1. Charman T, Jones CR, Pickles A, Simonoff E, Baird G, Happe F. {{Defining the cognitive phenotype of autism}}. {Brain Res} (Oct 25)
Although much progress has been made in determining the cognitive profile of strengths and weaknesses that characterise individuals with autism spectrum disorders (ASDs), there remain a number of outstanding questions. These include how universal strengths and deficits are; whether cognitive subgroups exist; and how cognition is associated with core autistic behaviours, as well as associated psychopathology. Several methodological factors have contributed to these limitations in our knowledge, including: small sample sizes, a focus on single domains of cognition, and an absence of comprehensive behavioural phenotypic information. To attempt to overcome some of these limitations, we assessed a wide range of cognitive domains in a large sample (N=100) of 14 to 16year old adolescents with ASDs who had been rigorously behaviourally characterised. In this review, we will use examples of some initial findings in the domains of perceptual processing, emotion processing and memory, both to outline different approaches we have taken to data analysis and to highlight the considerable challenges to better defining the cognitive phenotype(s) of ASDs. Enhanced knowledge of the cognitive phenotype may contribute to our understanding of the complex links between genes, brain and behaviour, as well as inform approaches to remediation.
2. Hansen JC, Ghosh RP, Woodcock CL. {{Binding of the Rett syndrome protein, MeCP2, to methylated and unmethylated DNA and chromatin}}. {IUBMB Life} (Oct);62(10):732-738.
Methylated CpG Binding Protein 2 (MeCP2) is a nuclear protein named for its ability to selectively recognize methylated DNA. Much attention has been focused on understanding MeCP2 structure and function in the context of its role in Rett syndrome, a severe neurodevelopmental disorder that afflicts one in 10,000-15,000 girls. Early studies suggested a connection between DNA methylation, MeCP2, and establishment of a repressive chromatin structure at specific gene promoters. However, it is now recognized that MeCP2 can both activate and repress specific genes depending on the context. Likewise, in the cell, MeCP2 is bound to unmethylated DNA and chromatin in addition to methylated DNA. Thus, to understand the molecular basis of MeCP2 functionality, it is necessary to unravel the complex interrelationships between MeCP2 binding to unmethylated and methylated regions of the genome. MeCP2 is unusual and interesting in that it is an intrinsically disordered protein, that is, much of its primary sequence fails to fold into secondary structure and yet is functional. The unique structure of MeCP2 is the subject of the first section of this article. We then discuss recent investigations of the in vitro binding of MeCP2 to unmethylated and methylated DNA, and the potential ramifications of this work for in vivo function. We close by focusing on mechanistic studies indicating that the binding of MeCP2 to chromatin results in compaction into local (secondary) and global (tertiary) higher order structures. MeCP2 also competes with histone H1 for nucleosomal binding sites. The recent finding that MeCP2 is found at near stoichiometric levels with nucleosomes in neuronal cells underscores the multiple modes of engagement of MeCP2 with the genome, which include the cooperative tracking of methylation density. (c) 2010 IUBMB IUBMB Life, 62(10): 732-738, 2010.
3. Johnson S, Hollis C, Hennessy E, Kochhar P, Wolke D, Marlow N. {{Screening for autism in preterm children: diagnostic utility of the Social Communication Questionnaire}}. {Arch Dis Child} (Oct 27)
Objective Preterm survivors are at high risk for autism spectrum disorders (ASD). The diagnostic utility of the Social Communication Questionnaire (SCQ) in screening for ASD was assessed in extremely preterm children at 11 years of age. Design All babies born at <26 weeks gestation in UK and Ireland from March through December 1995 were recruited to the EPICure Study. Of 307 survivors, 219 (71%) were assessed at 11 years. Parents of 173 children completed the SCQ to screen for autistic features and the Development and Well Being Assessment (DAWBA) psychiatric interview. A consensus diagnosis of ASD was assigned by two child psychiatrists following review of the DAWBA parental interview and corresponding DAWBA teacher questionnaire. Setting Community-based follow-up. Results Using the established SCQ cut-off (scores >/=15), 28 (16%) extremely preterm children screened positive for ASD. Eleven (6%) were assigned a diagnosis of ASD. Using this cut-off, the SCQ had 82% sensitivity and 88% specificity for identifying ASD in this population. Using a receiver operating characteristic curve, SCQ scores >/=14 had optimal diagnostic utility (area under curve: 0.94; sensitivity: 91%; specificity: 86%). Positive predictive value was relatively low (31%) resulting in numerous over-referrals. However, children with false positive screens had significantly worse neuro-developmental, cognitive and behavioural outcomes than those with true negative screens. Conclusion The SCQ has good diagnostic utility for identifying ASD in extremely preterm children and is a useful screening tool in this population. Children with false positive screens represent a high-risk group in whom further diagnostic assessment would be beneficial.
