1. Eric Barnes R, McCabe H. {{Should we welcome a cure for autism? A survey of the arguments}}. {Med Health Care Philos};2011 (Aug 12)
Substantial research efforts have been devoted to developing a cure for autism, but some advocates of people with autism claim that these efforts are misguided and even harmful. They claim that there is nothing wrong with people with autism, so there is nothing to cure. Others argue that autism is a serious and debilitating disorder and that a cure for autism would be a wonderful medical breakthrough. Our goal in this essay is to evaluate what assumptions underlie each of these positions. We evaluate the arguments made on each side, reject those that are implausible and then highlight the key assumptions of those that remain.
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2. Guenole F, Baleyte JM. {{Meta-analysing the effectiveness of melatonin for sleep-disturbed individuals with autism spectrum conditions: should Rett syndrome be included?}}. {Dev Med Child Neurol};2011 (Aug 12)
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3. van Daalen E, Kemner C, Verbeek NE, van der Zwaag B, Dijkhuizen T, Rump P, Houben R, van ‘t Slot R, de Jonge MV, Staal WG, Beemer FA, Vorstman JA, Burbach JP, van Amstel HK, Hochstenbach R, Brilstra EH, Poot M. {{Social responsiveness scale-aided analysis of the clinical impact of copy number variations in autism}}. {Neurogenetics};2011 (Aug 12)
Recent array-based studies have detected a wealth of copy number variations (CNVs) in patients with autism spectrum disorders (ASD). Since CNVs also occur in healthy individuals, their contributions to the patient’s phenotype remain largely unclear. In a cohort of children with symptoms of ASD, diagnosis of the index patient using ADOS-G and ADI-R was performed, and the Social Responsiveness Scale (SRS) was administered to the index patients, both parents, and all available siblings. CNVs were identified using SNP arrays and confirmed by FISH or array CGH. To evaluate the clinical significance of CNVs, we analyzed three families with multiple affected children (multiplex) and six families with a single affected child (simplex) in which at least one child carried a CNV with a brain-transcribed gene. CNVs containing genes that participate in pathways previously implicated in ASD, such as the phosphoinositol signaling pathway (PIK3CA, GIRDIN), contactin-based networks of cell communication (CNTN6), and microcephalin (MCPH1) were found not to co-segregate with ASD phenotypes. In one family, a loss of CNTN5 co-segregated with disease. This indicates that most CNVs may by themselves not be sufficient to cause ASD, but still may contribute to the phenotype by additive or epistatic interactions with inherited (transmitted) mutations or non-genetic factors. Our study extends the scope of genome-wide CNV profiling beyond de novo CNVs in sporadic patients and may aid in uncovering missing heritability in genome-wide screening studies of complex psychiatric disorders.
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4. Warren Z, Veenstra-VanderWeele J, Stone W, Bruzek JL, Nahmias AS, Foss-Feig JH, Jerome RN, Krishnaswami S, Sathe NA, Glasser AM, Surawicz T, McPheeters ML.2011 (Apr)
The Vanderbilt Evidence-based Practice Center systematically reviewed evidence on therapies for children ages 2 to 12 with autism spectrum disorders (ASDs). We focused on treatment outcomes, modifiers of treatment effectiveness, evidence for generalization of outcomes to other contexts, and evidence to support treatment decisions in children ages 0-2 at risk for an ASD diagnosis. We searched MEDLINE,(R) ERIC, and PsycInfo.(R) We included studies published in English from January 2000 to May 2010. We excluded medical studies with fewer than 30 participants; behavioral, educational, and allied health studies with fewer than 10 participants; and studies lacking relevance to treatment for ASDs. Of 159 unique studies included, 13 were good quality, 56 were fair, and 90 poor. The antipsychotic drugs risperidone and aripiprazole demonstrate improvement in challenging behavior that includes emotional distress, aggression, hyperactivity, and self-injury, but both have high incidence of harms. No current medical interventions demonstrate clear benefit for social or communication symptoms in ASDs. Evidence supports early intensive behavioral and developmental intervention, including the University of California, Los Angeles (UCLA)/Lovaas model and Early Start Denver Model (ESDM) for improving cognitive performance, language skills, and adaptive behavior in some groups of children. Data are preliminary but promising for intensive intervention in children under age 2. All of these studies need to be replicated, and specific focus is needed to characterize which children are most likely to benefit. Evidence suggests that interventions focusing on providing parent training and cognitive behavioral therapy (CBT) for bolstering social skills and managing challenging behaviors may be useful for children with ASDs to improve social communication, language use, and potentially, symptom severity. The Treatment and Education of Autistic and Communication related handicapped CHildren (TEACCH) program demonstrated some improvements in motor skills and cognitive measures. Little evidence is available to assess other behavioral interventions, allied health therapies, or complementary and alternative medicine. Information is lacking on modifiers of effectiveness, generalization of effects outside the treatment context, components of multicomponent therapies that drive effectiveness, and predictors of treatment success. Medical interventions including risperidone and aripiprazole show benefit for reducing challenging behaviors in some children with ASDs, but side effects are significant. Some behavioral and educational interventions that vary widely in terms of scope, target, and intensity have demonstrated effects, but the lack of consistent data limits our understanding of whether these interventions are linked to specific clinically meaningful changes in functioning. The needs for continuing improvements in methodologic rigor in the field and for larger multisite studies of existing interventions are substantial. Better characterization of children in these studies to target treatment plans is imperative.
5. Yasui DH, Scoles HA, Horike SI, Meguro-Horike M, Dunaway KW, Schroeder DI, Lasalle JM. {{15q11.2-13.3 chromatin analysis reveals epigenetic regulation of CHRNA7 with deficiencies in Rett and autism brain}}. {Hum Mol Genet};2011 (Aug 12)
Copy number variants (CNVs) within human 15q11.2-13.3 show reduced penetrance and variable expressivity in a range of neurologic disorders. Therefore, characterizing 15q11.2-13.3 chromatin structure is important for understanding the regulation of this locus during normal neuronal development. Deletion of the Prader-Willi imprinting center (PWS-IC) within 15q11.2-13.3 disrupts long range imprinted gene expression resulting in Prader-Willi syndrome. Previous results establish that MeCP2 binds to the PWS-IC and is required for optimal expression of distal GABRB3 and UBE3A. To examine the hypothesis that MeCP2 facilitates 15q11.2-13.3 transcription by linking the PWS-IC to distant elements, chromosome capture conformation on chip (4C) analysis was performed in human SH-SY5Y neuroblastoma cells. SH-SY5Y neurons had 2.84 fold fewer 15q11.2-13.3 PWS-IC chromatin interactions than undifferentiated SH-SY5Y neuroblasts, revealing developmental chromatin de-condensation of the locus. Out of 68 PWS-IC interactions with15q11.2-13.3 identified by 4C analysis and 62 15q11.2-13.3 MeCP2 binding sites identified by previous ChIP-chip studies only five sites showed overlap. Remarkably, two of these overlapping PWS-IC and MeCP2 bound sites mapped to sites flanking CHRNA7 encoding the cholinergic receptor, nicotinic, alpha 7. PWS-IC interaction with CHRNA7 in neurons was independently confirmed by FISH analysis. Subsequent quantitative transcriptional analyses of frontal cortex from Rett syndrome and autism patients revealed significantly reduced CHRNA7 expression compared to controls. Together, these results suggest that transcription of CHRNA7 is modulated by chromatin interactions with the PWS-IC. Thus loss of long-range chromatin interactions within 15q11.2-13.3 may contribute to multiple human neurodevelopmental disorders.
