1. Clarke RA, Lee S, Eapen V. {{Pathogenetic model for Tourette syndrome delineates overlap with related neurodevelopmental disorders including Autism}}. {Transl Psychiatry};2012;2:e163.
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2. Durand T, De Felice C, Signorini C, Oger C, Bultel-Ponce V, Guy A, Galano JM, Leoncini S, Ciccoli L, Pecorelli A, Valacchi G, Hayek J. {{F2-Dihomo-Isoprostanes and brain white matter damage in stage 1 Rett syndrome}}. {Biochimie};2012 (Sep 22)
Oxidative damage has been reported in Rett syndrome (RTT), a pervasive development disorder mainly caused in up to 95% of cases by mutations in the X-linked methyl-CpG binding protein 2 (MeCP2) gene. We have recently synthesized F(2)-Dihomo-isoprostanes (F(2)-Dihomo-IsoP), peroxidation products from adrenic acid (C22:4 n-6, AdA), a known component of myelin, and tested the potential value of F(2)-Dihomo-IsoPs as a novel disease marker and its relationship with clinical presentation, and disease progression. F(2)-Dihomo-IsoPs were determined by a gas chromatography/negative ion chemical ionization tandem mass spectrometry. The ent-7(RS)-F(2t)-Dihomo-IsoP and 17-F(2t)-Dihomo-IsoP were used as reference standards. The measured ions were the product ions at m/z 327 derived from the [M-181](-) precursor ions (m/z 597) produced from both the derivatized ent-7(RS)-F(2t)-Dihomo-IsoP and 17-F(2t)-Dihomo-IsoP. Average plasma F(2)-Dihomo-IsoP levels in RTT were about 1 order of magnitude higher than in healthy controls, being higher in typical RTT as compared to RTT variants, with a remarkable increase of about 2 orders of magnitude in patients at the earliest stage of the disease followed by a steady decrease during the natural clinical progression. These data indicate for the first time that quantification of F(2)-Dihomo-IsoPs in plasma represents an early marker of the disease and may provide a better understanding of the pathogenic mechanisms behind the neurological regression in patients with RTT.
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3. Gocel J, Larson J. {{Synaptic NMDA receptor-mediated currents in anterior piriform cortex are reduced in the adult fragile X mouse}}. {Neuroscience};2012 (Sep 27);221:170-181.
Fragile X syndrome is a neurodevelopmental condition caused by the transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. The Fmr1 knockout (KO) mouse exhibits age-dependent deficits in long term potentiation (LTP) at association (ASSN) synapses in anterior piriform cortex (APC). To investigate the mechanisms for this, whole-cell voltage-clamp recordings of ASSN stimulation-evoked synaptic currents were made in APC of slices from adult Fmr1-KO and wild-type (WT) mice, using the competitive N-methyl-d-aspartate (NMDA) receptor antagonist, CPP, to distinguish currents mediated by NMDA and AMPA receptors. NMDA/AMPA current ratios were lower in Fmr1-KO mice than in WT mice, at ages ranging from 3-18months. Since amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs) mediated by AMPA receptors were no different in Fmr1-KO and WT mice at these ages, the results suggest that NMDA receptor-mediated currents are selectively reduced in Fmr1-KO mice. Analyses of voltage-dependence and decay kinetics of NMDA receptor-mediated currents did not reveal differences between Fmr1-KO and WT mice, suggesting that reduced NMDA currents in Fmr1-KO mice are due to fewer synaptic receptors rather than differences in receptor subunit composition. Reduced NMDA receptor signaling may help to explain the LTP deficit seen at APC ASSN synapses in Fmr1-KO mice at 6-18months of age, but does not explain normal LTP at these synapses in mice 3-6months old. Evoked currents and mEPSCs were also examined in senescent Fmr1-KO and WT mice at 24-28months of age. NMDA/AMPA ratios were similar in senescent WT and Fmr1-KO mice, due to a decrease in the ratio in the WT mice, without significant change in AMPA receptor-mediated mEPSCs.
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4. Jung KM, Sepers M, Henstridge CM, Lassalle O, Neuhofer D, Martin H, Ginger M, Frick A, Dipatrizio NV, Mackie K, Katona I, Piomelli D, Manzoni OJ. {{Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome}}. {Nat Commun};2012 (Sep 25);3:1080.
Fragile X syndrome, the most commonly known genetic cause of autism, is due to loss of the fragile X mental retardation protein, which regulates signal transduction at metabotropic glutamate receptor-5 in the brain. Fragile X mental retardation protein deletion in mice enhances metabotropic glutamate receptor-5-dependent long-term depression in the hippocampus and cerebellum. Here we show that a distinct type of metabotropic glutamate receptor-5-dependent long-term depression at excitatory synapses of the ventral striatum and prefrontal cortex, which is mediated by the endocannabinoid 2-arachidonoyl-sn-glycerol, is absent in fragile X mental retardation protein-null mice. In these mutants, the macromolecular complex that links metabotropic glutamate receptor-5 to the 2-arachidonoyl-sn-glycerol-producing enzyme, diacylglycerol lipase-alpha (endocannabinoid signalosome), is disrupted and metabotropic glutamate receptor-5-dependent 2-arachidonoyl-sn-glycerol formation is compromised. These changes are accompanied by impaired endocannabinoid-dependent long-term depression. Pharmacological enhancement of 2-arachidonoyl-sn-glycerol signalling normalizes this synaptic defect and corrects behavioural abnormalities in fragile X mental retardation protein-deficient mice. The results identify the endocannabinoid signalosome as a molecular substrate for fragile X syndrome, which might be targeted by therapy.
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5. Liu Y, Winarni TI, Zhang L, Tassone F, Hagerman RJ. {{Fragile X- associated Tremor/Ataxia Syndrome (FXTAS) in Grey Zone Carriers}}. {Clin Genet};2012 (Sep 25)
The grey zone (GZ; 45-54 CGG repeats in the FMR1 gene) is considered a normal allele, however several studies have found a high frequency of GZ in movement disordered populations. Here, we describe neurological features of FXTAS in two carriers of GZ alleles, although FXTAS has been defined as occurring only in premutation carriers (55-200 CGG repeats). Both patients had family members who had the premutation and were diagnosed with FXTAS. The presence of relatively high GZ alleles with elevated FMR1-mRNA combined with a family history of FXTAS that may represent a facilitating genetic background for FXTAS are the factors that led to the presence of FXTAS in these individuals with a GZ allele. Further research into clinical involvement of GZ alleles is recommended and the definition of FXTAS may requires revision.
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6. Roke Y, van Harten PN, Buitelaar JK, Tenback DE, Quekel L, de Rijke Y, Boot A. {{Bone mineral density in male adolescents with autism spectrum disorders and disruptive behavior disorder with or without antipsychotic treatment}}. {Eur J Endocrinol};2012 (Sep 25)
Objective:To investigate the long-term effects of antipsychotic (AP) treatment and AP-induced hyperprolactinemia on bone mineral density (BMD) and body composition in male adolescents with autism spectrum disorders (ASD) and/or disruptive behavior disorder (DBD).Design:Physically healthy 10-to 20-year-old boys with ASD and/ or DBD, chronically treated (N=56; mean 52 months, range 16-126 months) or not treated (N=47) with an AP were recruited to this observational study. Prolactin levels and biochemical bone parameters were measured and BMD of the lumbar spine and total body, and body composition were assessed by dual energy X-ray absorptiometry (DXA), and volumetric BMD of the lumbar spine calculated. Group differences were tested with Student’s t-, Chi-square, Fisher exact tests, and logistic regression analysis.Results:49% of the boys treated with an AP had hyperprolactinemia. The mean volumetric lumbar spine BMD z-score was lower (p=0.043), the total % body fat z-score was higher (p=0.032), and biochemical bone marker carboxyterminal cross-linking telopeptide of bone collagen (CTx) was lower in the AP-treated boys with hyperprolactinemia than in the AP-treated boys without hyperprolactinemia. 7-11% of the hyperprolactinemic boys had low BMD. The mean lumbar spine and total body BMD z-scores and body composition were similar in the boys who were or were not treated with an AP. The total study population had a lower mean lean tissue mass (mean z-score -0.37, p=0.004) and a higher % total body fat (mean Z-score 1.16, p<0.001) than healthy controls (normative data); biochemical bone parameters were within normal limits.Conclusion:AP-induced hyperprolactinemia in boys with ASD or DBD may have a negative effect on lumbar spine BMD. Longitudinal studies are needed to confirm this finding and further disentangle the effects of the disorder, lifestyle, treatment and hyperprolactinemia.
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7. Sachse M, Schlitt S, Hainz D, Ciaramidaro A, Schirman S, Walter H, Poustka F, Bolte S, Freitag CM. {{Executive and Visuo-motor Function in Adolescents and Adults with Autism Spectrum Disorder}}. {J Autism Dev Disord};2012 (Sep 26)
This study broadly examines executive (EF) and visuo-motor function in 30 adolescent and adult individuals with high-functioning autism spectrum disorder (ASD) in comparison to 28 controls matched for age, gender, and IQ. ASD individuals showed impaired spatial working memory, whereas planning, cognitive flexibility, and inhibition were spared. Pure movement execution during visuo-motor information processing also was intact. In contrast, execution time of reading, naming, and of visuo-motor information processing tasks including a choice component was increased in the ASD group. Results of this study are in line with previous studies reporting only minimal EF difficulties in older individuals with ASD when assessed by computerized tasks. The finding of impaired visuo-motor information processing should be accounted for in further neuropsychological studies in ASD.
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8. Schwartzer JJ, Koenig CM, Berman RF. {{Using mouse models of autism spectrum disorders to study the neurotoxicology of gene-environment interactions}}. {Neurotoxicol Teratol};2012 (Sep 7)
To better study the role of genetics in autism, mouse models have been developed which mimic the genetics of specific autism spectrum and related disorders. These models have facilitated research on the role genetic susceptibility factors in the pathogenesis of autism in the absence of environmental factors. Inbred mouse strains have been similarly studied to assess the role of environmental agents on neurodevelopment, typically without the complications of genetic heterogeneity of the human population. What has not been as actively pursued, however, is the methodical study of the interaction between these factors (e.g., gene and environmental interactions in neurodevelopment). This review suggests that a genetic predisposition paired with exposure to environmental toxicants plays an important role in the etiology of neurodevelopmental disorders including autism, and may contribute to the largely unexplained rise in the number of children diagnosed with autism worldwide. Specifically, descriptions of the major mouse models of autism and toxic mechanisms of prevalent environmental chemicals are provided followed by a discussion of current and future research strategies to evaluate the role of gene and environment interactions in neurodevelopmental disorders.
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9. Tonnsen BL, Malone PS, Hatton DD, Roberts JE. {{Early Negative Affect Predicts Anxiety, not Autism, in Preschool Boys with Fragile X Syndrome}}. {J Abnorm Child Psychol};2012 (Aug 5)
Children with fragile X syndrome (FXS) face high risk for anxiety disorders, yet no studies have explored FXS as a high-risk sample for investigating early manifestations of anxiety outcomes. Negative affect is one of the most salient predictors of problem behaviors and has been associated with both anxiety and autistic outcomes in clinical and non-clinical pediatric samples. In light of the high comorbidity between autism and anxiety within FXS, the present study investigates the relationship between longitudinal trajectories of negative affect (between 8 and 71 months) and severity of anxiety and autistic outcomes in young males with FXS (n = 25). Multilevel models indicated associations between elevated anxiety and higher fear and sadness, lower soothability, and steeper longitudinal increases in approach. Autistic outcomes were unrelated to negative affect. These findings suggest early negative affect differentially predicts anxiety, not autistic symptoms, within FXS. Future research is warranted to determine the specificity of the relationship between negative affect and anxiety, as well as to explore potential moderators. Characterizing the relationship between early negative affect and anxiety within FXS may inform etiology and treatment considerations specific to children with FXS, as well as lend insight into precursors of anxiety disorders in other clinical groups and community samples.
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10. Vogan K. {{New recessive autism syndrome}}. {Nat Genet};2012 (Oct);44(10):1079.
