1. Yasui DH, Scoles HA, Horike SI, Meguro-Horike M, Dunaway KW, Schroeder DI, Lasalle JM. {{15q11.2-13.3 chromatin analysis reveals epigenetic regulation of CHRNA7 with deficiencies in Rett and autism brain}}. {Hum Mol Genet};2011 (Aug 12)
Copy number variants (CNVs) within human 15q11.2-13.3 show reduced penetrance and variable expressivity in a range of neurologic disorders. Therefore, characterizing 15q11.2-13.3 chromatin structure is important for understanding the regulation of this locus during normal neuronal development. Deletion of the Prader-Willi imprinting center (PWS-IC) within 15q11.2-13.3 disrupts long range imprinted gene expression resulting in Prader-Willi syndrome. Previous results establish that MeCP2 binds to the PWS-IC and is required for optimal expression of distal GABRB3 and UBE3A. To examine the hypothesis that MeCP2 facilitates 15q11.2-13.3 transcription by linking the PWS-IC to distant elements, chromosome capture conformation on chip (4C) analysis was performed in human SH-SY5Y neuroblastoma cells. SH-SY5Y neurons had 2.84 fold fewer 15q11.2-13.3 PWS-IC chromatin interactions than undifferentiated SH-SY5Y neuroblasts, revealing developmental chromatin de-condensation of the locus. Out of 68 PWS-IC interactions with15q11.2-13.3 identified by 4C analysis and 62 15q11.2-13.3 MeCP2 binding sites identified by previous ChIP-chip studies only five sites showed overlap. Remarkably, two of these overlapping PWS-IC and MeCP2 bound sites mapped to sites flanking CHRNA7 encoding the cholinergic receptor, nicotinic, alpha 7. PWS-IC interaction with CHRNA7 in neurons was independently confirmed by FISH analysis. Subsequent quantitative transcriptional analyses of frontal cortex from Rett syndrome and autism patients revealed significantly reduced CHRNA7 expression compared to controls. Together, these results suggest that transcription of CHRNA7 is modulated by chromatin interactions with the PWS-IC. Thus loss of long-range chromatin interactions within 15q11.2-13.3 may contribute to multiple human neurodevelopmental disorders.
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2. Kaluzna-Czaplinska J, Socha E, Rynkowski J. {{B vitamin supplementation reduces excretion of urinary dicarboxylic acids in autistic children}}. {Nutr Res};2011 (Jul);31(7):497-502.
Urinary dicarboxylic acids are an important source of information about metabolism and potential problems especially connected with energy production, intestinal dysbiosis, and nutritional individuality in autistic children. A diet rich in vitamins and macroelements is a new idea of intervention in autism. The objective of the present study was to test the hypothesis that vitamin B2, vitamin B6, and magnesium supplementation is effective in reducing the level of dicarboxylic acids in the urine of autistic children. We examined the levels of succinic, adipic, and suberic acids in the urine of autistic children before and after vitamin supplementation. Thirty children with autism received magnesium (daily dose, 200 mg), vitamin B6 (pyridoxine; daily dose, 500 mg), and vitamin B2 (riboflavin; daily dose, 20 mg). The treatment was provided for a period of 3 months. Organic acids were determined using gas chromatography/mass spectrometry. Before supplementation, the levels of succinic, adipic, and suberic acids in the urine of autistic children were 41.47 +/- 50.40 mumol/mmol creatinine, 15.61 +/- 15.31 mumol/mmol creatinine, 8.02 +/- 6.08 mumol/mmol creatinine; and after supplementation, the levels were 9.90 +/- 8.26 mumol/mmol creatinine, 2.92 +/- 2.41 mumol/mmol creatinine, and 2.57 +/- 3.53 mumol/mmol creatinine, respectively. The results suggest that the supplementation reduces the level of dicarboxylic acid in the urine of autistic children.
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3. Yu D, Sakurai F, Corey DR. {{Clonal Rett Syndrome cell lines to test compounds for activation of wild-type MeCP2 expression}}. {Bioorg Med Chem Lett};2011 (Jul 23)
Rett Syndrome is an X-linked progressive neurological disorder caused by inactivation of one allele of the MECP2 gene. There are no curative treatments, and activation of wild-type MECP2 expression is one strategy for stabilizing or reversing the disease. We isolated fibroblast clones that express exclusively either the wild-type or a 32-bp-deletion mutant form of MECP2. We developed a sensitive assay for measuring wild-type MECP2 mRNA levels and tested small molecule epigenetic activators for their ability to activate gene expression. Although our pilot screen did not identify activators of MECP2 expression, it established the value of using clonal cells and defined challenges that must be overcome.
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4. Burket JA, Herndon AL, Winebarger EE, Jacome LF, Deutsch SI. {{Complex effects of mGluR5 antagonism on sociability and stereotypic behaviors in mice: Possible implications for the pharmacotherapy of autism spectrum disorders}}. {Brain Res Bull};2011 (Aug 5)
Balb/c mice display deficits of sociability; for example, they show reduced locomotor activity in the presence of an enclosed or freely-moving social stimulus mouse. Transgenic mice with defective or diminished expression of NMDA receptors manifest impaired sociability, while a partial and full agonist of the obligatory glycine co-agonist binding site on the NMDA receptor improved sociability in the Balb/c mouse strain. Because 2-methyl-6-(phenylethynyl)-pyridine (MPEP), an antagonist of the mGluR5 metabotropic glutamate receptor (mGluR), reduced self-grooming behavior in BTBR T+tfJ (BTBR) mice, another inbred genetic mouse model of autism spectrum disorders (ASDs), and mGluR5 antagonism is emerging as an experimental treatment for the ‘fragile X syndrome, » which has a high prevalence of co-morbid ASDs, we examined the effects of MPEP on sociability and stereotypic behaviors in Balb/c and Swiss Webster mice in a standard paradigm. MPEP had complex effects on sociability, impairing some measures of sociability in both strains, while it reduced the intensity of some spontaneous measures of stereotypic behaviors emerging during free social interaction in Swiss Webster mice. Conceivably, mGluR5 antagonism exacerbates diminished endogenous tone of NMDA receptor-mediated neurotransmission in neural circuits relevant to at least some measures of sociability in Balb/c mice; the mGluR5 receptor contributes to regulation of the phosphorylation status of the NMDA receptor. In any event, although stereotypies are an important therapeutic target in ASDs, medication strategies to attenuate their severity via antagonism of mGluR5 receptors must be pursued cautiously because of their potential to worsen at least some measures of sociability.
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5. Voineagu I. {{Gene expression studies in autism: Moving from the genome to the transcriptome and beyond}}. {Neurobiol Dis};2011 (Jul 28)
Autism is a clinically and genetically heterogeneous neurodevelopmental disorder. Although multiple genes, risk alleles and copy number variants (CNVs) have been implicated in ASD, none of the currently established genetic causes of ASD accounts for more than 2% of the cases, and a genetic diagnosis is not yet possible for most autism patients. Thus, advancing our understanding of autism genetics requires the integration of genetic information with information on genome function, as provided by transcriptomic data. We review recent autism transcriptome studies, in the context of current knowledge of autism genetics, and discuss the utility of gene expression data in evaluating the functional relevance of genetic variants and identifying common molecular pathways dysregulated in autism.
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6. Guenole F, Baleyte JM. {{Meta-analysing the effectiveness of melatonin for sleep-disturbed individuals with autism spectrum conditions: should Rett syndrome be included?}}. {Dev Med Child Neurol};2011 (Aug 12)
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7. Stefanatos GA, Baron IS. {{The Ontogenesis of Language Impairment in Autism: A Neuropsychological Perspective}}. {Neuropsychol Rev};2011 (Aug 13)
Autistic Disorder (AD) is a phenotypically heterogeneous condition characterized by impairments in social interaction, communication, and the presence of repetitive behavior and restricted interests. It is a model syndrome to investigate neural interaction and integration at the nexus of language and social cognition. This paper considers the problems of language acquisition in AD from an evolutionary and ontogenetic context. Following a review of normal language development during the formative years of brain development, we examine what is known about infant linguistic and nonlinguistic precursors of language acquisition in AD and examine how anomalies of several processes relate to language abnormalities manifest by the early elementary school years. Population heterogeneity and practical limitations inherent to the study of children currently limit a comprehensive understanding of the significance of specific neurological abnormalities in relation to observed deficits. However, convergent evidence implicates anomalies of a widely distributed neural network, involving superior temporal sulcus, superior temporal gyrus, supramarginal gyrus, insula, inferior frontal gyrus, hippocampus, amygdala and cerebellum. These anomalies reflect the cumulative effects of genetic, epigenetic and environmental influences. Neuropsychological studies of language in AD provide an important means to define the phenotypic variation resulting from alterations in neural architecture. By mapping broad relationships between key symptoms, neuropsychological impairment and neural substrate, information derived from these studies enable a level of analysis that bridges the gap between the genome and the syndrome. Further study of children during the critical first 2 years of life using behavioral, electrophysiological, and functional neuroimaging methods is essential.
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8. De Rubeis S, Bagni C. {{Regulation of molecular pathways in the Fragile X Syndrome: insights into Autism Spectrum Disorders}}. {J Neurodev Disord};2011 (Aug 13)
The Fragile X syndrome (FXS) is a leading cause of intellectual disability (ID) and autism. The disease is caused by mutations or loss of the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein playing multiple functions in RNA metabolism. The expression of a large set of neuronal mRNAs is altered when FMRP is lost, thus causing defects in neuronal morphology and physiology. FMRP regulates mRNA stability, dendritic targeting, and protein synthesis. At synapses, FMRP represses protein synthesis by forming a complex with the Cytoplasmic FMRP Interacting Protein 1 (CYFIP1) and the cap-binding protein eIF4E. Here, we review the clinical, genetic, and molecular aspects of FXS with a special focus on the receptor signaling that regulates FMRP-dependent protein synthesis. We further discuss the FMRP-CYFIP1 complex and its potential relevance for ID and autism.
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9. Barton ML, Dumont-Mathieu T, Fein D. {{Screening Young Children for Autism Spectrum Disorders in Primary Practice}}. {J Autism Dev Disord};2011 (Aug 13)
The increasing prevalence of autism spectrum disorders as well as emerging evidence of the efficacy of early intervention has focused attention on the need for early identification of young children suspected of having an ASSD. Several studies have suggested that while parents report concerns early in development, it may be months before children can be evaluated and services provided, and these delays may be even more marked in under-served populations. The American Academy of Pediatrics recently recommended universal screening for autism spectrum disorders at the 18- and 24-month well-child pediatric visit. The authors review several early screening tools currently in use and offer recommendations for integrating autism specific screening into primary care practice.
