1. Ben-David E, Granot-Hershkovitz E, Monderer-Rothkoff G, Lerer E, Levi S, Yaari M, Ebstein RP, Yirmiya N, Shifman S. {{Identification of a functional rare variant in autism using genome-wide screen for monoallelic expression}}. Hum Mol Genet. 2011; 20(18): 3632-41.
Recent work has led to the identification of several susceptibility genes for autism spectrum disorder (ASD) and an increased appreciation of the importance of rare and de novo mutations. Some of the mutations may be very hard to detect using current strategies, especially if they are located in regulatory regions. We present a new approach to identify functional mutations that exploit the fact that many rare mutations disrupt the expression of genes from a single parental chromosome. The method incorporates measurement of the relative expression of the two copies of a gene across the genome using single nucleotide polymorphism arrays. Allelic expression has been successfully used to study common regulatory polymorphisms; however, it has not been implemented as a screening tool for rare mutation. We tested the potential of this approach by screening for monoallelic expression in lymphoblastoid cell lines derived from a small ASD cohort. After filtering regions shared across multiple samples, we identified genes showing monoallelic expression in specific ASD samples. Validation by quantitative sequencing demonstrated that the genes (or only part of them) are monoallelic expressed. The genes included both previously suspected risk factors for ASD and novel candidates. In one gene, named autism susceptibility candidate 2 (AUTS2), we identified a rare duplication that is likely to be the cause of monoallelic expression. Our results demonstrate the ability to identify rare regulatory mutations using genome-wide allelic expression screens, capabilities that could be expanded to other diseases, especially those with suspected involvement of rare dominantly acting mutations.
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2. Blackwell E, Ceman S. {{A new regulatory function of the region proximal to the RGG box in the Fragile X mental retardation protein}}. J Cell Sci. 2011; 124(Pt 18): 3060-5.
Fragile X mental retardation protein (FMRP) is required for normal cognition. FMRP has two autosomal paralogs, which although similar to FMRP, cannot compensate for the loss of FMRP expression in brain. The arginine- and glycine-rich region of FMRP (the RGG box) is unique; it is the high-affinity RNA-binding motif in FMRP and is encoded by exon 15. Alternative splicing occurs in the 5′ end of exon 15, which is predicted to affect the structure of the distally encoded RGG box. Here, we provide evidence that isoform 3, which removes 25 amino acids from the 5′ end of exon 15, has an altered conformation that reduces binding of a specific antibody and renders the RGG box unable to efficiently associate with polyribosomes. Isoform 3 is also compromised in its ability to form granules and to associate with a key messenger ribonucleoprotein Yb1 (also known as p50, NSEP1 and YBX1). Significantly, these functions are similarly compromised when the RGG box is absent from FMRP, suggesting an important regulatory role of the N-terminal region encoded by exon 15.
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3. Breslin CM, Rudisill ME. {{The Effect of Visual Supports on Performance of the TGMD-2 for Children With Autism Spectrum Disorder}}. Adapt Phys Activ Q. 2011; 28(4): 342-53.
The purpose of this study was to examine the effects of visual supports on the performance of the Test of Gross Motor Development (TGMD-2) for children with autism spectrum disorder (ASD). Participants (N = 22) performed the TGMD-2 under three different protocols (traditional protocol, picture task card protocol, and picture activity schedule protocol). Gross motor quotient scores on the TGMD-2 were measured and statistically analyzed using a within-subjects repeated-measures ANOVA. Results indicated statistically significant differences between protocols, while post hoc tests indicated that the picture task card condition produced significantly higher gross motor quotient scores than the traditional protocol and the picture activity schedule. The results suggest that more accurate gross motor quotient scores on the TGMD-2 by children with ASD can be elicited using the picture task card protocol.
4. Copur M, Erdogan A. {{Risperidone Rechallenge for Marked Liver Function Test Abnormalities in an Autistic Child}}. Recent Pat Endocr Metab Immune Drug Discov. 2011.
Risperidone have been reported to commonly lead to asymptomatic elevation of liver enzymes in adult population, and recently in children and adolescents. Results from controlled clinical trials, reports of spontaneous adverse events, and published studies/ case reports suggest that severe hepatotoxicity may be rare but can occur in the pediatric population. In the following case report, we describe a 5-year-old male patient diagnosed as autism with severe distruptive behavior. Substantial improvement was achieved with risperidone therapy. Increase in liver enzymes at the beginning of the risperidone treatment was successfully managed with multidisciplinary approach as the treatment was initially withdrawn, afterwards restarted and carefully continued. We demonstrated that risperidone may be cautiously rechallenged in selected pediatric patients who showed marked psychiatric improvement with risperidone on the face of liver enzymes elevation. Some important patents on risperidone delivery and their use for the treatment of autism are also outlined.
5. Gantman A, Kapp SK, Orenski K, Laugeson EA. {{Social Skills Training for Young Adults with High-Functioning Autism Spectrum Disorders: A Randomized Controlled Pilot Study}}. J Autism Dev Disord. 2011.
Despite the psychosocial difficulties common among young adults with autism spectrum disorders (ASD), little to no evidence-based social skills interventions exist for this population. Using a randomized controlled trial (RCT) design, the current study tested the effectiveness of an evidence-based, caregiver-assisted social skills intervention known as PEERS for Young Adults with high-functioning young adults with ASD (ages 18-23) using self- and caregiver-report measures. Results revealed that treated young adults reported significantly less loneliness and improved social skills knowledge, while caregivers reported significant improvements in young adults’ overall social skills, social responsiveness, empathy, and frequency of get-togethers. Results support the effectiveness of using this caregiver-assisted, manualized intervention for young adults with ASD.
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6. Miriam J, Szeftel R, Sulman-Smith H, Mandelbaum S, Vargas M, Ishak W. {{Use of telepsychiatry to train medical students in developmental disabilities}}. Acad Psychiatry. 2011; 35(4): 268-9.
7. Scheel C, Rotarska-Jagiela A, Schilbach L, Lehnhardt FG, Krug B, Vogeley K, Tepest R. {{Imaging derived cortical thickness reduction in high-functioning autism: Key regions and temporal slope}}. Neuroimage. 2011; 58(2): 391-400.
Cortical thickness (CT) changes possibly contribute to the complex symptomatology of autism. The aberrant developmental trajectories underlying such differences in certain brain regions and their continuation in adulthood are a matter of intense debate. We studied 28 adults with high-functioning autism (HFA) and 28 control subjects matched for age, gender, IQ and handedness. A surface-based whole brain analysis utilizing FreeSurfer was employed to detect CT differences between the two diagnostic groups and to investigate the time course of age-related changes. Direct comparison with control subjects revealed thinner cortex in HFA in the posterior superior temporal sulcus (pSTS) of the left hemisphere. Considering the time course of CT development we found clusters around the pSTS and cuneus in the left and the paracentral lobule in the right hemisphere to be thinner in HFA with comparable age-related slopes in patients and controls. Conversely, we found clusters around the supramarginal gyrus and inferior parietal lobule (IPL) in the left and the precentral and postcentral gyrus in the right hemisphere to be thinner in HFA, but with different age-related slopes in patients and controls. In the latter regions CT showed a steady decrease in controls but no analogous thinning in HFA. CT analyses contribute in characterizing neuroanatomical correlates of HFA. Reduced CT is present in brain regions involved in social cognition. Furthermore, our results demonstrate that aberrant brain development leading to such differences is proceeding throughout adulthood. Discrepancies in prior morphometric studies may be induced by the complex time course of cortical changes.
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8. Shandley K, Austin DW. {{Ancestry of pink disease (infantile acrodynia) identified as a risk factor for autism spectrum disorders}}. J Toxicol Environ Health A. 2011; 74(18): 1185-94.
Pink disease (infantile acrodynia) was especially prevalent in the first half of the 20th century. Primarily attributed to exposure to mercury (Hg) commonly found in teething powders, the condition was developed by approximately 1 in 500 exposed children. The differential risk factor was identified as an idiosyncratic sensitivity to Hg. Autism spectrum disorders (ASD) have also been postulated to be produced by Hg. Analogous to the pink disease experience, Hg exposure is widespread yet only a fraction of exposed children develop an ASD, suggesting sensitivity to Hg may also be present in children with an ASD. The objective of this study was to test the hypothesis that individuals with a known hypersensitivity to Hg (pink disease survivors) may be more likely to have descendants with an ASD. Five hundred and twenty-two participants who had previously been diagnosed with pink disease completed a survey on the health outcomes of their descendants. The prevalence rates of ASD and a variety of other clinical conditions diagnosed in childhood (attention deficit hyperactivity disorder, epilepsy, Fragile X syndrome, and Down syndrome) were compared to well-established general population prevalence rates. The results showed the prevalence rate of ASD among the grandchildren of pink disease survivors (1 in 22) to be significantly higher than the comparable general population prevalence rate (1 in 160). The results support the hypothesis that Hg sensitivity may be a heritable/genetic risk factor for ASD.
