Pubmed du 15/12/12

Pubmed du jour

2012-12-15 12:03:50

1. Archibald AD, Hickerton CL, Jaques AM, Wake S, Cohen J, Metcalfe SA. {{« It’s about having the choice »: Stakeholder perceptions of population-based genetic carrier screening for fragile X syndrome}}. {Am J Med Genet A};2012 (Dec 13)
This project explored, the views of key stakeholders regarding population-based genetic carrier screening for fragile X syndrome (FXS). Interviews and focus groups were conducted with healthcare providers, relatives of individuals with FXS and members of the general population. Data were transcribed verbatim and coded into themes. 188 individuals took part in this study. Perceived benefits of carrier screening included: learning the risk of having a child with FXS; learning the risk of fragile X-associated primary ovarian insufficiency; and the opportunity for carriers to access reproductive options. Concerns included: the emotional impact of screening and receiving a carrier result; the predictive testing nature of the carrier test with respect to fragile X-associated tremor/ataxia syndrome; potential confusion created by receiving an intermediate result; and implications of genetic screening for society. Overall, population-based genetic carrier screening was perceived to be acceptable provided it is optional and offered at an appropriate stage of life. With the support of the participants to promote individual choice by offering a population-based carrier screening program for FXS, it is essential to carefully consider how screening might be offered in order to ensure broad accessibility and facilitation of decision-making. (c) 2012 Wiley Periodicals, Inc.

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2. Crunkhorn S. {{Neurological disorders: Targeting translation in autism}}. {Nat Rev Drug Discov};2012 (Dec 14)

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3. Das DK, Mehta B, Menon SR, Raha S, Udani V. {{Novel Mutations in Cyclin-Dependent Kinase-Like 5 (CDKL5) Gene in Indian Cases of Rett Syndrome}}. {Neuromolecular Med};2012 (Dec 15)
Rett syndrome is a severe neurodevelopmental disorder, almost exclusively affecting females and characterized by a wide spectrum of clinical manifestations. Both the classic and atypical forms of Rett syndrome are primarily due to mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with atypical Rett syndrome, X-linked infantile spasms sharing common features of generally early-onset seizures and mental retardation. CDKL5 is known as serine/threonine protein kinase 9 (STK9) and is mapped to the Xp22 region. It has a conserved serine/threonine kinase domain within its amino terminus and a large C-terminal region. Disease-causing mutations are distributed in both the amino terminal domain and in the large C-terminal domain. We have screened the CDKL5 gene in 44 patients with atypical Rett syndrome who had tested negative for MECP2 gene mutations and have identified 6 sequence variants, out of which three were novel and three known mutations. Two of these novel mutations p.V966I and p.A1011V were missense and p.H589H a silent mutation. Other known mutations identified were p.V999M, p.Q791P and p.T734A. Sequence homology for all the mutations revealed that the two mutations (p.Q791P and p.T734A) were conserved across species. This indicated the importance of these residues in structure and function of the protein. The damaging effects of these mutations were analysed in silico using PolyPhen-2 online software. The PolyPhen-2 scores of p.Q791P and p.T734A were 0.998 and 0.48, revealing that these mutations could be deleterious and might have potential functional effect. All other mutations had a low score suggesting that they might not alter the activity of CDKL5. We have also analysed the position of the mutations in the CDKL5 protein and found that all the mutations were present in the C-terminal domain of the protein. The C-terminal domain is required for cellular localization through protein-protein interaction; any mutations in this domain might alter this function of the protein. This is the first report from India showing the mutation in CDKL5 gene in Indian cases of Rett syndrome. Our study emphasizes the role of CDKL5 mutation screening in cases of atypical Rett syndrome with congenital seizure variant.

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4. Equit M, Piro-Hussong A, Niemczyk J, Curfs L, von Gontard A. {{Elimination disorders in persons with prader-willi and fragile-X syndromes}}. {Neurourol Urodyn};2012 (Dec 12)
AIMS: Elimination disorders are common in typically developing children. Only few studies have addressed elimination disorders in persons with intellectual disability (ID)-and even fewer studies in those with specific syndromes. The aim of the study was to investigate the rates of elimination disorders and behavioral symptoms in persons with Prader-Willi (PWS) and Fragile-X syndromes (FXS) in a large sample. METHODS: Three hundred fifty-seven persons with PWS or FXS were recruited through parent self-help groups. A questionnaire regarding elimination symptoms, as well as the child behavior checklist (CBCL)/young adult behavior checklist (YABCL) were filled out by parents or caregivers. RESULTS: The sample included 191 persons with PWS (54.5% male) with a mean age of 20.0 years and 166 persons with FXS (92.2% male) with a mean age of 15.4 years. Persons with FXS were significantly more often affected by elimination disorders. 29.3% of persons with PWS and 48.8% of persons with FXS had at least one elimination disorder. Persons with FXS also had more often DUI (29.5% vs. 12.0%) and FI (28.9% vs. 12.6%). Rates of NE were similar in both groups (22.0% in PWS vs. 28.9% in FXS). Young adults with PWS had more behavioral symptoms in the clinical range (70.8% vs. 48.3%). Incontinence and behavioral symptoms were significantly associated in persons with FXS. CONCLUSIONS: NE, DUI, and FI are very common in persons with FXS and PWS and are associated with other behavioral symptoms in persons with FXS. They persist into adulthood. Early assessment and treatment are recommended. Neurourol. Urodynam. (c) 2012 Wiley Periodicals, Inc.

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5. Falter CM, Braeutigam S, Nathan R, Carrington S, Bailey AJ. {{Enhanced Access to Early Visual Processing of Perceptual Simultaneity in Autism Spectrum Disorders}}. {J Autism Dev Disord};2012 (Dec 14)
We compared judgements of the simultaneity or asynchrony of visual stimuli in individuals with autism spectrum disorders (ASD) and typically-developing controls using Magnetoencephalography (MEG). Two vertical bars were presented simultaneously or non-simultaneously with two different stimulus onset delays. Participants with ASD distinguished significantly better between real simultaneity (0 ms delay between two stimuli) and apparent simultaneity (17 ms delay between two stimuli) than controls. In line with the increased sensitivity, event-related MEG activity showed increased differential responses for simultaneity versus apparent simultaneity. The strongest evoked potentials, observed over occipital cortices at about 130 ms, were correlated with performance differences in the ASD group only. Superior access to early visual brain processes in ASD might underlie increased resolution of visual events in perception.

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6. Li JP, Law T, Lam GY, To CK. {{Role of sentence-final particles and prosody in irony comprehension in Cantonese-speaking children with and without Autism Spectrum Disorders}}. {Clin Linguist Phon};2013 (Jan);27(1):18-32.

English-speaking children with Autism Spectrum Disorders (ASD) are less capable of using prosodic cues such as intonation for irony comprehension. Prosodic cues, in particular intonation, in Cantonese are relatively restricted while sentence-final particles (SFPs) may be used for this pragmatic function. This study investigated the use of prosodic cues and SFPs in irony comprehension in Cantonese-speaking children with and without ASD. Thirteen children with ASD (8;3-12;9) were language-matched with 13 typically developing (TD) peers. By manipulating prosodic cues and SFPs, 16 stories with an ironic remark were constructed. Participants had to judge the speaker’s belief and intention. Both groups performed similarly well in judging the speaker’s belief. For the speaker’s intention, the TD group relied more on SFPs. The ASD group performed significantly poorer and did not rely on either cue. SFPs may play a salient role in Cantonese irony comprehension. The differences between the two groups were discussed by considering the literature on theory of mind.

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7. Lu AT, Dai X, Martinez-Agosto JA, Cantor RM. {{Support for calcium channel gene defects in autism spectrum disorders}}. {Mol Autism};2012 (Dec 15);3(1):18.

ABSTRACT: BACKGROUND: Alternation of synaptic homeostasis is a biological process whose disruption might predispose children to autism spectrum disorders (ASD). Calcium channel genes (CCG) contribute to modulating neuronal function and evidence implicating CCG in ASD has been accumulating. We conducted a targeted association analysis of CCG using existing genome-wide association study (GWAS) data and imputation methods in a combined sample of parent/affected child trios from two ASD family collections to explore this hypothesis. METHODS: A total of 2,176 single-nucleotide polymorphisms (SNP) (703 genotyped and 1,473 imputed) covering the genes that encode the alpha1 subunit proteins of 10 calcium channels were tested for association with ASD in a combined sample of 2,781 parent/affected child trios from 543 multiplex Caucasian ASD families from the Autism Genetics Resource Exchange (AGRE) and 1,651 multiplex and simplex Caucasian ASD families from the Autism Genome Project (AGP). SNP imputation using IMPUTE2 and a combined reference panel from the HapMap3 and the 1,000 Genomes Project increased coverage density of the CCG. Family-based association was tested using the FBAT software which controls for population stratification and accounts for the non-independence of siblings within multiplex families. The level of significance for association was set at 2.3E-05, providing a Bonferroni correction for this targeted 10-gene panel. RESULTS: Four SNPs in three CCGs were associated with ASD. One, rs10848653, is located in CACNA1C, a gene in which rare de novo mutations are responsible for Timothy syndrome, a Mendelian disorder that features ASD. Two others, rs198538 and rs198545, located in CACN1G, and a fourth, rs5750860, located in CACNA1I, are in CCGs that encode T-type calcium channels, genes with previous ASD associations. CONCLUSIONS: These associations support a role for common CCG SNPs in ASD.

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8. McLeod F, Ganley R, Williams L, Selfridge J, Bird A, Cobb SR. {{Reduced seizure threshold and altered network oscillatory properties in a mouse model of Rett syndrome}}. {Neuroscience};2012 (Dec 10)
Rett syndrome (RTT) is a disorder with a pronounced neurological phenotype and is caused mainly by mutations in the X-linked gene MECP2. A common feature of RTT is an abnormal EEG and a propensity for seizures. In the current study we aimed to assess brain network excitability and seizure propensity in a mouse model of RTT. Mice in which Mecp2 expression was silenced (Mecp2(stop/y)) showed a higher seizure score (mean = 6 +/- 0.8 compared to 4 +/- 0.2 in wild-type, WT) and more rapid seizure onset (median onset = 10 mins in Mecp2(stop/y) and 32 mins in WT) when challenged with the convulsant drug kainic acid (25mg/Kg). Hippocampal slices from Mecp2(stop/y) brain displayed no spontaneous field potential activities under control conditions but showed higher power gamma frequency field potential oscillations compared to WT in response to kainic acid (400 nM) in vitro. Brain slices challenged with the GABA(A) receptor antagonist bicuculline (0.1-10muM) and the potassium channel blocker 4-aminopyridine (1-50muM) also revealed differences between genotypes with hippocampal circuits from Mecp2(stop/y) mouse slices showing enhanced epileptiform burst duration and frequency. In contrast to these network level findings, single cell analysis of pyramidal cells by whole-cell patch clamp recording revealed no detectable differences in synaptic or biophysical properties between MeCP2-containing and MeCP2-deficient neurons. These data support the proposal that loss of MeCP2 alters network level excitability in the brain to promote epileptogenesis.

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9. McMahon CM, Vismara LA, Solomon M. {{Measuring Changes in Social Behavior During a Social Skills Intervention for Higher-Functioning Children and Adolescents with Autism Spectrum Disorder}}. {J Autism Dev Disord};2012 (Dec 14)
The social behavior of children and adolescents with Autism Spectrum Disorder was evaluated weekly over 19 weeks of a social skills training program. Participants’ vocalizations were coded as initiating, responding, or other (e.g., self-talk). Participants’ interactions were coded as dyadic peer interactions, dyadic leader interactions, interactions with a group of peers, interactions with a group of peer(s) and leader(s), or time spent by self. Over the course of the intervention, participants made fewer initiating and other vocalizations, more responding vocalizations, spent more time interacting with a group of peers, and spent marginally less time interacting with a leader. Gender, age, and intervention attendance effects on social behavior are also noted.

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10. Onore CE, Nordahl CW, Young GS, Van de Water JA, Rogers SJ, Ashwood P. {{Levels of soluble platelet endothelial cell adhesion molecule-1 and p-selectin are decreased in children with autism spectrum disorder}}. {Biol Psychiatry};2012 (Dec 15);72(12):1020-1025.

BACKGROUND: Although the etiopathology of autism spectrum disorder (ASD) is not clear, there is increasing evidence that dysfunction in the immune system affects many children with ASD. Findings of immune dysfunction in ASD include increases in inflammatory cytokines, chemokines, and microglial activity in brain tissue and cerebrospinal fluid, as well as abnormal peripheral immune cell function. METHODS: Adhesion molecules, such as platelet endothelial adhesion molecule-1 (PECAM-1), intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), P-selectin, and L-selectin, function to facilitate leukocyte transendothelial migration. We assessed concentrations of soluble adhesion molecules, sPECAM-1, sICAM-1, sVCAM-1, sP-selectin, and sL-selectin in the plasma of 49 participants with ASD and 31 typically developing controls of the same age, all of whom were enrolled as part of the Autism Phenome Project. Behavioral assessment, the levels of soluble adhesion molecules, and head circumference were compared in the same subjects. RESULTS: Levels of sPECAM-1 and sP-selectin were significantly reduced in the ASD group compared to typically developing controls (p < .02). Soluble PECAM-1 levels were negatively associated with repetitive behavior and abnormal brain growth in children with ASD (p = .03). CONCLUSIONS: Because adhesion molecules modulate the permeability and signaling at the blood-brain barrier as well as leukocyte infiltration into the central nervous system, the current data suggest a role for these molecules in the complex pathophysiology of ASD.

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11. Pettygrove S, Pinborough-Zimmerman J, John Meaney F, Van Naarden Braun K, Nicholas J, Miller L, Miller J, Rice C. {{Predictors of Ascertainment of Autism Spectrum Disorders Across Nine US Communities}}. {J Autism Dev Disord};2012 (Dec 14)
Autism spectrum disorders (ASD) prevalence estimates derived from a single data source under-identify children and provide a biased profile of case characteristics. We analyzed characteristics of 1,919 children with ASD identified by the Autism and Developmental Disabilities Monitoring Network. Cases ascertained only at education sources were compared to those identified at health sources. 38 % were education-only. These were older at their earliest evaluation (54.5 vs. 42.0 months, p < 0.001) and earliest ASD diagnosis (62 vs. 53 months, p < 0.001). More lived in census blocks with lower adult education (p < 0.001). Lower educational attainment of adults in census blocks of residence of education-only cases suggests disparities in access to clinical services with the schools providing crucial services to many families.

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12. Saxena V, Ramdas S, Ochoa CR, Wallace D, Bhide P, Kohane I. {{Structural, Genetic, and Functional Signatures of Disordered Neuro-Immunological Development in Autism Spectrum Disorder}}. {PLoS One};2012;7(12):e48835.

BACKGROUND: Numerous linkage studies have been performed in pedigrees of Autism Spectrum Disorders, and these studies point to diverse loci and etiologies of autism in different pedigrees. The underlying pattern may be identified by an integrative approach, especially since ASD is a complex disorder manifested through many loci. METHOD: Autism spectrum disorder (ASD) was studied through two different and independent genome-scale measurement modalities. We analyzed the results of copy number variation in autism and triangulated these with linkage studies. RESULTS: Consistently across both genome-scale measurements, the same two molecular themes emerged: immune/chemokine pathways and developmental pathways. CONCLUSION: Linkage studies in aggregate do indeed share a thematic consistency, one which structural analyses recapitulate with high significance. These results also show for the first time that genomic profiling of pathways using a recombination distance metric can capture pathways that are consistent with those obtained from copy number variations (CNV).

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13. Stevenson RA. {{Using functional connectivity analyses to investigate the bases of autism spectrum disorders and other clinical populations}}. {J Neurosci};2012 (Dec 12);32(50):17933-17934.

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14. Walker L, Gozzi M, Lenroot R, Thurm A, Behseta B, Swedo S, Pierpaoli C. {{Diffusion tensor imaging in young children with autism: biological effects and potential confounds}}. {Biol Psychiatry};2012 (Dec 15);72(12):1043-1051.

BACKGROUND: Diffusion tensor imaging (DTI) has been used over the past decade to study structural differences in the brains of children with autism compared with typically developing children. These studies generally find reduced fractional anisotropy (FA) and increased mean diffusivity (MD) in children with autism; however, the regional pattern of findings varies greatly. METHODS: We used DTI to investigate the brains of sedated children with autism (n = 39) and naturally asleep typically developing children (n = 39) between 2 and 8 years of age. Tract based spatial statistics and whole brain voxel-wise analysis were performed to investigate the regional distribution of differences between groups. RESULTS: In children with autism, we found significantly reduced FA in widespread regions and increased MD only in posterior brain regions. Significant age x group interaction was found, indicating a difference in developmental trends of FA and MD between children with autism and typically developing children. The magnitude of the measured differences between groups was small, on the order of approximately 1%-2%. Subjects and control subjects showed distinct regional differences in imaging artifacts that can affect DTI measures. CONCLUSIONS: We found statistically significant differences in DTI metrics between children with autism and typically developing children, including different developmental trends of these metrics. However, this study indicates that between-group differences in DTI studies of autism should be interpreted with caution, because their small magnitude make these measurements particularly vulnerable to the effects of artifacts and confounds, which might lead to false positive and/or false negative biological inferences.

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