1. Ghanizadeh A. {{Atomoxetine for Treating ADHD Symptoms in Autism: A Systematic Review}}. {J Atten Disord}. 2012.
Objective: This study systematically reviews the current literature on the administration of atomoxetine for treating children and adolescents with comorbidity on autism spectrum disorder (ASD) and ADHD. Method: PubMed/Medline and Google Scholar databases were electronically searched to find the published trials on atomoxetine and ASD. Results: Six articles reported the clinical trials of atomoxetine for treatment of ADHD symptoms in patients with autism or pervasive development disorders. Only one study that was placebo-controlled crossover pilot trial reported that it is effective. Atomoxetine may be effective in high-functioning patients with autism or patients with low severity. Those with high severity of ASD may be more vulnerable to the adverse effects of atomoxetine. Conclusion: There are not enough controlled clinical trials for showing the efficacy of atomoxetine for treatment of ADHD symptoms in autism. Although evidence suggests potential efficacy of atomoxetine, the current evidences are not conclusive. (J. of Att. Dis. 2012; XX(X) 1-XX).
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2. Griswold AJ, Ma D, Cukier HN, Nations LD, Schmidt MA, Chung RH, Jaworski JM, Salyakina D, Konidari I, Whitehead PL, Wright HH, Abramson RK, Williams SM, Menon R, Martin ER, Haines JL, Gilbert JR, Cuccaro ML, Pericak-Vance MA. {{Evaluation of Copy Number Variations Reveals Novel Candidate Genes in Autism Spectrum Disorder Associated Pathways}}. {Hum Mol Genet}. 2012.
Autism spectrum disorders (ASDs) are highly heritable, yet relatively few associated genetic loci have been replicated. Copy number variations (CNVs) have been implicated in autism; however, the majority of loci contribute to less than 1% of the disease population. Therefore, independent studies are important to refine associated CNV regions and discover novel susceptibility genes. In this study, a genome-wide SNP array was utilized for CNV detection by two distinct algorithms in a European ancestry case-control dataset. We identify a significantly higher burden in the number and size of deletions, and disrupting more genes in ASD cases. Moreover, eighteen deletions larger than 1Mb were detected exclusively in cases, implicating novel regions at 2q22.1, 3p26.3, 4q12, and 14q23. Case-specific CNVs provided further evidence for pathways previously implicated in ASDs, revealing new candidate genes within the GABAergic signaling and neural development pathways. These include DBI, an allosteric binder of GABA receptors, GABARAPL1, the GABA receptor-associated protein, and SLC6A11, a postsynaptic GABA transporter. We also identified CNVs in COBL, deletions of which cause defects in neuronal cytoskeleton morphogenesis in model vertebrates, and DNER, a neuron specific Notch ligand required for cerebellar development. Moreover, we found evidence of genetic overlap between ASDs and other neurodevelopmental and neuropsychiatric diseases. These genes include glutamate receptors (GRID1, GRIK2 and GRIK4), synaptic regulators (NRXN3, SLC6A8, and SYN3), transcription factor (ZNF804A), and RNA binding protein FMR1. Taken together, these CNVs may be a few of the missing pieces of ASD heritability and lead to discovering novel etiological mechanisms.
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3. Hall SS, Hammond JL, Hirt M, Reiss AL. {{A ‘learning platform’ approach to outcome measurement in fragile X syndrome: a preliminary psychometric study}}. {J Intellect Disabil Res}. 2012.
Background Clinical trials of medications to alleviate the cognitive and behavioural symptoms of individuals with fragile X syndrome (FXS) are now underway. However, there are few reliable, valid and/or sensitive outcome measures available that can be directly administered to individuals with FXS. The majority of assessments employed in clinical trials may be suboptimal for individuals with intellectual disability (ID) because they require face-to-face interaction with an examiner, taxing administration periods, and do not provide reinforcement and/or feedback during the test. We therefore examined the psychometric properties of a new computerised ‘learning platform’ approach to outcome measurement in FXS. Method A brief computerised test, incorporated into the Discrete Trial Trainer(c)- a commercially available software program designed for children with ID – was administered to 13 girls with FXS, 12 boys with FXS and 15 matched ID controls aged 10 to 23 years (mental age = 4 to 12 years). The software delivered automated contingent access to reinforcement, feedback, token delivery and prompting procedures (if necessary) on each trial to facilitate responding. The primary outcome measure was the participant’s learning rate, derived from the participant’s cumulative record of correct responses. Results All participants were able to complete the test and floor effects appeared to be minimal. Learning rates averaged approximately five correct responses per minute, ranging from one to eight correct responses per minute in each group. Test-retest reliability of the learning rates was 0.77 for girls with FXS, 0.90 for boys with FXS and 0.90 for matched ID controls. Concurrent validity with raw scores obtained on the Arithmetic subtest of the Wechsler Intelligence Scale for Children-III was 0.35 for girls with FXS, 0.80 for boys with FXS and 0.56 for matched ID controls. The learning rates were also highly sensitive to change, with effect sizes of 1.21, 0.89 and 1.47 in each group respectively following 15 to 20, 15-min sessions of intensive discrete trial training conducted over 1.5 days. Conclusions These results suggest that a learning platform approach to outcome measurement could provide investigators with a reliable, valid and highly sensitive measure to evaluate treatment efficacy, not only for individuals with FXS but also for individuals with other ID.
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4. Jordan I, Robertson D, Catani M, Craig M, Murphy D. {{Aripiprazole in the treatment of challenging behaviour in adults with autism spectrum disorder}}. {Psychopharmacology (Berl)}. 2012.
BACKGROUND: Autism spectrum disorders (ASD) are associated with repetitive behaviours and often also with hyperactivity, aggression, self-injurious behaviour, irritability and lability of mood. There is emerging evidence that aripiprazole, an antipsychotic with partial agonist dopaminergic effect, may be effective in the treatment of these challenging behaviours. Nevertheless, there is little evidence for their efficacy in adults with ASD. OBJECTIVES: The aim of this article is to present preliminary data on the use of aripiprazole in the treatment of challenging behaviour in the setting of ASD. METHODS: We present a consecutive series of five inpatients of normal intelligence with challenging behaviour associated with ASD, diagnosed according to ICD-10 criteria, which was resistant to treatment with other medical and behavioural interventions and which was treated with aripiprazole. RESULTS: Four out of five patients were classified as « much improved » or « very much improved » according to the Clinical Global Impression-Improvement scale. Aripiprazole caused akathisia, at a dose of 30 mg in the one patient who was not classified as a responder but was otherwise well tolerated. CONCLUSIONS: This is the first case series of adults with ASD presenting with challenging behaviour who have been treated with aripiprazole. While the results are promising, controlled trials are required to confirm the findings.
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5. Kalkbrenner AE, Braun JM, Durkin MS, Maenner MJ, Cunniff C, Lee LC, Pettygrove S, Nicholas JS, Daniels JL. {{Maternal Smoking During Pregnancy and the Prevalence of Autism Spectrum Disorders Using Data from the Autism and Developmental Disabilities Monitoring Network}}. {Environ Health Perspect}. 2012.
Background: Reported associations between gestational tobacco exposure and autism spectrum disorders (ASDs) have been inconsistent. Objective: We estimated the association between maternal smoking during pregnancy and ASDs among children aged 8 years. Methods: This population-based case-cohort study included 633,989 children, identified using publicly available birth certificate data, born in 1992, 1994, 1996, and 1998 from parts of 11 US states subsequently under ASD surveillance. Of these children, 3,315 were identified as having an ASD by the active, records-based surveillance of the Autism and Developmental Disabilities Monitoring Network. We estimated prevalence ratios (PRs) of maternal smoking from birth certificate report and ASDs using logistic regression, adjusting for maternal education, race/ethnicity, marital status, and maternal age; separately examining higher and lower-functioning case subgroups; and correcting for assumed under-ascertainment of autism by level of maternal education. Results: About 13% of the source population and 11% of children with an ASD had a report of maternal smoking in pregnancy: adjusted PR (95% confidence interval) of 0.90 (0.80, 1.01). The association for the case subgroup Autistic Disorder (1,310 cases) was similar: 0.88 (0.72, 1.08), while that for ASD Not Otherwise Specified (ASD-NOS) (375 cases) was positive, albeit including the null: 1.26 (0.91, 1.75). Unadjusted associations corrected for assumed under-ascertainment were 1.06 (0.98, 1.14) for all ASDs, 1.12 (0.97, 1.30) for Autistic Disorder, and 1.63 (1.30, 2.04) for ASD-NOS. Conclusions: After accounting for the potential of under-ascertainment bias, we found a null association between maternal smoking in pregnancy and ASDs, generally. The possibility of an association with a higher-functioning ASD subgroup was suggested, and warrants further study.
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6. Kelleher Iii RJ, Geigenmuller U, Hovhannisyan H, Trautman E, Pinard R, Rathmell B, Carpenter R, Margulies D. {{High-Throughput Sequencing of mGluR Signaling Pathway Genes Reveals Enrichment of Rare Variants in Autism}}. {PLoS One}. 2012; 7(4): e35003.
Identification of common molecular pathways affected by genetic variation in autism is important for understanding disease pathogenesis and devising effective therapies. Here, we test the hypothesis that rare genetic variation in the metabotropic glutamate-receptor (mGluR) signaling pathway contributes to autism susceptibility. Single-nucleotide variants in genes encoding components of the mGluR signaling pathway were identified by high-throughput multiplex sequencing of pooled samples from 290 non-syndromic autism cases and 300 ethnically matched controls on two independent next-generation platforms. This analysis revealed significant enrichment of rare functional variants in the mGluR pathway in autism cases. Higher burdens of rare, potentially deleterious variants were identified in autism cases for three pathway genes previously implicated in syndromic autism spectrum disorder, TSC1, TSC2, and SHANK3, suggesting that genetic variation in these genes also contributes to risk for non-syndromic autism. In addition, our analysis identified HOMER1, which encodes a postsynaptic density-localized scaffolding protein that interacts with Shank3 to regulate mGluR activity, as a novel autism-risk gene. Rare, potentially deleterious HOMER1 variants identified uniquely in the autism population affected functionally important protein regions or regulatory sequences and co-segregated closely with autism among children of affected families. We also identified rare ASD-associated coding variants predicted to have damaging effects on components of the Ras/MAPK cascade. Collectively, these findings suggest that altered signaling downstream of mGluRs contributes to the pathogenesis of non-syndromic autism.
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7. Pecorelli A, Leoncini S, De Felice C, Signorini C, Cerrone C, Valacchi G, Ciccoli L, Hayek J. {{Non-protein-bound iron and 4-hydroxynonenal protein adducts in classic autism}}. {Brain Dev}. 2012.
A link between oxidative stress and autism spectrum disorders (ASDs) remains controversial with opposing views on its role in the pathogenesis of the disease. We investigated for the first time the levels of non-protein-bound iron (NPBI), a pro-oxidant factor, and 4-hydroxynonenal protein adducts (4-HNE PAs), as a marker of lipid peroxidation-induced protein damage, in classic autism. Patients with classic autism (n=20, mean age 12.0+/-6.2years) and healthy controls (n=18, mean age 11.7+/-6.5years) were examined. Intraerythrocyte and plasma NPBI were measured by high performance liquid chromatography (HPLC), and 4-HNE PAs in erythrocyte membranes and plasma were detected by Western blotting. The antioxidant defences were evaluated as erythrocyte glutathione (GSH) levels using a spectrophotometric assay. Intraerythrocyte and plasma NPBI levels were significantly increased (1.98- and 3.56-folds) in autistic patients, as compared to controls (p=0.0019 and p<0.0001, respectively); likewise, 4-HNE PAs were significantly higher in erythrocyte membranes and in plasma (1.58- and 1.6-folds, respectively) from autistic patients than controls (p=0.0043 and p=0.0001, respectively). Erythrocyte GSH was slightly decreased (-10.34%) in patients compared to controls (p=0.0215). Our findings indicate an impairment of the redox status in classic autism patients, with a consequent imbalance between oxidative stress and antioxidant defences. Increased levels of NPBI could contribute to lipid peroxidation and, consequently, to increased plasma and erythrocyte membranes 4-HNE PAs thus amplifying the oxidative damage, potentially contributing to the autistic phenotype.
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8. Shelton JF, Hertz-Picciotto I, Pessah IN. {{Tipping the Balance of Autism Risk: Potential Mechanisms Linking Pesticides and Autism}}. {Environ Health Perspect}. 2012.
Background: Autism spectrum disorders (ASDs) have been increasing in many parts of the world and a portion of cases are attributable to environmental exposures. So far, conclusive replicated findings have yet to appear on any specific exposure, but mounting evidence suggests gestational pesticides exposures are strong candidates. Because multiple developmental processes are implicated in ASDs during gestation and early life, biological plausibility is more likely if these agents can be shown to affect core pathophysiological features. Here we review shared mechanisms between autism pathophysiology and effects of pesticide exposures, focusing on neuroexcitability, oxidative stress, and immune functions. Objectives: The objectives of this review are to outline the biological correlates between pesticide exposure and autism risk. Methods: We review and discuss previous research related to autism risk, developmental effects of early pesticide exposure, and basic biological mechanisms by which pesticides may induce or exacerbate pathophysiological features of autism. Discussion: Based on experimental and observational research, certain pesticides may be capable of inducing core features of autism but little is known about the timing, dose, or which of various mechanisms is sufficient to induce this condition. Conclusions: In animal studies, we encourage more research on gene X environment interactions, as well as experimental exposure to mixtures of compounds. Similarly, epidemiologic studies in humans with exceptionally high exposures can identify which pesticide classes are of greatest concern, and studies focused on gene X environment are needed to determine if there are susceptible sub-populations at greater risk from pesticide exposures.
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9. Testa C, Nuti F, Hayek J, De Felice C, Chelli M, Rovero P, Latini G, Papini AM. {{Di(2-ethylhexyl)phthalate and Autism Spectrum Disorders}}. {ASN Neuro}. 2012.
Autism spectrum disorders (ASDs) are a complex group of neurodevelopment disorders, still poorly understood, steadily rising in frequency, and treatment-refractory. Extensive research has been so far unable to explain the aetiology of this condition, whereas a growing body of evidence suggests the involvement of environmental factors. Phthalates, given their extensive use and their persistence, are ubiquitous environmental contaminants. They are endocrine-disrupting chemicals suspected to interfere with neurodevelopment. Therefore, they represent interesting candidate risk factors for ASDs pathogenesis. Aim of this study was to evaluate the levels of the primary and secondary metabolites of the di(2-ethylhexyl)phthalate (DEHP) in children with ASDs. A total of 48 children with ASDs [M: 36, F: 12; mean age: 11 years +/- 5 years] and 45 age and sex comparable healthy controls (HCs, M: 25, F: 20; mean age: 12 years+/- 5 years) were enrolled. A diagnostic methodology, based on the determination of urinary concentrations of DEHP metabolites by HPLC-ESI-MS, was applied to urine spot samples. MEHP, 6-OH-MEHP, 5-OH-MEHP, and 5-oxo-MEHP were measured and compared to unequivocally characterised, pure synthetic compounds (<98%) taken as standards. In ASDs patients, significantly increased 5-OH-MEHP (52.1%, median 0.18) and 5-oxo-MEHP (46.0%, median 0.096) urinary concentrations were detected, with a significant positive correlation between 5-OH-MEHP and 5-oxo-MEHP (rs = 0.668, p < 0.0001). The fully oxidised form 5-oxo-MEHP showed 91.1% specificity in identifying patients with ASDs. Our findings, demonstrate for the first time an association between phthalates exposure and ASDs, thus suggesting a previously unrecognized role for these ubiquitous environmental contaminants in the pathogenesis of autism.
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10. van Steijn DJ, Richards JS, Oerlemans AM, de Ruiter SW, van Aken MA, Franke B, Buitelaar JK, Rommelse NN. {{The co-occurrence of autism spectrum disorder and attention-deficit/hyperactivity disorder symptoms in parents of children with ASD or ASD with ADHD}}. {J Child Psychol Psychiatry}. 2012.
Background: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) share about 50-72% of their genetic factors, which is the most likely explanation for their frequent co-occurrence within the same patient or family. An additional or alternative explanation for the co-occurrence may be (cross-)assortative mating, e.g., the tendency to choose a partner that is similar or dissimilar to oneself. Another issue is that of parent-of-origin effect which refers to the possibility of parents differing in the relative quantity of risk factors they transmit to the offspring. The current study sets out to examine (cross-)assortative mating and (cross-)parent-of-origin effects of ASD and ADHD in parents of children with either ASD or ASD with ADHD diagnosis. Methods: In total, 121 families were recruited in an ongoing autism-ADHD family genetics project. Participating families consisted of parents and at least one child aged between 2 and 20 years, with either autistic disorder, Asperger disorder or PDD-NOS, and one or more biological siblings. All children and parents were carefully screened for the presence of ASD and ADHD. Results: No correlations were found between maternal and paternal ASD and ADHD symptoms. Parental ASD and ADHD symptoms were predictive for similar symptoms in the offspring, but with maternal hyperactive-impulsive symptoms, but not paternal symptoms, predicting similar symptoms in daughters. ASD pathology in the parents was not predictive for ADHD pathology in the offspring, but mother’s ADHD pathology was predictive for offspring ASD pathology even when corrected for maternal ASD pathology. Conclusions: Cross-assortative mating for ASD and ADHD does not form an explanation for the frequent co-occurrence of these disorders within families. Given that parental ADHD is predictive of offspring’ ASD but not vice versa, risk factors underlying ASD may overlap to a larger degree with risk factors underlying ADHD than vice versa. However, future research is needed to clarify this issue.
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11. Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, Conlon MA. {{Elevated Fecal Short Chain Fatty Acid and Ammonia Concentrations in Children with Autism Spectrum Disorder}}. {Dig Dis Sci}. 2012.
BACKGROUND AND AIM: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder where a high frequency of gastrointestinal disturbance (e.g., constipation and diarrhea) is reported. As large bowel fermentation products can have beneficial or detrimental effects on health, these were measured in feces of children with and without ASD to examine whether there is an underlying disturbance in fermentation processes in the disorder. METHODS: Fecal samples (48 h) were collected from children with ASD (n = 23), and without ASD (n = 31) of similar age. Concentrations of short chain fatty acids, phenols and ammonia were measured. RESULTS: Fecal total short chain fatty acid concentrations were significantly higher in children with ASD compared to controls (136.6 +/- 8.7 vs. 111.1 +/- 6.6 mmol/kg). Moreover, when concentrations of fecal acetic, butyric, isobutyric, valeric, isovaleric and caproic acids were measured, all were significantly higher in children with ASD compared with controls except for caproic acid. The concentration of fecal ammonia was also significantly greater in ASD participants than controls (42.7 +/- 3.3 vs. 32.3 +/- 1.9 mmol/kg). Fecal phenol levels and pH did not differ between groups. Macronutrient intake, as determined from dietary records kept by caregivers, also did not differ significantly between study groups. CONCLUSIONS: Our results suggest fermentation processes or utilization of fermentation products may be altered in children with ASD compared to children without ASD.
