1. Duerden EG, Card D, Roberts SW, Mak-Fan KM, Chakravarty MM, Lerch JP, Taylor MJ. {{Self-injurious behaviours are associated with alterations in the somatosensory system in children with autism spectrum disorder}}. {Brain Struct Funct};2013 (May 5)
Children with autism spectrum disorder (ASD) frequently engage in self-injurious behaviours, often in the absence of reporting pain. Previous research suggests that altered pain sensitivity and repeated exposure to noxious stimuli are associated with morphological changes in somatosensory and limbic cortices. Further evidence from postmortem studies with self-injurious adults has indicated alterations in the structure and organization of the temporal lobes; however, the effect of self-injurious behaviour on cortical development in children with ASD has not yet been determined. Thirty children and adolescents (mean age = 10.6 +/- 2.5 years; range 7-15 years; 29 males) with a clinical diagnosis of ASD and 30 typically developing children (N = 30, mean age = 10.7 +/- 2.5 years; range 7-15 years, 26 males) underwent T1-weighted magnetic resonance and diffusion tensor imaging. No between-group differences were seen in cerebral volume, surface area or cortical thickness. Within the ASD group, self-injury scores negatively correlated with thickness in the right superior parietal lobule t = 6.3, p < 0.0001, bilateral primary somatosensory cortices (SI) (right: t = 4.4, p = 0.02; left: t = 4.48, p = 0.004) and the volume of the left ventroposterior (VP) nucleus of the thalamus (r = -0.52, p = 0.008). Based on these findings, we performed an atlas-based region-of-interest diffusion tensor imaging analysis between SI and the VP nucleus and found that children who engaged in self-injury had significantly lower fractional anisotropy (r = -0.4, p = 0.04) and higher mean diffusivity (r = 0.5, p = 0.03) values in the territory of the left posterior limb of the internal capsule. Additionally, greater incidence of self-injury was associated with increased radial diffusivity values in bilateral posterior limbs of the internal capsule (left: r = 0.5, p = 0.02; right: r = 0.5, p = 0.009) and corona radiata (left: r = 0.6, p = 0.005; right: r = 0.5, p = 0.009). Results indicate that self-injury is related to alterations in somatosensory cortical and subcortical regions and their supporting white-matter pathways. Findings could reflect use-dependent plasticity in the somatosensory system or disrupted brain development that could serve as a risk marker for self-injury.
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2. Halfon N, Kuo AA. {{What DSM-5 Could Mean to Children With Autism and Their Families}}. {JAMA Pediatr};2013 (May 3):1-6.
The American Psychiatric Association will update its Diagnostic and Statistical Manual of Mental Disorders to its fifth edition (DSM-5). With this new edition, the classification and diagnostic criteria for the spectrum of autistic disorders will change and become more specific and potentially more restrictive. Rather than maintaining several subcategories of autism including Asperger syndrome, there will be one new category called autism spectrum disorder. This change may alter which children are diagnosed as having autism as well as modify eligibility for treatment, educational, and other support services. We review the history and rationale for the proposed changes as well as several recent studies that have attempted to gauge the impact of these changes on children and families. We also consider how the proposed changes are likely to create new challenges for parents who are attempting to organize their children’s care and for pediatricians who are providing that care and assisting with care coordination.
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3. Karam RA, Rezk NA, Abdelrahman HM, Hassan TH, Mohammad D, Hashim HM, Fattah NR. {{Catechol-O-methyltransferase Val158Met polymorphism and hyperactivity symptoms in Egyptian children with autism spectrum disorder}}. {Res Dev Disabil};2013 (Apr 30);34(7):2092-2097.
Catechol-O-methyltransferase (COMT) plays an important role in the catabolism of brain dopamine and norepinephrine, which have been implicated in the pathogenesis of Autism spectrum disorder (ASD) as well as in other neuropsychatric disorders. We aimed to investigate the association of COMT Val158Met gene polymorphism with ASD and to examine the influence of such genotypes on hyperactivity symptoms in ASD patients. Eighty ASD patients (mean age 9+/-1.9 years) and 100 control children (mean age 8.9+/-1.9 years) were examined. COMT Val58Met polymorphism was genotyped using Tetra-primer ARMS-PCR method. The clinical diagnosis of ASD and ADHD were confirmed according to the DSM-IV criteria for research. We found no significant difference in genotypes or alleles’ frequencies of COMT Val158Met polymorphism between ASD patients and control group. There was a significant association between COMT (Val/Val) genotype and both increasing CARS (p=0.001) and hyperactivity scores (p=0.006). Regarding Conner’s Score, the DSM-IV hyperactive impulsive were significantly higher in Val/Val genotype than both Met/Val and Met/Met genotypes (p=0.03). Our data suggested an association between COMT Val58Met polymorphism and hyperactivity symptoms in Egyptian children with ASD.
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4. Karlsson L, Rastam M, Wentz E. {{The SWedish Eating Assessment for Autism spectrum disorders (SWEAA)-Validation of a self-report questionnaire targeting eating disturbances within the autism spectrum}}. {Res Dev Disabil};2013 (Apr 30);34(7):2224-2233.
The aim was to design and validate a questionnaire pertaining to eating problems in individuals with normal intelligence, within the autism spectrum. The questionnaire was based on literature search and clinical experience. The validation focused on psychometric properties of reliability and validity using a clinical group of individuals with autism spectrum disorders (ASD) (n=57) and a matched, healthy comparison group (n=31). The instrument showed high levels of reliability, convergent and discriminant validity and scaling properties. Logistic regression analyses discerned the single item Simultaneous capacity and the subscale Social situation at mealtime as the best predictors of ASD. In conclusion, the questionnaire is valid and reliable to detect disturbed eating behaviours in individuals with ASD and normal intelligence.
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5. Kerr DM, Downey L, Conboy M, Finn DP, Roche M. {{Alterations in the endocannabinoid system in the rat valproic acid model of autism}}. {Behav Brain Res};2013 (May 1)
The endocannabinoid system plays a crucial role in regulating emotionality and social behaviour, however it is unknown whether this system plays a role in symptoms associated with autism spectrum disorders. The current study evaluated if alterations in the endocannabinoid system accompany behavioural changes in the valproic acid (VPA) rat model of autism. Adolescent rats prenatally exposed to VPA exhibited impaired social investigatory behaviour, hypoalgesia and reduced lococmotor activity on exposure to a novel aversive arena. Levels of the endocananbinoids, anandamide (AEA) and 2-arachidonylglycerol (2-AG) in the hippocampus, frontal cortex or cerebellum were not altered in VPA- versus saline-exposed animals. However, the expression of mRNA for diacylglycerol lipase alpha, the enzyme primarily responsible for the synthesis of 2-AG, was reduced in the cerebellum of VPA-exposed rats. Furthermore, while the expression of mRNA for the 2-AG-catabolising enzyme monoacylglycerol lipase was reduced, the activity of this enzyme was increased, in the hippocampus of VPA-exposed animals. CB1 or CB2 receptor expression was not altered in any of the regions examined, however VPA-exposed rats exhibited reduced PPARalpha and GPR55 expression in the frontal cortex and PPARgamma and GPR55 expression in the hippocampus, additional receptor targets of the endocannabinoids. Furthermore, tissue levels of the fatty acid amide hydrolase substrates, AEA, oleoylethanolamide and palmitoylethanolamide, were higher in the hippocampus of VPA-exposed rats immediately following social exposure. These data indicate that prenatal VPA exposure is associated with alterations in the brain’s endocannabinoid system and support the hypothesis that endocannabinoid dysfunction may underlie behavioural abnormalities observed in autism spectrum disorders.
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6. Kim MJ, Kim DJ, Kim SY, Yang JH, Kim MH, Lee SW, Jeong SO, Park SY, Ryu HM. {{Fragile X carrier screening in Korean women of reproductive age}}. {J Med Screen};2013 (May 3)
OBJECTIVE: To estimate the distribution of the FMR1 alleles and the prevalence of the premutaion (PM) and full mutation (FM) of the FMR1 gene in Korean women of reproductive age. METHODS: Using polymerase chain reaction and Southern blot, 5829 women of reproductive age were screened (low-risk group n = 5470 and high-risk group n = 359) and 11 prenatal diagnoses were completed between September 2003 and December 2011. RESULTS: Of the 5829 women screened, normal FMR1 alleles (11,607) had a bimodal distribution with most alleles having 29 (37.87%) and 30 (31.87%) CGG repeats. Of the 5470 women in the low-risk group, 7 PM were identified, giving a PM carrier frequency of 1:781; none of the women had Fragile X syndrome. We also identified 38 intermediate alleles, with a reported incidence of 1:143. Of the 11 prenatal diagnoses, five were normal, five had a premutation, and one had a full mutation allele. CONCLUSIONS: The carrier frequency is 1/781 (0.13%) in Korean women of reproductive age. This is lower than among Caucasians, but relatively higher than in other Asian populations. Although there may be a founder effect, these results might be valuable in understanding Fragile X syndrome in Koreans and Asians as a whole.
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7. Lindell AK, Hudry K. {{Atypicalities in Cortical Structure, Handedness, and Functional Lateralization for Language in Autism Spectrum Disorders}}. {Neuropsychol Rev};2013 (May 7)
Language is typically a highly lateralized function, with atypically reduced or reversed lateralization linked to language impairments. Given the diagnostic and prognostic role of impaired language for autism spectrum disorders (ASDs), this paper reviews the growing body of literature that examines patterns of lateralization in individuals with ASDs. Including research from structural and functional imaging paradigms, and behavioral evidence from investigations of handedness, the review confirms that atypical lateralization is common in people with ASDs. The evidence indicates reduced structural asymmetry in fronto-temporal language regions, attenuated functional activation in response to language and pre-linguistic stimuli, and more ambiguous (mixed) hand preferences, in individuals with ASDs. Critically, the evidence emphasizes an intimate relationship between atypical lateralization and language impairment, with more atypical asymmetries linked to more substantive language impairment. Such evidence highlights opportunities for the identification of structural and functional biomarkers of ASDs, affording the potential for earlier diagnosis and intervention implementation.
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8. Lloyd-Fox S, Blasi A, Elwell CE, Charman T, Murphy D, Johnson MH. {{Reduced neural sensitivity to social stimuli in infants at risk for autism}}. {Proc Biol Sci};2013 (May 7);280(1758):20123026.
In the hope of discovering early markers of autism, attention has recently turned to the study of infants at risk owing to being the younger siblings of children with autism. Because the condition is highly heritable, later-born siblings of diagnosed children are at substantially higher risk for developing autism or the broader autism phenotype than the general population. Currently, there are no strong predictors of autism in early infancy and diagnosis is not reliable until around 3 years of age. Because indicators of brain functioning may be sensitive predictors, and atypical social interactions are characteristic of the syndrome, we examined whether temporal lobe specialization for processing visual and auditory social stimuli during infancy differs in infants at risk. In a functional near-infrared spectroscopy study, infants aged 4-6 months at risk for autism showed less selective neural responses to social stimuli (auditory and visual) than low-risk controls. These group differences could not be attributed to overall levels of attention, developmental stage or chronological age. Our results provide the first demonstration of specific differences in localizable brain function within the first 6 months of life in a group of infants at risk for autism. Further, these differences closely resemble known patterns of neural atypicality in children and adults with autism. Future work will determine whether these differences in infant neural responses to social stimuli predict either later autism or the broader autism phenotype frequently seen in unaffected family members.
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9. Pu D, Shen Y, Wu J. {{Association between MTHFR Gene Polymorphisms and the Risk of Autism Spectrum Disorders: A Meta-Analysis}}. {Autism Res};2013 (May 7)
Methylenetetrahydrofolate reductase (MTHFR) is essential for DNA biosynthesis and the epigenetic process of DNA methylation, and its gene polymorphisms have been implicated as risk factors for birth defects, neurological disorders, and cancers. However, reports on the association of MTHFR polymorphisms with autism spectrum disorders (ASD) are inconclusive. Therefore, we investigated the relationship of the MTHFR polymorphisms (C677T and A1298C) and the risk of ASD by meta-analysis. Up to December 2012, eight case-control studies involving 1672 patients with ASD and 6760 controls were included for meta-analysis. The results showed that the C677T polymorphism was associated with significantly increased ASD risk in all the comparison models [T vs. C allele (frequency of allele): odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.09-1.85; CT vs. CC (heterozygote): OR = 1.48, 95% CI: 1.09-2.00; TT vs. CC (homozygote): OR = 1.86, 95% CI: 1.08-3.20; CT+TT vs. CC (dominant model): OR = 1.56, 95% CI: 1.12-2.18; and TT vs. CC+CT (recessive model): OR = 1.51, 95% CI: 1.02-2.22], whereas the A1298C polymorphism was found to be significantly associated with reduced ASD risk but only in a recessive model (CC vs. AA+AC: OR = 0.73, 95% CI: 0.56-0.97). In addition, we stratified the patient population based on whether they were from a country with food fortification of folic acid or not. The meta-analysis showed that the C677T polymorphism was found to be associated with ASD only in children from countries without food fortification. Our study indicated that the MTHFR C677T polymorphism contributes to increased ASD risk, and periconceptional folic acid may reduce ASD risk in those with MTHFR 677C>T polymorphism. Autism Res 2013, : -. (c) 2013 International Society for Autism Research, Wiley Periodicals, Inc.
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10. Robinson L, Plano A, Cobb S, Riedel G. {{Long-term home cage activity scans reveal lowered exploratory behaviour in symptomatic female Rett mice}}. {Behav Brain Res};2013 (May 1)
Numerous experimental models have been developed to reiterate endophenotypes of Rett syndrome, a neurodevelopmental disorder with a multitude of motor, cognitive and vegetative symptoms. Here, female Mecp2Stop mice (Guy et al., 2007) [1] were characterised at mild symptomatic conditions in tests for anxiety (open field, elevated plus maze) and home cage observation systems for food intake, locomotor activity and circadian rhythms. Aged 8-9 months, Mecp2Stop mice presented with heightened body weight, lower overall activity in the open field, but no anxiety phenotype. Although home cage activity scans conducted in two different observation systems, PhenoMaster and PhenoTyper, confirmed normal circadian activity, they revealed severely compromised habituation to a novel environment in all parameters registered including those derived from a non-linear decay model such as initial exploration maximum, decay half-life of activity and span, as well as plateau. Furthermore, overall activity was significantly reduced in nocturnal periods due to reductions in both fast ambulatory movements, but also a slow lingering. In contrast, light-period activity profiles during which the amount of sleep was highest remained normal in Mecp2Stop mice. These data confirm the slow and progressive development of Rett-like symptoms in female Mecp2Stop mice resulting in a prominent reduction of overall locomotor activity, while circadian rhythms are maintained. Alterations in the time-course of habituation may indicate deficiencies in cognitive processing.
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11. Russo AJ. {{Decreased Epidermal Growth Factor (EGF) Associated with HMGB1 and Increased Hyperactivity in Children with Autism}}. {Biomark Insights};2013;8:35-41.
BACKGROUND: Autism spectrum disorders (ASDs), characterized by impaired social interactions and deficits in verbal and nonverbal communication, are thought to affect 1 in 88 children in the United States. There is much support for the role of growth factors in the etiology of autism. Recent research has shown that epithelial growth factor (EGF) is decreased in young autistic children (2-4 years of age). This study was designed to determine plasma levels of EGF in an older group of autistic children (mean age 10.6 years) and to correlate these EGF levels with putative biomarkers HGF, uPA, uPAR, GAD2, MPO GABA, and HMGB1, as well as symptom severity of 19 different symptoms. SUBJECTS AND METHODS: Plasma from 38 autistic children, 11 children with pervasive developmental disorder (PDD-NOS) and 40 neurotypical, age and gender similar controls was assessed for EGF concentration using ELISAs. Severity of 19 symptoms (awareness, expressive language, receptive language, (conversational) pragmatic language, focus/attention, hyperactivity, impulsivity, perseveration, fine motor skills, gross motor skills, hypotonia (low muscle tone), tiptoeing, rocking/pacing, stimming, obsessions/fixations, eye contact, sound sensitivity, light sensitivity, and tactile sensitivity) was assessed and then compared to EGF concentrations. RESULTS: In this study, we found EGF levels in autistic children and those with PDD-NOS to be significantly lower when compared with neurotypical controls. EGF levels correlated with HMGB1 levels but not the other tested putative biomarkers, and EGF correlated negatively with hyperactivity, gross motor skills, and tiptoeing but not other symptoms. CONCLUSIONS: These results suggest an association between decreased plasma EGF levels and selected symptom severity. We also found a strong correlation between plasma EGF and HMGB1, suggesting inflammation is associated with decreased EGF.
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12. Teng BL, Nonneman RJ, Agster KL, Nikolova VD, Davis TT, Riddick NV, Baker LK, Pedersen CA, Jarstfer MB, Moy SS. {{Prosocial effects of oxytocin in two mouse models of autism spectrum disorders}}. {Neuropharmacology};2013 (May 3)
Clinical evidence suggests that oxytocin treatment improves social deficits and repetitive behavior in autism spectrum disorders (ASDs). However, the neuropeptide has a short plasma half-life and poor ability to penetrate the blood-brain barrier. In order to facilitate the development of more bioavailable oxytocinergic compounds as therapeutics to treat core ASD symptoms, small animal models must be validated for preclinical screens. This study examined the preclinical utility of two inbred mouse strains, BALB/cByJ and C58/J, that exhibit phenotypes relevant to core ASD symptoms. Mice from both strains were intraperitoneally administered oxytocin, using either acute or sub-chronic regimens. Acute oxytocin did not increase sociability in BALB/cByJ; however, sub-chronic oxytocin had significant prosocial effects in both BALB/cByJ and C58/J. Increased sociability was observed 24 h following the final oxytocin dose in BALB/cByJ, while prosocial effects of oxytocin emerged 1-2 weeks post-treatment in C58/J. Furthermore, acute oxytocin decreased motor stereotypy in C58/J and did not induce hypoactivity or anxiolytic-like effects in an open field test. This study demonstrates that oxytocin administration can attenuate social deficits and repetitive behavior in mouse models of ASD, dependent on dose regimen and genotype. These findings provide validation of the BALB/cByJ and C58/J models as useful platforms for screening novel drugs for intervention in ASDs and for elucidating the mechanisms contributing to the prosocial effects of oxytocin.
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13. van Steensel FJ, Dirksen CD, Bogels SM. {{A Cost of Illness Study of Children with High-Functioning Autism Spectrum Disorders and Comorbid Anxiety Disorders as Compared to Clinically Anxious and Typically Developing Children}}. {J Autism Dev Disord};2013 (May 5)
The study’s aim was to estimate the societal costs of children with high-functioning ASD and comorbid anxiety disorder(s) (ASD + AD-group; n = 73), and to compare these costs to children with anxiety disorders (AD-group; n = 34), and typically developing children (controls; n = 87). Mean total costs for the ASD + AD-group amounted <euro>17,380 per year. Societal costs were estimated at almost 142 million euro per year. Costs in the ASD + AD-group were four times higher compared to the AD-group, and 27 times higher compared to controls. ASD-related costs were higher in the ASD + AD-group; anxiety-related costs did not differ between the ASD + AD- and AD-group; costs due to physical or other reasons did not differ across groups. The findings suggest that costs can be decreased if effective treatment options for treating anxiety in ASD are established, however, the remaining costs associated with ASD would still be large. A limitation of the study is that a group of children with ASD without anxiety disorders is lacking.
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14. Ziats MN, Rennert OM. {{Sex-biased gene expression in the developing brain: implications for autism spectrum disorders}}. {Mol Autism};2013 (May 7);4(1):10.
Autism spectrum disorders affect significantly more males than females. Understanding sex differences in normal human brain development may provide insight into the mechanism(s) underlying this disparity; however, studies of sex differences in brain development at the genomic level are lacking. Here, we report a re-analysis of sex-specific gene expression from a recent large transcriptomic study of normal human brain development, to determine whether sex-biased genes relate to specific mechanistic processes. We discovered that male-biased genes are enriched for the processes of extracellular matrix formation/glycoproteins, immune response, chromatin, and cell cytoskeleton. We highlight that these pathways have been repeatedly implicated in autism and demonstrate that autism candidate genes are also enriched for these pathways. We propose that the overlap of these male-specific brain transcriptional modules with the same pathways in autism spectrum disorders may partially explain the increased incidence of autism in males.
