1. Baker JK, Fenning RM, Howland MA, Baucom BR, Moffitt J, Erath SA. {{Brief Report: A Pilot Study of Parent-Child Biobehavioral Synchrony in Autism Spectrum Disorder}}. {J Autism Dev Disord};2015 (Jul 17)
The theory of biobehavioral synchrony proposes that the predictive power of parent-child attunement likely lies in the manner with which behaviors are aligned with relevant biological processes. Symptoms of autism spectrum disorder (ASD) may challenge the formation of behavioral and physiological synchrony, but maintenance of such parent-child attunement could prove beneficial. The present study is the first to examine parent-child physiological synchrony in ASD. Parent and child electrodermal activity (EDA) was measured continuously during naturalistic free play. Parent-child EDA synchrony (positive covariation) was positively correlated with observed parent-child emotional attunement. Hierarchical linear modeling revealed that child ASD symptoms moderated the association between parent EDA and child EDA, such that EDA synchrony was stronger for children with lower ASD symptom levels.
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2. Bergmann T, Sappok T, Diefenbacher A, Dames S, Heinrich M, Ziegler M, Dziobek I. {{Music-based Autism Diagnostics (MUSAD) – A newly developed diagnostic measure for adults with intellectual developmental disabilities suspected of autism}}. {Res Dev Disabil};2015 (Jul 13);43-44:123-135.
The MUSAD was developed as a diagnostic observational instrument in an interactional music framework. It is based on the ICD-10/DSM-5 criteria for autism spectrum disorder (ASD) and was designed to assess adults on a lower level of functioning, including individuals with severe language impairments. This study aimed to evaluate the psychometric properties of the newly developed instrument. METHODS: Calculations were based on a consecutive clinical sample of N=76 adults with intellectual and developmental disabilities (IDD) suspected of ASD. Objectivity, test-retest reliability, and construct validity were calculated and a confirmatory factor analysis was applied to verify a reduced and optimized test version. RESULTS: The structural model showed a good fit, while internal consistency of the subscales was excellent (omega>.92). Item difficulties ranged between .04</=pi</=.82 and item-total correlation from .21 to .85. Objectivity was assessed by comparing the scorings of two external raters based on a subsample of n=12; interrater agreement was .71 (ICC 2, 1). Reliability was calculated for four test repetitions: the average ICC (3, 1) was .69. Convergent ASD measures correlated significantly with the MUSAD, while the discriminant Modified Overt Aggression Scale (MOAS) showed no significant overlap. CONCLUSION: Confirmation of factorial structure and acceptable psychometric properties suggest that the MUSAD is a promising new instrument for diagnosing ASD in adults with IDD.
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3. De Filippis B, Musto M, Altabella L, Romano E, Canese R, Laviola G. {{Deficient Purposeful Use of Forepaws in Female Mice Modelling Rett Syndrome}}. {Neural Plast};2015;2015:326184.
Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioural and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases. Motor abnormalities represent a significant part of the spectrum of RTT symptoms. In the present study we investigated motor coordination and fine motor skill domains in MeCP2-308 female mice, a validated RTT model. This was complemented by the in vivo magnetic resonance spectroscopy (MRS) analysis of metabolic profile in behaviourally relevant brain areas. MeCP2-308 heterozygous female mice (Het, 10-12 months of age) were impaired in tasks validated for the assessment of purposeful and coordinated forepaw use (Morag test and Capellini handling task). A fine-grain analysis of spontaneous behaviour in the home-cage also revealed an abnormal handling pattern when interacting with the nesting material, reduced motivation to explore the environment, and increased time devoted to feeding in Het mice. The brain MRS evaluation highlighted decreased levels of bioenergetic metabolites in the striatal area in Het mice compared to controls. Present results confirm behavioural and brain alterations previously reported in MeCP2-308 males and identify novel endpoints on which the efficacy of innovative therapeutic strategies for RTT may be tested.
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4. Eslick GD. {{Answers regarding the link between vaccines and the development of autism: A question of appropriate study design, ethics, and bias}}. {Vaccine};2015 (Jul 18)
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5. Griswold AJ, Dueker ND, Van Booven D, Rantus JA, Jaworski JM, Slifer SH, Schmidt MA, Hulme W, Konidari I, Whitehead PL, Cuccaro ML, Martin ER, Haines JL, Gilbert JR, Hussman JP, Pericak-Vance MA. {{Targeted massively parallel sequencing of autism spectrum disorder-associated genes in a case control cohort reveals rare loss-of-function risk variants}}. {Mol Autism};2015;6:43.
BACKGROUND: Autism spectrum disorder (ASD) is highly heritable, yet genome-wide association studies (GWAS), copy number variation screens, and candidate gene association studies have found no single factor accounting for a large percentage of genetic risk. ASD trio exome sequencing studies have revealed genes with recurrent de novo loss-of-function variants as strong risk factors, but there are relatively few recurrently affected genes while as many as 1000 genes are predicted to play a role. As such, it is critical to identify the remaining rare and low-frequency variants contributing to ASD. METHODS: We have utilized an approach of prioritization of genes by GWAS and follow-up with massively parallel sequencing in a case-control cohort. Using a previously reported ASD noise reduction GWAS analyses, we prioritized 837 RefSeq genes for custom targeting and sequencing. We sequenced the coding regions of those genes in 2071 ASD cases and 904 controls of European white ancestry. We applied comprehensive annotation to identify single variants which could confer ASD risk and also gene-based association analysis to identify sets of rare variants associated with ASD. RESULTS: We identified a significant over-representation of rare loss-of-function variants in genes previously associated with ASD, including a de novo premature stop variant in the well-established ASD candidate gene RBFOX1. Furthermore, ASD cases were more likely to have two damaging missense variants in candidate genes than controls. Finally, gene-based rare variant association implicates genes functioning in excitatory neurotransmission and neurite outgrowth and guidance pathways including CACNAD2, KCNH7, and NRXN1. CONCLUSIONS: We find suggestive evidence that rare variants in synaptic genes are associated with ASD and that loss-of-function mutations in ASD candidate genes are a major risk factor, and we implicate damaging mutations in glutamate signaling receptors and neuronal adhesion and guidance molecules. Furthermore, the role of de novo mutations in ASD remains to be fully investigated as we identified the first reported protein-truncating variant in RBFOX1 in ASD. Overall, this work, combined with others in the field, suggests a convergence of genes and molecular pathways underlying ASD etiology.
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6. Kurtz PF, Chin MD, Robinson AN, O’Connor JT, Hagopian LP. {{Functional analysis and treatment of problem behavior exhibited by children with fragile X syndrome}}. {Res Dev Disabil};2015 (Jul 13);43-44:150-166.
The efficacy of function-based interventions for the treatment of severe problem behavior exhibited by individuals with intellectual and developmental disabilities (IDD) is well established. However, few studies have reported on behavioral interventions in fragile X syndrome (FXS) specifically. The present study is a consecutive case-series analysis that reports on functional analysis and treatment of problem behavior of nine children with FXS. Assessment findings were consistent with previous research indicating that among individuals with FXS, problem behavior is more commonly maintained by escape from demands and access to tangible items, relative to the broader population of individuals with IDD. Functional analysis-based behavioral interventions resulted in a mean reduction in problem behavior of 95.2% across the nine participants. Additionally, generalization of treatment effects from controlled clinical settings to home, school, and community was demonstrated. The current findings suggest that function-based behavioral interventions shown to be effective with the broader population of individuals with IDD are also effective for individuals with FXS. Our results in combination with those of previous studies describing functional analysis outcomes provide additional evidence for a unique functional behavioral phenotype for severe problem behavior in individuals with FXS. Implications of study findings for early intervention and prevention of problem behavior in children with FXS are discussed.
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7. Leigh JP, Du J. {{Brief Report: Forecasting the Economic Burden of Autism in 2015 and 2025 in the United States}}. {J Autism Dev Disord};2015 (Jul 17)
Few US estimates of the economic burden of autism spectrum disorders (ASD) are available and none provide estimates for 2015 and 2025. We forecast annual direct medical, direct non-medical, and productivity costs combined will be $268 billion (range $162-$367 billion; 0.884-2.009 % of GDP) for 2015 and $461 billion (range $276-$1011 billion; 0.982-3.600 % of GDP) for 2025. These 2015 figures are on a par with recent estimates for diabetes and attention deficit and hyperactivity disorder (ADHD) and exceed the costs of stroke and hypertension. If the prevalence of ASD continues to grow as it has in recent years, ASD costs will likely far exceed those of diabetes and ADHD by 2025.
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8. Mariani J, Coppola G, Zhang P, Abyzov A, Provini L, Tomasini L, Amenduni M, Szekely A, Palejev D, Wilson M, Gerstein M, Grigorenko EL, Chawarska K, Pelphrey KA, Howe JR, Vaccarino FM. {{FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders}}. {Cell};2015 (Jul 16);162(2):375-390.
Autism spectrum disorder (ASD) is a disorder of brain development. Most cases lack a clear etiology or genetic basis, and the difficulty of re-enacting human brain development has precluded understanding of ASD pathophysiology. Here we use three-dimensional neural cultures (organoids) derived from induced pluripotent stem cells (iPSCs) to investigate neurodevelopmental alterations in individuals with severe idiopathic ASD. While no known underlying genomic mutation could be identified, transcriptome and gene network analyses revealed upregulation of genes involved in cell proliferation, neuronal differentiation, and synaptic assembly. ASD-derived organoids exhibit an accelerated cell cycle and overproduction of GABAergic inhibitory neurons. Using RNA interference, we show that overexpression of the transcription factor FOXG1 is responsible for the overproduction of GABAergic neurons. Altered expression of gene network modules and FOXG1 are positively correlated with symptom severity. Our data suggest that a shift toward GABAergic neuron fate caused by FOXG1 is a developmental precursor of ASD.
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9. Moses L, Katz N, Weizman A. {{Impact of epilepsy and antiepileptic medications on the metabolic profile in adults with autism spectrum disorder and intellectual disabilities}}. {Int Clin Psychopharmacol};2015 (Jul 14)
Epilepsy is common in individuals with autism spectrum disorder (ASD) and intellectual disabilities (ID). Antiepileptic medications, such as valproic acid (VPA), were associated with changes in BMI, metabolic syndrome, dyslipidemia, and hyperinsulinemia. This study aimed to investigate how epilepsy and antiepileptic treatments affect BMI, fasting blood glucose (FBG), and total cholesterol of individuals with ASD or ID. Data on epilepsy diagnoses, treatment with VPA, carbamazepine or other antiepileptics, BMI, FBG, and total cholesterol levels were obtained from the medical charts of 80 adults with ASD and 77 adults with ID and analyzed using appropriate statistical tools. Participants with epilepsy had lower BMI and FBG than participants without epilepsy (BMI: 23.18+/-5.43 vs. 25.61+/-5.74 kg/m, respectively, F=6.64, d.f.=1.140; P=0.011, FBG: 72.53+/-11.26 vs. 79.98+/-14.64 mg/dl, respectively, F=10.46, d.f.=1.135 P=0.002). Those treated with VPA had lower total cholesterol levels compared with those untreated (156.56+/-26.13 vs. 172.42+/-33.82 mg/dl, respectively, F=7.44, d.f.=1.150; P=0.007), but did not differ in BMI and FBG. Individuals with ASD or ID, and epilepsy were leaner and had lower FBG than those without epilepsy. In addition, total cholesterol levels were lower in VPA-treated participants than in untreated ones, but BMI and FBG levels were similar.
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10. Ohta H, Nordahl CW, Iosif AM, Lee A, Rogers S, Amaral DG. {{Increased Surface Area, but not Cortical Thickness, in a Subset of Young Boys With Autism Spectrum Disorder}}. {Autism Res};2015 (Jul 16)
The Autism Phenome Project is the largest, single site, longitudinal magnetic resonance imaging (MRI) study of young children with autism spectrum disorder (ASD). Previous analyses from this cohort have shown that the children with autism have a total brain volume at time 1 ( approximately 3 years of age) that is 6% larger than typically developing (TD) children. This finding is driven primarily by 15% of the boys with ASD that have disproportionate megalencephaly (ASD-DM) or brain size that is 1.5 standard deviations above what would be expected for the child’s height. In the current study, cerebral cortical grey matter volume, thickness, and surface area were assayed from MRI scans of 112, 3-year-old boys with ASD and 50 age-matched TD boys. The boys with ASD-DM (n = 17) were analyzed separately from the boys with normal brain size (ASD-N, n = 95). Previous studies of cortical thickness and surface area for ASD children in this age range have come to diametrically different conclusions concerning the significance of cortical thickness vs. surface area. Current analyses indicate that cortical thickness was comparable across the ASD and TD groups. However, surface area was significantly greater in the ASD group compared to the TD group. This result was driven largely by the children with ASD-DM. Even in the ASD-DM group, not all cortical regions demonstrated increased surface area. These results provide strong evidence that the early cortical overgrowth associated with ASD is due primarily to increased surface area and not to increased cortical thickness. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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11. Quintela I, Fernandez-Prieto M, Gomez-Guerrero L, Resches M, Eiris J, Barros F, Carracedo A. {{A 6q14.1-q15 microdeletion in a male patient with severe autistic disorder, lack of oral language, and dysmorphic features with concomitant presence of a maternally inherited Xp22.31 copy number gain}}. {Clin Case Rep};2015 (Jun);3(6):415-423.
We report on a male patient with severe autistic disorder, lack of oral language, and dysmorphic features who carries a rare interstitial microdeletion of 4.96 Mb at chromosome 6q14.1-q15. The patient also harbors a maternally inherited copy number gain of 1.69 Mb at chromosome Xp22.31, whose pathogenicity is under debate.
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12. Takano T. {{Interneuron Dysfunction in Syndromic Autism: Recent Advances}}. {Dev Neurosci};2015 (Jul 15)
Autism is an extremely heterogeneous disorder, but its frequent cooccurrence with epilepsy leads to speculation that there may be common mechanisms associated with these disorders. Inhibitory interneurons are considered to be the main cellular elements that control hyperexcitability in the brain, and interneuron dysfunction can cause pathological hyperexcitability linked to seizure susceptibility or epilepsy. This review summarizes some of the recent advances that support the relationship between interneuron dysfunction and cognitive impairment in human syndromic autism, with particular reference to the pathophysiological findings of murine experimental models of autism. Alterations in gamma-aminobutyric acid (GABA)ergic circuits include a wide variety of neurobiological dysfunctions and do not simply involve the loss or gain of any given type of inhibitory mechanism. The characteristics of interneuron dysfunction in each murine model of autism differ for each syndrome, and these diversities may be due to differences in genetic backgrounds or some other currently unknown variances. Future studies should give us a greater understanding of the involvement of different classes of GABAergic interneurons and allow us to define the relationship between the precise pathophysiological mechanisms and the corresponding clinical phenotypes in autism. (c) 2015 S. Karger AG, Basel.
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13. Tan DW, Russell-Smith SN, Simons JM, Maybery MT, Leung D, Ng HL, Whitehouse AJ. {{Perceived Gender Ratings for High and Low Scorers on the Autism-Spectrum Quotient Consistent with the Extreme Male Brain Account of Autism}}. {PLoS One};2015;10(7):e0131780.
The Extreme Male Brain (EMB) theory posits that autistic traits are linked to excessive exposure to testosterone in utero. While findings from a number of studies are consistent with this theory, other studies have produced contradictory results. For example, some findings suggest that rather than being linked to hypermasculinization for males, or defeminization for females, elevated levels of autistic traits are instead linked to more androgynous physical features. The current study provided further evidence relevant to the EMB and androgony positions by comparing groups of males selected for high or low scores on the Autism-spectrum Quotient (AQ) as to the rated masculinity of their faces and voices, and comparable groups of females as to the rated femininity of their faces and voices. The voices of High-AQ males were rated as more masculine than those of Low-AQ males, while the faces of High-AQ females were rated as less feminine than those of Low-AQ females. There was no effect of AQ group on femininity ratings for female voices or on masculinity ratings for male faces. The results thus provide partial support for a link between high levels of autistic-like traits and hypermasculinization for males and defeminization for females, consistent with the EMB theory.
