1. Jordan BR, Tsai DF. {{Whole-genome association studies for multigenic diseases: ethical dilemmas arising from commercialization–the case of genetic testing for autism}}. {J Med Ethics} (Jun 16)
This paper examines some ethical issues arising from whole-genome association studies for multigenic diseases, focusing on the case of autism. Events occurring following the announcement of a genetic test for autism in France (2005-2009) are described to exemplify the ethical controversies that can arise when genetic testing for autism is applied prematurely and inappropriately promoted by biotech companies. The authors argue that genetic tests assessing one or a few genes involved in highly multigenic disorders can only be useful if: (1) the genetic linkage found in the scientific study must be statistically convincing, reproducible and also applicable to the population to which the individual considered belongs (scientific validity); (2) the relative risk conferred by the ‘high-risk’ allele should be high enough to be significant to the patient (significant impact); (3) use of the test should lead to some improvement of outcome for the patient, resulting from adapted treatment if available, or at least from adjustment of lifestyle (or life goals) prompted by the new knowledge generated (clinical utility). Decisions concerning genetic testing for autism involve scientific judgement, value judgement and good knowledge of a constantly evolving therapeutic environment. The implementation of genetic tests for highly multigenic diseases thus requires strong mechanisms to ensure that they are used in a fashion that can benefit patients, and these mechanisms must be able to cope with rapid progress in scientific knowledge and therapeutic intervention.
2. Oblak AL, Gibbs TT, Blatt GJ. {{Decreased GABA(B) Receptors in the Cingulate Cortex and Fusiform Gyrus in Autism}}. {J Neurochem} (Jun 12)
Abstract Autism is a behaviorally defined neurodevelopmental disorder and among its symptoms are disturbances in face and emotional processing. Emerging evidence demonstrates abnormalities in the GABAergic (gamma-aminobutyric acid) system in autism, which likely contributes to these deficits. GABA(B) receptors play an important role in modulating synapses and maintaining the balance of excitation-inhibition in the brain. The density of GABA(B) receptors in subjects with autism and matched controls was quantified in the anterior and posterior cingulate cortex, important for socio-emotional and cognitive processing, and the fusiform gyrus, important for identification of faces and facial expressions. Significant reductions in GABA(B) receptor density were demonstrated in all three regions examined suggesting that alterations in this key inhibitory receptor subtype may contribute to the functional deficits in individuals with autism. Interestingly, the presence of seizure in a subset of autism cases did not have a significant effect on the density of GABA(B) receptors in any of the three regions.
3. Santesso DL, Drmic IE, Jetha MK, Bryson SE, Goldberg JO, Hall GB, Mathewson KJ, Segalowitz SJ, Schmidt LA. {{An event-related source localization study of response monitoring and social impairments in autism spectrum disorder}}. {Psychophysiology} (Jun 14)
Abstract A number of studies suggest anterior cingulate cortex (ACC) abnormalities in autism spectrum disorder (ASD), which might underlie response monitoring and social impairments exhibited by children and adolescents with ASD. The goal of the present study was to extend this work by examining error and correct response monitoring using event-related potentials (ERN, Pe, CRN) and LORETA source localization in high functioning adults with ASD and controls. Adults with ASD showed reduced ERN and Pe amplitudes and reduced rostral ACC activation compared with controls. Adults with ASD also showed less differentiation between error and correct ERP components. Social impairments and higher overall autism symptoms were related to reduced rostral ACC activity at the time of the ERN, particularly in adults with ASD. These findings suggest that reduced ACC activity may reflect a putative brain mechanism involved in the origins and maintenance of social impairments and raise the possibility of the presence of stable brain-behavior relation impairment across development in some individuals with ASD.
4. Shih P, Shen M, Ottl B, Keehn B, Gaffrey MS, Muller RA. {{Atypical Network Connectivity for Imitation in Autism Spectrum Disorder}}. {Neuropsychologia} (Jun 14)
Imitation has been considered as one of the precursors for sociocommunicative development. Impairments of imitation in autism spectrum disorder (ASD) could be indicative of dysfunctional underlying neural processes. Neuroimaging studies have found reduced activation in areas associated with imitation, but a functional connectivity MRI network perspective of these regions in autism is unavailable. Functional and effective connectivity was examined in 14 male participants with ASD and 14 matched typically developing (TD) participants. We analyzed intrinsic, low-frequency blood oxygen level dependent (BOLD) fluctuations of three regions in literature found to be associated with imitation (inferior frontal gyrus [IFG], inferior parietal lobule [IPL], superior temporal sulcus [STS]). Direct group comparisons did not show significantly reduced functional connectivity within the imitation network in ASD. Conversely, we observed greater connectivity with frontal regions, particularly superior frontal and anterior cingulate gyri, in the ASD compared to TD group. Structural equation modeling of effective connectivity revealed a significantly reduced effect of IPL on IFG together with an increased influence of a region in dorsal prefrontal cortex (dPFC) on IFG in the ASD group. Our results suggest atypical connectivity of the imitation network with an enhanced role of dPFC, which may relate to behavioral impairments.
5. Silverman JL, Yang M, Lord C, Crawley JN. {{Behavioural phenotyping assays for mouse models of autism}}. {Nat Rev Neurosci} (Jul);11(7):490-502.
Autism is a heterogeneous neurodevelopmental disorder of unknown aetiology that affects 1 in 100-150 individuals. Diagnosis is based on three categories of behavioural criteria: abnormal social interactions, communication deficits and repetitive behaviours. Strong evidence for a genetic basis has prompted the development of mouse models with targeted mutations in candidate genes for autism. As the diagnostic criteria for autism are behavioural, phenotyping these mouse models requires behavioural assays with high relevance to each category of the diagnostic symptoms. Behavioural neuroscientists are generating a comprehensive set of assays for social interaction, communication and repetitive behaviours to test hypotheses about the causes of austism. Robust phenotypes in mouse models hold great promise as translational tools for discovering effective treatments for components of autism spectrum disorders.
6. Tuchman R, Alessandri M, Cuccaro M. {{Autism spectrum disorders and epilepsy: Moving towards a comprehensive approach to treatment}}. {Brain Dev} (Jun 15)
The biological and phenotypic heterogeneity of children with autism spectrum disorders (ASD) and epilepsy presents a significant challenge to the development of effective treatment protocols. There is no single treatment or treatment protocol for children with ASD or epilepsy. Children with co-occurring ASD and epilepsy should undergo a comprehensive assessment that includes investigation of underlying biological etiologies as well assessment of cognitive, language, affective, social and behavioral function prior to initiating treatment. The comprehensive treatment of children with ASD is based on a combination of therapeutic psychosocial interventions in combination with pharmacological agents. A process-oriented approach to assessment and intervention allows careful analysis of the child’s response to treatment such that treatment protocols may be revised secondary to any changes in developmental trajectory of the child with ASD and epilepsy. The possibility of developing pharmacological interventions that target both ASD and epilepsy awaits definitive evidence. The best hope for good developmental outcomes in children with ASD and epilepsy is early recognition and comprehensive treatment of both the ASD and epilepsy.
