1. Anney RJ, Kenny EM, O’Dushlaine C, Yaspan BL, Parkhomenka E, Buxbaum JD, Sutcliffe J, Gill M, Gallagher L, Bailey AJ, Fernandez BA, Szatmari P, Scherer SW, Patterson A, Marshall CR, Pinto D, Vincent JB, Fombonne E, Betancur C, Delorme R, Leboyer M, Bourgeron T, Mantoulan C, Roge B, Tauber M, Freitag CM, Poustka F, Duketis E, Klauck SM, Poustka A, Papanikolaou K, Tsiantis J, Anney R, Bolshakova N, Brennan S, Hughes G, McGrath J, Merikangas A, Ennis S, Green A, Casey JP, Conroy JM, Regan R, Shah N, Maestrini E, Bacchelli E, Minopoli F, Stoppioni V, Battaglia A, Igliozzi R, Parrini B, Tancredi R, Oliveira G, Almeida J, Duque F, Vicente A, Correia C, Magalhaes TR, Gillberg C, Nygren G, Jonge MD, Van Engeland H, Vorstman JA, Wittemeyer K, Baird G, Bolton PF, Rutter ML, Green J, Lamb JA, Pickles A, Parr JR, Couteur AL, Berney T, McConachie H, Wallace S, Coutanche M, Foley S, White K, Monaco AP, Holt R, Farrar P, Pagnamenta AT, Mirza GK, Ragoussis J, Sousa I, Sykes N, Wing K, Hallmayer J, Cantor RM, Nelson SF, Geschwind DH, Abrahams BS, Volkmar F, Pericak-Vance MA, Cuccaro ML, Gilbert J, Cook EH, Guter SJ, Jacob S, Nurnberger Jr JI, McDougle CJ, Posey DJ, Lord C, Corsello C, Hus V, Kolevzon A, Soorya L, Parkhomenko E, Leventhal BL, Dawson G, Vieland VJ, Hakonarson H, Glessner JT, Kim C, Wang K, Schellenberg GD, Devlin B, Klei L, Minshew N, Sutcliffe JS, Haines JL, Lund SC, Thomson S, Coon H, Miller J, McMahon WM, Munson J, Estes A, Wijsman EM. {{Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders}}. {Eur J Hum Genet};2011 (Apr 27)
Recent genome-wide association studies (GWAS) have implicated a range of genes from discrete biological pathways in the aetiology of autism. However, despite the strong influence of genetic factors, association studies have yet to identify statistically robust, replicated major effect genes or SNPs. We apply the principle of the SNP ratio test methodology described by O’Dushlaine et al to over 2100 families from the Autism Genome Project (AGP). Using a two-stage design we examine association enrichment in 5955 unique gene-ontology classifications across four groupings based on two phenotypic and two ancestral classifications. Based on estimates from simulation we identify excess of association enrichment across all analyses. We observe enrichment in association for sets of genes involved in diverse biological processes, including pyruvate metabolism, transcription factor activation, cell-signalling and cell-cycle regulation. Both genes and processes that show enrichment have previously been examined in autistic disorders and offer biologically plausibility to these findings.European Journal of Human Genetics advance online publication, 27 April 2011; doi:10.1038/ejhg.2011.75.
2. Cho SC, Yoo HJ, Park M, Cho IH, Kim BN, Kim JW, Shin MS, Park TW, Son JW, Chung US, Kim HW, Yang YH, Kang JO, Yang SY, Kim SA. {{Genome-wide association scan of korean autism spectrum disorders with language delay: a preliminary study}}. {Psychiatry Investig};2011 (Mar);8(1):61-66.
OBJECTIVE: Communication problems are a prevalent symptom of autism spectrum disorders (ASDs), which have a genetic background. Although several genome-wide studies on ASD have suggested a number of candidate genes, few studies have reported the association or linkage of specific endophenotypes to ASDs. METHODS: Forty-two Korean ASD patients who showed a language delay were enrolled in this study with their parents. We performed a genome-wide scan by using the Affymetrix SNP Array 5.0 platform to identify candidate genes responsible for language delay in ASDs. RESULTS: We detected candidate single-nucleotide polymorphisms (SNPs) in chromosome 11, rs11212733 (p-value=9.76×10(-6)) and rs7125479 (p-value=1.48×10(-4)), as a marker of language delay in ASD using the transmission disequilibrium test and multifactor dimensionality reduction test. CONCLUSION: Although our results suggest that several SNPs are associated with language delay in ASD, rs11212733 we were not able to observe any significant results after correction of multiple comparisons. This may imply that more samples may be required to identify genes associated with language delay in ASD.
3. Giannotti F, Cortesi F, Cerquiglini A, Vagnoni C, Valente D. {{Sleep in children with autism with and without autistic regression}}. {J Sleep Res};2011 (Jun);20(2):338-347.
The purpose of the present investigation was to characterize and compare traditional sleep architecture and non-rapid eye movement (NREM) sleep microstructure in a well-defined cohort of children with regressive and non-regressive autism, and in typically developing children (TD). We hypothesized that children with regressive autism would demonstrate a greater degree of sleep disruption either at a macrostructural or microstructural level and a more problematic sleep as reported by parents. Twenty-two children with non-regressive autism, 18 with regressive autism without comorbid pathologies and 12 with TD, aged 5-10 years, underwent standard overnight multi-channel polysomnographic evaluation. Parents completed a structured questionnaire (Childrens’ Sleep Habits Questionnaire-CSHQ). The initial hypothesis, that regressed children have more disrupted sleep, was supported by our findings that they scored significantly higher on CSHQ, particularly on bedtime resistance, sleep onset delay, sleep duration and night wakings CSHQ subdomains than non-regressed peers, and both scored more than typically developing controls. Regressive subjects had significantly less efficient sleep, less total sleep time, prolonged sleep latency, prolonged REM latency and more time awake after sleep onset than non-regressive children and the TD group. Regressive children showed lower cyclic alternating pattern (CAP) rates and A1 index in light sleep than non-regressive and TD children. Our findings suggest that, even though no particular differences in sleep architecture were found between the two groups of children with autism, those who experienced regression showed more sleep disorders and a disruption of sleep either from a macro- or from a microstructural viewpoint.
4. Grodberg D, Weinger PM, Kolevzon A, Soorya L, Buxbaum JD. {{Brief Report: The Autism Mental Status Examination: Development of a Brief Autism-Focused Exam}}. {J Autism Dev Disord};2011 (Apr 26)
The Autism Mental Status Examination (AMSE) described here is an eight-item observational assessment that prompts the observation and recording of signs and symptoms of autism spectrum disorders (ASD). The AMSE is intended to take place seamlessly in the context of a clinical exam and produces a total score. Subjects were independently administered the AMSE and the Autism Diagnostic Observation Schedule (ADOS). The ADOS was used to estimate the most effective criterion cut-off on the AMSE. A score of five or greater produced excellent sensitivity and good specificity in a high-risk sample. Internal consistency was acceptable and inter-rater reliability was good to excellent. Preliminary findings indicate excellent classification accuracy and suggest that the AMSE provides a rapid and reliable observational assessment in a high-risk population.
5. Hutman T, Chela MK, Gillespie-Lynch K, Sigman M. {{Selective Visual Attention at Twelve Months: Signs of Autism in Early Social Interactions}}. {J Autism Dev Disord};2011 (Apr 26)
We examined social attention and attention shifting during (a) a play interaction between 12-month olds and an examiner and (b) after the examiner pretended to hurt herself. We coded the target and duration of infants’ visual fixations and frequency of attention shifts. Siblings of children with autism and controls with no family history of autism were tested at 12 months and screened for ASD at 36 months. Groups did not differ on proportion of attention to social stimuli or attention shifting during the play condition. All groups demonstrated more social attention and attention shifting during the distress condition. Infants later diagnosed with ASD tended to continue looking at a toy during the distress condition despite the salience of social information.
6. Melnyk S, Fuchs GJ, Schulz E, Lopez M, Kahler SG, Fussell JJ, Bellando J, Pavliv O, Rose S, Seidel L, Gaylor DW, Jill James S. {{Metabolic Imbalance Associated with Methylation Dysregulation and Oxidative Damage in Children with Autism}}. {J Autism Dev Disord};2011 (Apr 26)
Oxidative stress and abnormal DNA methylation have been implicated in the pathophysiology of autism. We investigated the dynamics of an integrated metabolic pathway essential for cellular antioxidant and methylation capacity in 68 children with autism, 54 age-matched control children and 40 unaffected siblings. The metabolic profile of unaffected siblings differed significantly from case siblings but not from controls. Oxidative protein/DNA damage and DNA hypomethylation (epigenetic alteration) were found in autistic children but not paired siblings or controls. These data indicate that the deficit in antioxidant and methylation capacity is specific for autism and may promote cellular damage and altered epigenetic gene expression. Further, these results suggest a plausible mechanism by which pro-oxidant environmental stressors may modulate genetic predisposition to autism.
7. Roesser J. {{Diagnostic Yield of Genetic Testing in Children Diagnosed With Autism Spectrum Disorders at a Regional Referral Center}}. {Clin Pediatr (Phila)};2011 (Apr 27)
The aim was to systematically review genetic testing guidelines in the evaluation of children with autism spectrum disorders (ASDs). The Clinical Report published by the American Academy of Pediatrics (AAP)(1) recommended individualizing the workup, including karyotype and specific DNA testing for fragile X syndrome. A recent publication reported higher rates of abnormalities on CGH microarray (CMA) testing on children with ASD.(2) The medical records of 507 children seen through the Kirch Developmental Services Center were abstracted for genetic testing and factors associated with this testing. Abnormalities were found on karyotype in 2.3% and in DNA for fragile X in 0.04%. The author concludes that the diagnostic yield of the genetic testing was low in this population. Furthermore, their findings support the theory that CMA can be considered as part of the initial genetic screening in children with ASD in most situations. Future studies will need to be done prospectively to evaluate children in a standard fashion.
8. Rossignol DA, Frye RE. {{Melatonin in autism spectrum disorders: a systematic review and meta-analysis}}. {Dev Med Child Neurol};2011 (Apr 19)
Aim The aim of this study was to investigate melatonin-related findings in autism spectrum disorders (ASD), including autistic disorder, Asperger syndrome, Rett syndrome, and pervasive developmental disorders, not otherwise specified. Method Comprehensive searches were conducted in the PubMed, Google Scholar, CINAHL, EMBASE, Scopus, and ERIC databases from their inception to October 2010. Two reviewers independently assessed 35 studies that met the inclusion criteria. Of these, meta-analysis was performed on five randomized double-blind, placebo-controlled studies, and the quality of these trials was assessed using the Downs and Black checklist. Results Nine studies measured melatonin or melatonin metabolites in ASD and all reported at least one abnormality, including an abnormal melatonin circadian rhythm in four studies, below average physiological levels of melatonin and/or melatonin derivates in seven studies, and a positive correlation between these levels and autistic behaviors in four studies. Five studies reported gene abnormalities that could contribute to decreased melatonin production or adversely affect melatonin receptor function in a small percentage of children with ASD. Six studies reported improved daytime behavior with melatonin use. Eighteen studies on melatonin treatment in ASD were identified; these studies reported improvements in sleep duration, sleep onset latency, and night-time awakenings. Five of these studies were randomized double-blind, placebo-controlled crossover studies; two of the studies contained blended samples of children with ASD and other developmental disorders, but only data for children with ASD were used in the meta-analysis. The meta-analysis found significant improvements with large effect sizes in sleep duration (73min compared with baseline, Hedge’s g 1.97 [95% confidence interval {CI} CI 1.10-2.84], Glass’s Delta 1.54 [95% CI 0.64-2.44]; 44min compared with placebo, Hedge’s g 1.07 [95% CI 0.49-1.65], Glass’s Delta 0.93 [95% CI 0.33-1.53]) and sleep onset latency (66min compared with baseline, Hedge’s g-2.42 [95% CI -1.67 to -3.17], Glass’s Delta-2.18 [95% CI -1.58 to -2.76]; 39min compared with placebo, Hedge’s g-2.46 [95% CI -1.96 to -2.98], Glass’s Delta-1.28 [95% CI -0.67 to -1.89]) but not in night-time awakenings. The effect size varied significantly across studies but funnel plots did not indicate publication bias. The reported side effects of melatonin were minimal to none. Some studies were affected by limitations, including small sample sizes and variability in the protocols that measured changes in sleep parameters. Interpretation Melatonin administration in ASD is associated with improved sleep parameters, better daytime behavior, and minimal side effects. Additional studies of melatonin would be helpful to confirm and expand on these findings.
9. Tateno M, Kikuchi S, Uehara K, Fukita K, Uchida N, Sasaki R, Saito T. {{Pervasive developmental disorders and autism spectrum disorders: are these disorders one and the same?}}. {Psychiatry Investig};2011 (Mar);8(1):67-70.
The concept of pervasive developmental disorders (PDD) and autism spectrum disorders (ASD) closely resemble each other. Both ICD-10 and DSM-IV use the term PDD. The authors surveyed the perception of PDD/ASD and attitudes toward terminology. The subjects of this study were 205 medical/social-welfare professionals working in fields relating to developmental disorders. Questionnaires were mailed to site investigators at the collaborating institutes. With regard to what the scope of ASD and PDD encompasses, the answers were almost equally divided among three views: ASD and PDD are the same, PDD is wider in scope and ASD is wider. The terms PDD and autism were used in slightly different ways depended upon the situation. Our results demonstrate that the parameters of PDD and ASD are unclear and that the terms related to PDD/ASD are often used differently. Further studies are required to develop more clear and reliable diagnostic criteria for PDD.
10. Warren ZE, Foss-Feig JH, Malesa EE, Lee EB, Taylor JL, Newsom CR, Crittendon J, Stone WL. {{Neurocognitive and Behavioral Outcomes of Younger Siblings of Children with Autism Spectrum Disorder at Age Five}}. {J Autism Dev Disord};2011 (Apr 26)
Later-born siblings of children with Autism Spectrum Disorders (ASD) are at increased risk for ASD as well as qualitatively similar traits not meeting clinical cutoffs for the disorder. This study examined age five neurocognitive and behavioral outcomes of 39 younger siblings of children with ASD (Sibs-ASD) and 22 younger siblings of typically developing children (Sibs-TD) previously assessed in a longitudinal investigation starting in the second year of life. There were few group differences between Sibs-TD and Sibs-ASD on global measures of IQ, language, or behavior problems. Sibs-ASD did show vulnerabilities on measures of executive functioning, social cognition, and repetitive behaviors. These results highlight the importance of following sibling risk groups over an extended time period and employing measures targeting broader aspects of development.
