1. De Felice C, Signorini C, Durand T, Ciccoli L, Leoncini S, D’Esposito M, Filosa S, Oger C, Guy A, Bultel-Ponce V, Galano JM, Pecorelli A, De Felice L, Valacchi G, Hayek J. {{Partial rescue of Rett syndrome by omega-3 polyunsaturated fatty acids (PUFAs) oil}}. {Genes Nutr};2012 (Mar 8)
Evidence of enhanced oxidative stress (O.S.) and lipid peroxidation has been reported in patients with Rett syndrome (RTT), a relatively rare neurodevelopmental disorder progressing in 4-stages, and mainly caused by loss-of-function mutations in the methyl-CpG-binding protein 2. No effective therapy for preventing or arresting the neurologic regression in the disease in its various clinical presentations is available. Based on our prior evidence of enhanced O.S. and lipid peroxidation in RTT patients, herein we tested the possible therapeutic effects of omega-3 polyunsaturated fatty acids (omega-3 PUFAs), known antioxidants with multiple effects, on the clinical symptoms and O.S. biomarkers in the earliest stage of RTT. A total of 20 patients in stage I were randomized (n = 10 subjects per arm) to either oral supplementation with omega-3 PUFAs-containing fish oil (DHA: 72.9 +/- 8.1 mg/kg b.w./day; EPA: 117.1 +/- 13.1 mg/kg b.w./day; total omega-3 PUFAs: 246.0 +/- 27.5 mg/kg b.w./day) for 6 months or no treatment. Primary outcomes were potential changes in clinical symptoms, with secondary outcomes including variations for five O.S. markers in plasma and/or erythrocytes (nonprotein bound iron, F(2)-dihomo-isoprostanes, F(3)-isoprostanes, F(4)-neuroprostanes, and F(2)-isoprostanes). A significant reduction in the clinical severity (in particular, motor-related signs, nonverbal communication deficits, and breathing abnormalities) together with a significant decrease in all the examined O.S. markers was observed in the omega-3 PUFAs supplemented patients, whereas no significant changes were evidenced in the untreated group. For the first time, these findings strongly suggest that a dietary intervention in this genetic disease at an early stage of its natural history can lead to a partial clinical and biochemical rescue.
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2. Fung LK, Quintin EM, Haas BW, Reiss AL. {{Conceptualizing neurodevelopmental disorders through a mechanistic understanding of fragile X syndrome and Williams syndrome}}. {Curr Opin Neurol};2012 (Apr);25(2):112-124.
PURPOSE OF REVIEW: The overarching goal of this review is to compare and contrast the cognitive-behavioral features of fragile X syndrome (FraX) and Williams syndrome and to review the putative neural and molecular underpinnings of these features. Information is presented in a framework that provides guiding principles for conceptualizing gene-brain-behavior associations in neurodevelopmental disorders. RECENT FINDINGS: Abnormalities, in particular cognitive-behavioral domains with similarities in underlying neurodevelopmental correlates, occur in both FraX and Williams syndrome including aberrant frontostriatal pathways leading to executive function deficits, and magnocellular/dorsal visual stream, superior parietal lobe, inferior parietal lobe, and postcentral gyrus abnormalities contributing to deficits in visuospatial function. Compelling cognitive-behavioral and neurodevelopmental contrasts also exist in these two disorders, for example, aberrant amygdala and fusiform cortex structure and function occurring in the context of contrasting social behavioral phenotypes, and temporal cortical and cerebellar abnormalities potentially underlying differences in language function. Abnormal dendritic development is a shared neurodevelopmental morphologic feature between FraX and Williams syndrome. Commonalities in molecular machinery and processes across FraX and Williams syndrome occur as well – microRNAs involved in translational regulation of major synaptic proteins; scaffolding proteins in excitatory synapses; and proteins involved in axonal development. SUMMARY: Although the genetic variations leading to FraX and Williams syndrome are different, important similarities and contrasts in the phenotype, neurocircuitry, molecular machinery, and cellular processes in these two disorders allow for a unique approach to conceptualizing gene-brain-behavior links occurring in neurodevelopmental disorders.
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3. McCanlies EC, Fekedulegn D, Mnatsakanova A, Burchfiel CM, Sanderson WT, Charles LE, Hertz-Picciotto I. {{Parental Occupational Exposures and Autism Spectrum Disorder}}. {J Autism Dev Disord};2012 (Mar 8)
Both self-report and industrial hygienist (IH) assessed parental occupational information were used in this pilot study in which 174 families (93 children with ASD and 81 unaffected children) enrolled in the Childhood Autism Risks from Genetics and Environment study participated. IH results indicated exposures to lacquer, varnish, and xylene occurred more often in the parents of children with ASD compared to the parents of unaffected children. Parents of children with ASD were more likely to report exposures to asphalt and solvents compared to parents of unaffected children. This study was limited by the small sample size, but results suggest that workplace exposures to some chemicals may be important in the etiology of ASD and deserve further investigation.
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4. Silva LM, Schalock M. {{Sense and self-regulation checklist, a measure of comorbid autism symptoms: initial psychometric evidence}}. {Am J Occup Ther};2012 (Mar-Apr);66(2):177-186.
Sensory and self-regulatory symptoms make up most of the comorbid symptoms in autism and are associated with increased autism severity. We validated a parent-caregiver measure of comorbid symptoms in autism, the Sense and Self-Regulation Checklist (SSC), in 265 children <6 yr with typical development (n = 138), autism (n = 99), or other developmental delay (n = 28); Cronbach’s alpha was .87. We report two new findings discriminating autism from other groups: (1) multifocal tactile sensory impairment, characterized by hyporeactivity to injurious stimuli and hyperreactivity to noninjurious stimuli (F[2, 262] = 86.8, p < .001) and (2) global self-regulatory delay (F[2, 262] = 122, p < .001). Both findings suggest an explanation for social delay in children with autism. The SSC reports a prevalence of sensory and self-regulatory findings approaching 100% in the autism group (96% and 98%, respectively), raising the possibility that sensory and self-regulatory difficulties represent a core part of autism.
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5. Storch EA, Wood JJ, Ehrenreich-May J, Jones AM, Park JM, Lewin AB, Murphy TK. {{Convergent and Discriminant Validity and Reliability of the Pediatric Anxiety Rating Scale in Youth with Autism Spectrum Disorders}}. {J Autism Dev Disord};2012 (Mar 1)
The psychometric properties of the Pediatric Anxiety Rating Scale (PARS), a clinician-administered measure for assessing severity of anxiety symptoms, were examined in 72 children and adolescents diagnosed with an autism spectrum disorder (ASD). The internal consistency of the PARS was 0.59, suggesting that the items were related but not repetitive. The PARS showed high 26-day test-retest (ICC = 0.83) and inter-rater reliability (ICC = 0.86). The PARS was strongly correlated with clinician-ratings of overall anxiety severity and parent-report anxiety measures, supporting convergent validity. Results for divergent validity were mixed. Although the PARS was not associated with the sum of the Social and Communication items on the Autism Diagnostic Observation System, it was moderately correlated with parent-reported inattention, aggression and externalizing behavior. Overall, these results suggest that the psychometric properties of the PARS are adequate for assessing anxiety symptoms in youth with ASD, although additional clarification of divergent validity is needed.
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6. Tachibana Y, Green J, Hwang Y, Emsley R. {{A systematic review with meta-analysis of comprehensive interventions for preschool children with autism spectrum disorder (ASD): study protocol}}. {BMJ Open};2012;2(2):e000679.
INTRODUCTION: The aims of this study are to (1) conduct a systematic review of the intervention literature in preschool children with autism spectrum disorder (ASD), including types of interventions that are tested and the classification of outcome measures used and (2) to undertake a meta-analysis of the studies, allowing for the first time the comparison of different approaches to intervention using comparative outcomes. There are a number of alternative modalities of intervention for preschool children with ASD in use with different theoretical background and orientation, each of which tend to use different trial designs and outcome measures. There is at this time an urgent need for comprehensive systematic review and meta-analyses of intervention studies for preschool children with ASD, covering studies of adequate quality across different intervention types and measurement methods, with a view to identifying the best current evidence for preschool interventions in the disorder. METHODS AND ANALYSIS: The authors will perform a systematic review of randomised controlled trials for preschool children with ASD aged 0-6 years, along with a meta-analysis of qualifying studies across intervention modality. The authors will classify the interventions for preschool children with ASD under three models: behaviour, multimodal developmental and communication focused. First, the authors will perform a systematic review. Then, the authors will conduct a meta-analysis by comparing the three models with various outcomes using an inverse variance method in a random effect model. The authors will synthesise each outcome of the studies for the three models using standardised mean differences. DISSEMINATION AND ETHICS: This study will identify each intervention’s strengths and weaknesses. This study may also suggest what kinds of elements future intervention programmes for children with ASD should have. The authors strongly believe those findings will be able to translated into the clinical practices and patients and their family benefits. Review registration: PROSPERO CRD42011001349.
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7. Toma C, Hervas A, Balmana N, Salgado M, Maristany M, Vilella E, Aguilera F, Orejuela C, Cusco I, Gallastegui F, Perez-Jurado LA, Caballero-Andaluz R, Diego-Otero YD, Guzman-Alvarez G, Ramos-Quiroga JA, Ribases M, Bayes M, Cormand B. {{Neurotransmitter systems and neurotrophic factors in autism: association study of 37 genes suggests involvement of DDC}}. {World J Biol Psychiatry};2012 (Mar 8)
Objectives. Neurotransmitter systems and neurotrophic factors can be considered strong candidates for autism spectrum disorder (ASD). The serotoninergic and dopaminergic systems are involved in neurotransmission, brain maturation and cortical organization, while neurotrophic factors (NTFs) participate in neurodevelopment, neuronal survival and synapses formation. We aimed to test the contribution of these candidate pathways to autism through a case-control association study of genes selected both for their role in central nervous system functions and for pathophysiological evidences. Methods. The study sample consisted of 326 unrelated autistic patients and 350 gender-matched controls from Spain. We genotyped 369 tagSNPs to perform a case-control association study of 37 candidate genes. Results. A significant association was obtained between the DDC gene and autism in the single-marker analysis (rs6592961, P = 0.00047). Haplotype-based analysis pinpointed a four-marker combination in this gene associated with the disorder (rs2329340C-rs2044859T-rs6592961A-rs11761683T, P = 4.988e-05). No significant results were obtained for the remaining genes after applying multiple testing corrections. However, the rs167771 marker in DRD3, associated with ASD in a previous study, displayed a nominal association in our analysis (P = 0.023). Conclusions. Our data suggest that common allelic variants in the DDC gene may be involved in autism susceptibility.
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8. Wang X, Snape M, Klann E, Stone JG, Singh A, Petersen RB, Castellani RJ, Casadesus G, Smith MA, Zhu X. {{Activation of the ERK Pathway Contributes to the Behavioral Deficit of Fragile X-Syndrome}}. {J Neurochem};2012 (Mar 6)
Fragile X syndrome (FXS) is a developmental disorder caused by the loss of Fragile X Mental Retardation 1 (FMR1) gene function due to a CGG repeat expansion (>200 repeats) in the gene. The molecular mechanism(s) linking loss of FMR1function to the molecular pathology and cognitive/behavioral disability remain unclear. Given the critical role of extracellular signal-regulated kinase (ERK) in synaptic plasticity and neurodevelopment, a number of recent studies have investigated ERK phosphorylation under basal conditions or upon mGluR-induction using neuronal and peripheral tissues from Fmr1 knockout mice and peripheral tissues from FXS patients. However, these reports have presented conflicting results. The current study is the first to focus on the levels of ERK phosphorylation in brain tissue from human FXS patients. In both human brain tissue and brain tissue from Fmr1 knockout mice there was significantly increased phosphorylation of MEK1/2 and ERK. Indeed, treating Fmr1 knockout mice with the MEK1/2 inhibitor SL327 abrogated audiogenic seizure activity, a feature of the Fmr1 knockout mice that replicates the symptom in patients with FXS. These findings suggest that activation of the ERK pathway results in some cardinal cognitive and clinical features in FXS patients and likely have profound translational implications. (c) 2012 The Authors Journal of Neurochemistry (c) 2012 International Society for Neurochemistry.
