share. These requesting gestures include reaching, pointing to request, and giving to gain assistance. Although these skills also relate to expressive language development, we know little about when they emerge and how they change as language develops in children with autism. Several studies report the emergence of nonverbal requests in children with autism to be similar to that of typically developing children, but other studies report impairments in such skills. This study investigates the emergence of nonverbal JA and requesting skills in typically developing children and in children with autism with expressive language ages between 12 and 60 months, using both a both cross-sectional and a longitudinal design. Results suggest that the sequence of JA skill emergence in autism differs from a normative model, while the sequence of requesting skills emerges in accord with typical development. Furthermore, several joint attention skills appeared to emerge later than in typical children. With regards to intervention it appears that a curriculum based on a normative developmental model for the emergence of requesting skills is mostly appropriate for use with children with autism. However, since children with autism acquired nonverbal joint attention skills in a sequence that differed from a normative model, it might be that a non-normative autism-specific joint attention curriculum would be more likely to benefit children with autism. Learning outcomes: The reader will (1) identify 3 specific initiating gestures used to communicate for the purpose of joint attention, (2) identify 2 specific nonverbal responsive joint attention skills, (3) be able to state that children with autism appear to develop specific nonverbal requesting gestures in a similar sequence to typically developing children, (4) be able to state that children with autism appear to develop specific nonverbal joint attention gestures in a different sequence than that of typically developing children, and (5) be able to identify 2 specific nonverbal joint attention skills that appear significantly impaired in children with autism relative to typically developing children.
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12. Parellada M, Boada L, Moreno C, Llorente C, Romo J, Muela C, Arango C. {{Specialty Care Programme for autism spectrum disorders in an urban population: A case-management model for health care delivery in an ASD population}}. Eur Psychiatry. 2011.
Subjects with autism spectrum disorders (ASD) have more medical needs and more difficulties accessing health care services than the general population. Their verbal and non-verbal communication difficulties and particular behaviors, along with lack of expertise on the part of physicians and failure of the services to make adjustments, make it difficult for them to obtain an appropriate health care. PURPOSE: To describe a model for health care delivery in an ASD population. METHOD: Review of relevant literature and a discussion process with stakeholders leading to the design of a service to meet the specialty health needs of subjects of all ages with ASD for a region with a population of 6,000,000. RESULTS: A service was designed centred around the concepts of case management, individualization, facilitation, accompaniment, continuous training and updating, and quality management. Five hundred and thirteen patients with ASD have been seen over a period of 18 months. The programme generated 1566 psychiatric visits and 1052 visits to other specialties (mainly Nutrition, Stomatology, Neurology, and Gastroenterology) in the same period. CONCLUSION: Persons with ASD may benefit from adjustments of health care services in order to improve their access to adequate health care at the quality level of the rest of the population.
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13. Potash J. {{End-of-Life Care for Children and Adults With Intellectual and Developmental Disabilities End-of-Life Care for Children and Adults With Intellectual and Developmental Disabilities , edited by Sandra L . Friedman and David T . Helm . Washington, DC : American Association on Intellectual and Developmental Disabilities , 2010}}. Intellect Dev Disabil. 2011; 49(5): 407-8.
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14. Rose NR. {{Conjugate vaccines and autism}}. Med Hypotheses. 2011.
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15. Stoger R, Genereux DP, Hagerman RJ, Hagerman PJ, Tassone F, Laird CD. {{Testing the FMR1 Promoter for Mosaicism in DNA Methylation among CpG Sites, Strands, and Cells in FMR1-Expressing Males with Fragile X Syndrome}}. PLoS One. 2011; 6(8): e23648.
Variability among individuals in the severity of fragile X syndrome (FXS) is influenced by epigenetic methylation mosaicism, which may also be common in other complex disorders. The epigenetic signal of dense promoter DNA methylation is usually associated with gene silencing, as was initially reported for FMR1 alleles in individuals with FXS. A paradox arose when significant levels of FMR1 mRNA were reported for some males with FXS who had been reported to have predominately methylated alleles. We have used hairpin-bisufite PCR, validated with molecular batch-stamps and barcodes, to collect and assess double-stranded DNA methylation patterns from these previously studied males. These patterns enable us to distinguish among three possible forms of methylation mosaicism, any one of which could explain FMR1 expression in these males. Our data indicate that cryptic inter-cell mosaicism in DNA methylation can account for the presence of FMR1 mRNA in some individuals with FXS.
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16. Thomas Curtis J, Chen Y, Buck DJ, Davis RL. {{Chronic inorganic mercury exposure induces sex-specific changes in central TNFalpha expression: Importance in autism?}}. Neurosci Lett. 2011.
Mercury is neurotoxic and increasing evidence suggests that environmental exposure to mercury may contribute to neuropathologies including Alzheimer’s disease and autism spectrum disorders. Mercury is known to disrupt immunocompetence in the periphery, however, little is known about the effects of mercury on neuroimmune signaling. Mercury-induced effects on central immune function are potentially very important given that mercury exposure and neuroinflammation both are implicated in certain neuropathologies (i.e., autism). Furthermore, mounting evidence points to the involvement of glial activation in autism. Therefore, we utilized an in vivo model to assess the effects of mercury exposure on neuroimmune signaling. In prairie voles, 10 week mercury exposure (60ppm HgCl(2) in drinking water) resulted in a male-specific increase in TNFalpha protein expression in the cerebellum and hippocampus. These findings are consistent with our previously reported male-specific mercury-induced deficits in social behavior and further support a role for heavy metals exposure in neuropathologies such as autism. Subsequent studies should further evaluate the mechanism of action and biological consequences of heavy metals exposure. Additionally, these observations highlight the potential of neuroimmune markers in male voles as biomarkers of environmental mercury toxicity.
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17. Tyler CV, Schramm SC, Karafa M, Tang AS, Jain AK. {{Chronic disease risks in young adults with autism spectrum disorder: forewarned is forearmed}}. Am J Intellect Dev Disabil. 2011; 116(5): 371-80.
Abstract An emerging, cost-effective method to examine prevalent and future health risks of persons with disabilities is electronic health record (EHR) analysis. As an example, a case-control EHR analysis of adults with autism spectrum disorder receiving primary care through the Cleveland Clinic from 2005 to 2008 identified 108 adults with autism spectrum disorder. In this cohort, rates of chronic disease included 34.9% for obesity, 31.5% for hyperlipidemia, and 19.4% for hypertension. Compared with a control cohort of patients from the same health system matched for age, sex, race, and health insurance status, adults with autism spectrum disorder were more likely to be diagnosed with hyperlipidemia (odds ratio = 2.0, confidence interval = 1.2-3.4, p = .012). Without intervention, adults with autism spectrum disorder appear to be at significant risk for developing diabetes, coronary heart disease, and cancer by midlife.
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18. Vecchio D, Salzano E, Vecchio A, Di Filippo T, Roccella M. {{A case of femoral-facial syndrome in a patient with autism spectrum disorders}}. Minerva Pediatr. 2011; 63(4): 341-4.
The Femoral hypoplasia – unusual facies syndrome (FHUF) or Femoral – facial syndrome (FFS) was at first described in 1975. Up to now about 60 cases have been reported. According to our knowledge only 4 cases have had congenital central nervous system’s malformations, furthermore the main stages of psychomotor development are almost always reported as normal or slightly altered in early childhood. We describe the first case of autism spectrum disorders (ASD) in a patient with FFS, emphasizing that this rare association could be one of many unrecognized underlying features.
