Boston Connection April 2015
Tags: Boston Connection
Turner TN, Sharma K, Oh EC, Liu YP, Collins RL, Sosa MX, Auer DR, Brand H, Sanders SJ, Moreno-De-Luca D8, Pihur V, Plona T, Pike K, Soppet DR, Smith MW, Cheung SW, Martin CL, State MW, Talkowski ME, Cook E, Huganir R, Katsanis N, Chakravarti A.
Nature. 2015 Mar 25. doi: 10.1038/nature14186.
Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated δ-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.
Levin AR, Nelson CA.
Neurotherapeutics. 2015 Mar 27
Autism spectrum disorder (ASD) is a behaviorally defined and heterogeneous disorder. Biomarkers for ASD offer the opportunity to improve prediction, diagnosis, stratification by severity and subtype, monitoring over time and in response to interventions, and overall understanding of the underlying biology of this disorder. A variety of potential biomarkers, from the level of genes and proteins to network-level interactions, is currently being examined. Many of these biomarkers relate to inhibition, which is of particular interest because in many cases ASD is thought to be a disorder of imbalance between excitation and inhibition. Abnormalities in inhibition at the cellular level lead to emergent properties in networks of neurons. These properties take into account a more complete genetic and cellular background than findings at the level of individual genes or cells, and are able to be measured in live humans, offering additional potential as diagnostic biomarkers and predictors of behaviors. In this review we provide examples of how altered inhibition may inform the search for ASD biomarkers at multiple levels, from genes to cells to networks.
J Child Psychol Psychiatry. 2015 Mar;56(3):248-50.
Autism (autistic spectrum disorder, ASD) and attention deficit hyperactivity disorder (ADHD) are two highly prevalent neurodevelopmental disorders. Current estimates for autism exceed 1% For ADHD, the 2013 US-based life time prevalence figure is 11%. Both disorders are also highly heritable. Intriguingly, approximately 50% of children with ASD also meet criteria for ADHD. Between their high heritability and comorbidity, some have wondered whether these two seemingly different disorders might in fact be related at some deep neurobiological level. The notion that these two disorders may be related is surprising when one considers the fact that autism generally appears in the first 1-2 years of life, whereas it is virtually impossible to identify ADHD during this time frame; indeed, inattentiveness and hyperactivity tend to be traits that are shared by nearly all toddlers, making a stable diagnosis of ADHD virtually impossible until early childhood (although a reliable diagnosis can generally be made during the preschool period). Like many neurodevelopmental disorders, early identification and early treatment are essential to easing the life time burden of these disorders. Of course, early treatment is predicated on early identification and it is for this reason that the review article by Johnson and colleagues is so intriguing, as it sets out to determine whether these disorders can be identified in the infancy period. It also raises a number of puzzling issues that remain undiscussed.
Baumer FM1, Song JW2, Mitchell PD3, Pienaar R4, Sahin M1, Grant PE5, Takahashi E6.
Pediatr Neurol. 2015 Feb 16. pii: S0887-8994(15)00059-4.
BACKGROUND: Abnormal white matter development in patients with tuberous sclerosis complex, a multisystem hamartomatous disorder caused by aberrant neural proliferation and axonal maturation, may be associated with poorer neurocognitive outcomes. The purpose of this study is to identify predictors of longitudinal changes in diffusion properties of white matter tracts in patients with tuberous sclerosis complex.
METHODS: Diffusion magnetic resonance imaging was carried out in 17 subjects with tuberous sclerosis complex (mean age, 7.2 ± 4.4 years) with at least two magnetic resonance imaging scans (mean number of days between scans, 419.4 ± 105.4). There were 10 males; 5 of 17 had autism spectrum disorder and 10 of 17 had epilepsy. Regions of interest were placed to delineate the internal capsule/corona radiata, cingulum, and corpus callosum. The outcomes were mean change in apparent diffusion coefficient and fractional anisotropy. Data were analyzed using Pearson's correlation and multiple linear regression analyses.
RESULTS: Gender was a significant predictor of mean change in apparent diffusion coefficient in the left internal capsule, right and left cingulum bundles, and corpus callosum and a significant predictor of mean change in fractional anisotropy in the corpus callosum. Epilepsy was a significant predictor of mean change in apparent diffusion coefficient in the left internal capsule. Autism spectrum disorder was not predictive of diffusion changes in any of the studied pathways.
CONCLUSION: Clinical variables, including gender and epilepsy, have an effect on the development of white matter pathways. These variables should be taken into consideration when counseling tuberous sclerosis complex patients and in future imaging studies in this population.