1. Casey JP, Magalhaes T, Conroy JM, Regan R, Shah N, Anney R, Shields DC, Abrahams BS, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bolton PF, Bourgeron T, Brennan S, Cali P, Correia C, Corsello C, Coutanche M, Dawson G, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Foley S, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Green J, Guter SJ, Hakonarson H, Holt R, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Lamb JA, Leboyer M, Le Couteur A, Leventhal BL, Lord C, Lund SC, Maestrini E, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Miller J, Minopoli F, Mirza GK, Munson J, Nelson SF, Nygren G, Oliveira G, Pagnamenta AT, Papanikolaou K, Parr JR, Parrini B, Pickles A, Pinto D, Piven J, Posey DJ, Poustka A, Poustka F, Ragoussis J, Roge B, Rutter ML, Sequeira AF, Soorya L, Sousa I, Sykes N, Stoppioni V, Tancredi R, Tauber M, Thompson AP, Thomson S, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Vorstman JA, Wallace S, Wang K, Wassink TH, White K, Wing K, Wittemeyer K, Yaspan BL, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Geschwind DH, Haines JL, Hallmayer J, Monaco AP, Nurnberger JI, Jr., Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vieland VJ, Wijsman EM, Green A, Gill M, Gallagher L, Vicente A, Ennis S. {{A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder}}. {Hum Genet};2011 (Oct 14)
Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
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2. Coury D. {{Very little high-quality evidence to support most medications for children with autism spectrum disorders}}. {J Pediatr};2011 (Nov);159(5):872-873.
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3. Golubchik P, Sever J, Weizman A. {{Low-Dose Quetiapine for Adolescents With Autistic Spectrum Disorder and Aggressive Behavior: Open-Label Trial}}. {Clin Neuropharmacol};2011 (Oct 8)
BACKGROUND:: Atypical antipsychotics may be useful in treating aggression associated with autistic spectrum disorder (ASD). We evaluated the effectiveness of low-dose quetiapine treatment in ASD adolescent patients with aggressive behavior. METHOD:: Eleven adolescent patients (8 boys and 3 girls) diagnosed with ASD, aged 13 to 17 years, were treated with quetiapine in an open-label study over an 8-week period. The severity of ASD, aggressive behavior, and sleep disturbances were assessed using the Clinical Global Impression-Severity (CGI-S), Overt Aggression Scale, and Child Sleep Habits Questionnaire, respectively. RESULTS:: Nonsignificant changes were obtained in autistic behavior after quetiapine treatment (CGI-S: 4.0 +/- 0.6 vs CGI-S after: 3.1 +/- 1.1; 2-tailed paired t = 1.93; df = 10; P = 0.08). Severity of aggressive behavior decreased significantly after quetiapine treatment (Overt Aggression Scale: 2.1 +/- 0.94 vs 1.3 +/- 0.64, respectively; 2-tailed paired t = 2.37; df = 10; P = 0.028). Sleep disturbances improved significantly (Child Sleep Habits Questionnaire: 49.0 +/- 12 vs 44.1 +/- 9.6; 2-tailed paired t = 2.98; df = 10; P = 0.014) and a positive correlation was found between the improvements in aggression and sleep (Spearman correlation: r = 0.43; N = 11; P = 0.013). Quetiapine was well tolerated. CONCLUSION:: Short-term low-dose quetiapine treatment may reduce aggression levels and improve sleep quality in adolescents with ASD.
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4. Shimmura C, Suda S, Tsuchiya KJ, Hashimoto K, Ohno K, Matsuzaki H, Iwata K, Matsumoto K, Wakuda T, Kameno Y, Suzuki K, Tsujii M, Nakamura K, Takei N, Mori N. {{Alteration of plasma glutamate and glutamine levels in children with high-functioning autism}}. {PLoS One};2011;6(10):e25340.
BACKGROUND: It has recently been hypothesized that hyperglutamatergia in the brain is involved in the pathophysiology of autism. However, there is no conclusive evidence of the validity of this hypothesis. As peripheral glutamate/glutamine levels have been reported to be correlated with those of the central nervous system, the authors examined whether the levels of 25 amino acids, including glutamate and glutamine, in the platelet-poor plasma of drug-naive, male children with high-functioning autism (HFA) would be altered compared with those of normal controls. METHODOLOGY/PRINCIPAL FINDINGS: Plasma levels of 25 amino acids in male children (N = 23) with HFA and normally developed healthy male controls (N = 22) were determined using high-performance liquid chromatography. Multiple testing was allowed for in the analyses. Compared with the normal control group, the HFA group had higher levels of plasma glutamate and lower levels of plasma glutamine. No significant group difference was found in the remaining 23 amino acids. The effect size (Cohen’s d) for glutamate and glutamine was large: 1.13 and 1.36, respectively. Using discriminant analysis with logistic regression, the two values of plasma glutamate and glutamine were shown to well-differentiate the HFA group from the control group; the rate of correct classification was 91%. CONCLUSIONS/SIGNIFICANCE: The present study suggests that plasma glutamate and glutamine levels can serve as a diagnostic tool for the early detection of autism, especially normal IQ autism. These findings indicate that glutamatergic abnormalities in the brain may be associated with the pathobiology of autism.
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5. Solvsten C, Nielsen AL. {{FMR1 CGG repeat lengths mediate different regulation of reporter gene expression in comparative transient and locus specific integration assays}}. {Gene};2011 (Oct 15);486(1-2):15-22.
The Fragile X mental retardation (FMR1) gene contains a polymorphic CGG trinucleotide repeat in the 5′-untranslated region. The repeat length in the normal population is between 5 and 54 repeats. A repeat length between 55 and 200 is defined as the pre-mutation repeat size. Elderly carriers of the pre-mutation can develop the progressive neurodegenerative disease Fragile X-associated tremor/ataxia syndrome (FXTAS). In FXTAS the FMR1 mRNA levels are increased and it is hypothesized that FXTAS is caused by a RNA gain of function mechanism. Repeat lengths beyond 200 CGGs are defined as the full-mutation and causes Fragile X-syndrome which is the most common inherited form of mental retardation. The full-mutation results in the absence of the FMR1 mRNA and protein, FMRP, through abnormal CpG methylation and FMR1 gene silencing. In this report we have used the Flp-In T-REx system to generate locus directed stable cell lines harboring the FMR1 5′-UTR with varying CGG repeat lengths in front of a reporter gene. By this system the influence of various CGG repeat lengths for reporter gene expression can be comparatively examined in cell lines where the only genetic difference is CGG repeat lengths. In such cell lines we find that a full-mutation CGG repeat confers inhibition of reporter gene expression, whereas a pre-mutation CGG repeat did not increase reporter gene expression. In transient transfection assays using the same expression vectors the pre-mutation and full-mutation CGG repeats increased reporter gene expression. This study shows that locus directed integration of model FMR1 CGG transgenes could be a new basic tool to further elucidating the basic molecular mechanisms behind transcriptional deregulation of the FMR1 gene in fragile X-syndrome and FXTAS.
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6. Sugranyes G, Kyriakopoulos M, Corrigall R, Taylor E, Frangou S. {{Autism spectrum disorders and schizophrenia: meta-analysis of the neural correlates of social cognition}}. {PLoS One};2011;6(10):e25322.
CONTEXT: Impaired social cognition is a cardinal feature of Autism Spectrum Disorders (ASD) and Schizophrenia (SZ). However, the functional neuroanatomy of social cognition in either disorder remains unclear due to variability in primary literature. Additionally, it is not known whether deficits in ASD and SZ arise from similar or disease-specific disruption of the social cognition network. OBJECTIVE: To identify regions most robustly implicated in social cognition processing in SZ and ASD. DATA SOURCES: Systematic review of English language articles using MEDLINE (1995-2010) and reference lists. STUDY SELECTION: Studies were required to use fMRI to compare ASD or SZ subjects to a matched healthy control group, provide coordinates in standard stereotactic space, and employ standardized facial emotion recognition (FER) or theory of mind (TOM) paradigms. DATA EXTRACTION: Activation foci from studies meeting inclusion criteria (n = 33) were subjected to a quantitative voxel-based meta-analysis using activation likelihood estimation, and encompassed 146 subjects with ASD, 336 SZ patients and 492 healthy controls. RESULTS: Both SZ and ASD showed medial prefrontal hypoactivation, which was more pronounced in ASD, while ventrolateral prefrontal dysfunction was associated mostly with SZ. Amygdala hypoactivation was observed in SZ patients during FER and in ASD during more complex ToM tasks. Both disorders were associated with hypoactivation within the Superior Temporal Sulcus (STS) during ToM tasks, but activation in these regions was increased in ASD during affect processing. Disease-specific differences were noted in somatosensory engagement, which was increased in SZ and decreased in ASD. Reduced thalamic activation was uniquely seen in SZ. CONCLUSIONS: Reduced frontolimbic and STS engagement emerged as a shared feature of social cognition deficits in SZ and ASD. However, there were disease- and stimulus-specific differences. These findings may aid future studies on SZ and ASD and facilitate the formulation of new hypotheses regarding their pathophysiology.
