1. Falivelli G, De Jaco A, Favaloro FL, Kim H, Wilson J, Dubi N, Ellisman MH, Abrahams BS, Taylor P, Comoletti D. {{Inherited genetic variants in autism-related CNTNAP2 show perturbed trafficking and ATF6 activation}}. {Hum Mol Genet};2012 (Aug 7)
Although genetic variation in several genes encoding for synaptic adhesion proteins have been found to be associated with autism spectrum disorders, one of the most consistently replicated genes has been CNTNAP2, encoding for contactin-associated protein-like 2 (CASPR2), a multidomain transmembrane protein of the neurexin superfamily. Using immunofluorescence confocal microscopy and complementary biochemical techniques, we compared wild type CASPR2 to twelve point mutations identified in individuals with autism. In contrast to the wild-type protein, localized to the cell surface, some of the mutants show altered cellular disposition. In particular, CASPR2-D1129H is largely retained in the endoplasmic reticulum in HEK-293 cells and in hippocampal neurons. BiP/Grp78, Calnexin, and ERp57, key endoplasmic reticulum chaperons, appear to be responsible for retention of this mutant and activation of one signaling pathway of the unfolded protein response. The presence of this mutation also lowers expression and activates proteosomal degradation. A frame-shift mutation that causes a form of syndromic epilepsy (CASPR2-1253*), results in a secreted protein with seemingly normal folding and oligomerization. Taken together, these data indicate that CASPR2-D1129H has severe trafficking abnormalities and CASPR2-1253* is a secreted soluble protein, suggesting that the structural or signaling functions of the membrane tethered form are lost. Our data support a complex genetic architecture in which multiple distinct risk factors interact with others to shape autism risk and presentation.
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2. Haebig E, McDuffie A, Weismer SE. {{The Contribution of Two Categories of Parent Verbal Responsiveness to Later Language for Toddlers and Preschoolers on the Autism Spectrum}}. {Am J Speech Lang Pathol};2012 (Aug 9)
PURPOSE: Longitudinal associations between two categories of parent verbal responsiveness and language comprehension and production one year later were examined in 40 toddlers and preschoolers with a diagnosis of an autism spectrum disorder (ASD). METHOD: Parent-child play samples using a standard toy set were digitally captured and coded for child engagement with objects and communication acts and for parent verbal responses to play and communication. RESULTS: After controlling for parent education, child engagement and initial language level, only parent directives for language that followed into the child’s focus of attention accounted for unique variance in predicting both comprehension and production one year later. A series of exploratory analyses revealed that parent comments that followed into the child’s focus of attention also accounted for unique variance in later comprehension and production for children who were minimally verbal at the initial time period. CONCLUSIONS: Child developmental level may warrant different types of linguistic input to facilitate language learning. Children with ASD who have minimal linguistic skills may benefit from parent language input that follows into the child’s focus of attention. Children with ASD who are verbally fluent may need more advanced language input to facilitate language development.
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3. Mayor S. {{Advertising watchdog orders website to remove claims linking MMR vaccine with autism}}. {BMJ};2012;345:e5420.
4. Nagamani SC, Erez A, Ben-Zeev B, Frydman M, Winter S, Zeller R, El-Khechen D, Escobar L, Stankiewicz P, Patel A, Wai Cheung S. {{Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders}}. {Eur J Hum Genet};2012 (Aug 8)
Small genomic rearrangements and copy-number variations (CNVs) involving a single gene have been associated recently with many neurocognitive phenotypes, including intellectual disability (ID), behavioral abnormalities, and autistic spectrum disorders (ASDs). Such small CNVs in the Autism susceptibility candidate 2 (AUTS2) gene have been shown to be associated with seizures, ID, and ASDs. We report four patients with small CNVs ranging in size between 133-319 kb that disrupt AUTS2. Two patients have duplications involving single exons, whereas two have deletions that removed multiple exons. All patients had developmental delay, whereas two patients had a diagnosis of ASDs. The CNVs were detected by an exon-targeted array CGH with dense oligonucleotide coverage in exons of genes known or hypothesized to be causative of multiple human phenotypes. Our report further shows that disruption of AUTS2 results in a variety of neurobehavioral phenotypes. More importantly, it demonstrates the utility of targeted exon array as a highly sensitive clinical diagnostic tool for the detection of small genomic rearrangements in the clinically relevant regions of the human genome.European Journal of Human Genetics advance online publication, 8 August 2012; doi:10.1038/ejhg.2012.157.
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5. Pankhurst MW, McLennan IS. {{Inhibin B and anti-Mullerian hormone/Mullerian-inhibiting substance may contribute to the male bias in autism}}. {Transl Psychiatry};2012;2:e148.
The autistic spectrum disorders have a significant male bias in incidence, which is unexplained. The Sertoli cells of the immature testes secrete supra-adult levels of Mullerian-inhibiting substance/anti-Mullerian hormone (AMH) and inhibin B (InhB), with both hormones being putative regulators of brain development. We report here, that 82 boys with an autism spectrum disorder have normal levels of InhB and AMH. However, the boys’ level of InhB correlated with their autism diagnostic interview-revised (ADI-R) scores for the social interaction (R=0.29, P=0.009, N=82) and communication domains (R=0.29, P=0.022, N=63), and with the number of autistic traits the boys exhibited (R=0.34 and 0.27, respectively). The strengths of the abovementioned correlates were stronger in the boys with milder autism (R=0.42 and 0.50, respectively), with AMH exhibiting a significant negative correlation to the ADI-R score in these boys (R=-0.44 and R=-0.39, respectively). Neither hormone correlated to the incidence of stereotyped and repetitive behaviours. This suggests that the male bias in the autistic spectrum has multiple determinants, which modulate the effects of an otherwise non-dimorphic pathology. Furthermore, AMH and InhB have opposing effects on the SMAD1/5/8 pathway, and opposing correlates to autistic traits, implicating the SMAD pathways as a putative point of molecular convergence for the autistic spectrum.
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6. Robinson SJ. {{Childhood Epilepsy and Autism Spectrum Disorders: Psychiatric Problems, Phenotypic Expression, and Anticonvulsants}}. {Neuropsychol Rev};2012 (Aug 9)
Epilepsy and autism spectrum disorders (ASDs) frequently co-occur during childhood, however, the characteristics of psychiatric or behavioural problems in these children remains largely unknown. This article contributes to these discussions by reporting on the prevalence and presentation of psychiatric or behavioural problems in children with epilepsy and ASDs, as well as on the use of anticonvulsants in these children. The current evidence suggests that children with epilepsy and ASDs may present with a distinct clinical profile, with a greater number of developmental difficulties, and a more severe expression of the ASD phenotype that can not solely be accounted for by level of intellectual functioning. Positive effects of anticonvulsants on behavioural symptoms associated with ASDs were also reported, though pharmacoresistance and a lack of clear treatment guidelines may contribute to an elevated risk of adverse side effects. In relation to clinical presentation and management there is a need for careful consideration of potential interaction effects between disorder specific factors (e.g., age of seizure onset/ASD diagnosis), cognitive characteristics (e.g., intellectual functioning, memory), and psychosocial variables (e.g., coping strategies). Ultimately however, many conclusions are tentative and this review highlights the need for more empirically validated research on children with epilepsy and ASDs.
