Pubmed du 24/06/09

jeudi 25 juin 2009

1. Bourgeron T. A synaptic trek to autism. Curr Opin Neurobiol ;2009 (Jun 20)

Autism spectrum disorders (ASD) are diagnosed on the basis of three behavioral features namely deficits in social communication, absence or delay in language, and stereotypy. The susceptibility genes to ASD remain largely unknown, but two major pathways are emerging. Mutations in TSC1/TSC2, NF1, or PTEN activate the mTOR/PI3K pathway and lead to syndromic ASD with tuberous sclerosis, neurofibromatosis, or macrocephaly. Mutations in NLGN3/4, SHANK3, or NRXN1 alter synaptic function and lead to mental retardation, typical autism, or Asperger syndrome. The mTOR/PI3K pathway is associated with abnormal cellular/synaptic growth rate, whereas the NRXN-NLGN-SHANK pathway is associated with synaptogenesis and imbalance between excitatory and inhibitory currents. Taken together, these data strongly suggest that abnormal synaptic homeostasis represent a risk factor to ASD.

2. Campbell DB, Warren D, Sutcliffe JS, Lee EB, Levitt P. Association of MET with social and communication phenotypes in individuals with autism spectrum disorder. Am J Med Genet B Neuropsychiatr Genet ;2009 (Jun 22)

Autism is a complex neurodevelopmental disorder diagnosed by impairments in social interaction, communication, and behavioral flexibility. Autism is highly heritable, but it is not known whether a genetic risk factor contributes to all three core domains of the disorder or autism results from the confluence of multiple genetic risk factors for each domain. We and others reported previously association of variants in the gene encoding the MET receptor tyrosine kinase in five independent samples. We further described enriched association of the MET promoter variant rs1858830 C allele in families with co-occurring autism and gastrointestinal conditions. To test the contribution of this functional MET promoter variant to the domains of autism, we analyzed its association with quantitative scores derived from three instruments used to diagnose and describe autism phenotypes : the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observation Schedule (ADOS), and both the parent and the teacher report forms of the Social Responsiveness Scale (SRS). In 748 individuals from 367 families, the transmission of the MET C allele from parent to child was consistently associated with both social and communication phenotypes of autism. Stratification by gastrointestinal conditions revealed a similar pattern of association with both social and communication phenotypes in 242 individuals with autism from 118 families with co-occurring gastrointestinal conditions, but a lack of association with any domain in 181 individuals from 96 families with ASD and no co-occurring gastrointestinal condition. These data indicate that the MET C allele influences at least two of the three domains of the autism triad. (c) 2009 Wiley-Liss, Inc.

3. Daoud H, Bonnet-Brilhault F, Vedrine S, Demattei MV, Vourc’h P, Bayou N, Andres CR, Barthelemy C, Laumonnier F, Briault S. Autism and Nonsyndromic Mental Retardation Associated with a De Novo Mutation in the NLGN4X Gene Promoter Causing an Increased Expression Level. Biol Psychiatry ;2009 (Jun 20)

BACKGROUND : Pathogenic mutations in the X-linked Neuroligin 4 gene (NLGN4X) in autism spectrum disorders (ASDs) and/or mental retardation (MR) are rare. However, nothing is known regarding a possible altered expression level of NLGN4X that would be caused by mutations in regulatory sequences. We investigated this issue by analyzing these regions in patients with ASDs and no mutation in the NLGN4X coding sequence. METHODS : We studied 96 patients who met all DSM-IV criteria for autism. The entire coding sequence and the regulatory sequences of the NLGN4X gene were analyzed by polymerase chain reaction and direct sequencing. RESULTS : We identified a de novo 1 base pair (-335G>A) substitution located in the promoter region in a patient with autism and nonsyndromic profound MR. Interestingly, this variation is associated with an increased level of the NLGN4X transcript in the patient compared with male control subjects as well as his father. Further in vitro luciferase reporter and electrophoretic mobility shift assays confirmed, respectively, that this mutation increases gene expression and is probably caused by altered binding of transcription factors in the mutated promoter sequence. CONCLUSIONS : This result brings further insight about the phenotypic spectrum of NLGN4X mutations and suggests that the analysis of the expression level of NLGN4X might detect new cases.

4. Jones CR, Happe F, Baird G, Simonoff E, Marsden AJ, Tregay J, Phillips RJ, Goswami U, Thomson JM, Charman T. Auditory Discrimination and Auditory Sensory Behaviours in Autism Spectrum Disorders. Neuropsychologia ;2009 (Jun 19)

It has been hypothesised that auditory processing may be enhanced in autism spectrum disorders (ASD). We tested auditory discrimination ability in 72 adolescents with ASD (39 childhood autism ; 33 other ASD) and 57 IQ and age-matched controls, assessing their capacity for successful discrimination of the frequency, intensity and duration differences in pairs of sounds. At the group level, auditory discrimination ability did not differ between the adolescents with and without ASD. However, we found a subgroup of 20% of individuals in the ASD group who showed ’exceptional’ frequency discrimination skills (defined as 1.65 SDs above the control mean) and who were characterised by average intellectual ability and delayed language onset. Auditory sensory behaviours (i.e. behaviours in response to auditory sensory input) are common in ASD and we hypothesised that these would relate to auditory discrimination ability. For the ASD group, poor performers on the intensity discrimination task reported more auditory sensory behaviours associated with coping with loudness levels. Conversely, those who performed well on the duration discrimination task reported more auditory sensory behaviours across the full range measured. Frequency discrimination ability did not associate with auditory sensory behaviours. We therefore conclude that (i) enhanced frequency discrimination is present in around 1 in 5 individuals with ASD and may represent a specific phenotype ; and (ii) individual differences in auditory discrimination ability in ASD may influence the expression of auditory sensory behaviours by modulating the degree to which sounds are detected or missed in the environment.

5. Kumar RA, Sudi J, Babatz TD, Brune CW, Oswald D, Yen M, Nowak NJ, Cook EH, Christian SL, Dobyns WB. A de novo 1p34.2 microdeletion identifies the synaptic vesicle gene RIMS3 as a novel candidate for autism. J Med Genet ;2009 (Jun 21)

BACKGROUND : We report a child with autism and mild microcephaly who was found to have a de novo 3.3 Mb microdeletion on chromosome 1p34.2p34.3. Here, we test the hypothesis that this microdeletion contains one or more genes that underlie the autism phenotype in this child and in other children with autism spectrum disorders. METHODS : To search for submicroscopic chromosomal rearrangements in the child, we performed array comparative genomic hybridization (aCGH) using a 19K whole-genome human BAC array and the Illumina 610-Quad BeadChip microarray. Ingenuity Pathway Analysis (IPA) was used to construct functional biological networks to identify candidate autism genes. To identify putative functional variants in candidate genes, we performed mutation screening using PCR-based Sanger sequencing in 512 unrelated autism patients and 462 control subjects. RESULTS : We identified a de novo 3.3 Mb deletion containing 43 genes in chromosome 1p34.2p34.3 that we confirmed using fluorescence in situ hybridization (FISH). Literature review and bioinformatics analyses identified RIMS3 (Regulating Synaptic Membrane Exocytosis 3) as the most promising autism candidate gene. Mutation screening of this gene in autism patients identified five inherited coding variants, including one (p.E177A) that segregated with the autism phenotype in a sibship, was predicted to be deleterious, and was absent in 1,161 controls. CONCLUSIONS : Our case report and mutation screening data suggest that RIMS3 is an autism causative or contributory gene. Functional studies of RIMS3 variants such as p.E177A should provide additional insight into the role of synaptic proteins in the pathophysiology of autism.

6. Posserud M, Lundervold AJ, Lie SA, Gillberg C. The prevalence of autism spectrum disorders : impact of diagnostic instrument and non-response bias. Soc Psychiatry Psychiatr Epidemiol ;2009 (Jun 24)

BACKGROUND : A large part of the variability in rates of autism spectrum disorders (ASD) across studies is non-aetiologic, and can be explained by differences in diagnostic criteria, case-finding method, and other issues of study design. AIM : To investigate the effects on ASD prevalence of two methodological issues ; non-response bias and case ascertainment. We compared the findings of using a semi-structured parent interview versus in-depth clinical assessment, including an ASD specific interview. We further explored whether including information on non-responders affected the ASD prevalence estimate. METHOD : A total population of 7- to 9-year olds (N = 9,430) was screened for ASD with the autism spectrum screening questionnaire (ASSQ) in the Bergen Child Study (BCS). Children scoring above the 98th percentile on parent and/or teacher ASSQ were invited to participate in the second and subsequently in the third phase of the BCS where they were assessed for ASD using the Development and Well-Being Assessment (DAWBA), and the Diagnostic Interview for Social and Communication disorders (DISCO), respectively. RESULTS : Clinical assessment using DISCO confirmed all DAWBA ASD cases, but also diagnosed additional cases. DISCO-generated minimum prevalence for ASD was 0.21%, whereas estimated prevalence was 0.72%, increasing to 0.87% when adjusting for non-responders. The DAWBA estimate for the same population was 0.44%. CONCLUSION : Large variances in prevalence rates across studies can be explained by methodological differences. Both information about assessment method and non-response are crucial when interpreting prevalence rates of ASD.

7. Sanders JL. Qualitative or Quantitative Differences Between Asperger’s Disorder and Autism ? Historical Considerations. J Autism Dev Disord ;2009 (Jun 23)

The histories of autism and Asperger’s Disorder (AD), based on original contributions by Kanner and Asperger, are reviewed in relation to DSM-IV diagnostic criteria. Their original articles appear to have influenced the distinction between AD and autism made in the DSM-IV. Based on up-to-date empirical research, however, it appears that AD and autism are not qualitatively distinct disorders, but are different quantitative manifestations of the same disorder. The differences between AD and autism may be a function of individual variability in these areas, not the manifestation of qualitatively distinct disorders. The DSM-IV criteria for AD and autism need to be considered with their historical developments, and based on empirical evidence, the DSM-IV diagnostic criteria may be subject to critical review.

8. Simon EW, Haas-Givler B, Finucane B. A longitudinal follow-up study of autistic symptoms in children and adults with duplications of 15q11-13. Am J Med Genet B Neuropsychiatr Genet ;2009 (Jun 22)

We completed a longitudinal follow-up of autistic symptoms in a cohort of children and young adults with duplications of chromosome 15q11-13. In our initial investigation of 29 individuals, tentative conclusions were drawn based on cross-sectional data suggesting that autistic symptoms increased with age, most specifically in the area of social interaction. We were able to re-assess 22 individuals from the original study an average of 7 years later using the same standardized autism screening measure. As predicted, autistic symptoms were found to increase for the younger children in the cohort but remained constant for the older participants. This global change in autistic symptoms among the younger children could not be ascribed to any particular autism subscale and reflects small but cumulatively significant increases across several domains. (c) 2009 Wiley-Liss, Inc.


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