Behavioural phenotypes in translation.

03Original abstract

Research into developmental disabilities associated with genetic syndromes has taken great strides in recent years in terms of understanding the mechanisms underlying both cognitive disabilities and associated behavioural phenomenology. Genetic testing moved beyond simple karyotyping, which has helped us to make advances in our understanding of the impact of copy number variants, other genetic mutations and epigenetic mechanisms. New methodologies and technological advances are continuing to rapidly increase our understanding of intellectual disabilities and other developmental disorders, both in terms of the aetiology of these conditions and the early predictors of long-term outcome. Yet, despite these advances, clinical application of many of these developments has not yet become established, sometimes because of unique challenges associated with involving individuals with these rare syndromes in research. The 18th international symposium for the Society for the Study of Behavioural Phenotypes (SSBP) in London has a ‘bench to bedside’ theme, aiming to get researchers and clinicians working in the field of developmental disabilities to be more closely aligned, in order to put them at the forefront of an application of an explosion of discoveries in neuroscience. This year, Professor Sir Mike Rutter is delivering the Tom Oppé lecture (Invited Speakers 2015). He will emphasise that an understanding of genetic and epigenetic mechanisms combined with a rigorous study of specific behavioural patterns are crucial in helping us to identify potential treatment strategies for troublesome behavioural phenotypes and cognitive deficits associated with developmental disabilities. These mechanisms are being explored in animal and cellular studies and include how coding and non-coding genes interact and affect outcome, how environmental factors are able to modify methylation of DNA leading to variable and differential outcomes and how imprinting and inheritance can lead to fundamental differences in clinical presentations of individuals. By linking the mechanisms of action with the phenotypic outcomes in these rare but important disorders, we are beginning to establish a level of understanding that allows for the development of effective interventions at different developmental stages, and at biological, environmental and psychological levels. Previous Society for the Study of Behavioural Phenotypes (SSBP) symposia have aimed at encouraging a broader understanding of underlying pathways and developmental trajectories (Oliver 2014), whilst others have focused more closely on specific disorders. For example, recent advances in the understanding of the Mammalian target of rapamycin signalling pathway and its relationship to tuberous sclerosis (TCS) has been explored, culminating in clinical trials demonstrating the impact of targeted medications to treat and improve aspects of TCS (Curatolo et al. 2015). Elsewhere, such as in Fragile X syndrome, clinical trials had less favourable outcomes. It has been shown that the metabotropic glutamate receptors (mGluR) are affected in Fragile X syndrome which has led to several current clinical trials of mGluR inhibitors. Unfortunately, development of these drugs were halted after several phase 2 trials had disappointing results, which may have been related to limitations of the outcome measures, heterogeneity within the population and perhaps the limited potential for impacting upon synaptic plasticity in older adults (Mullard 2015). However, efforts to understand molecular biomarkers associated with differential outcome (Oral Abstracts 2015) and to develop and trial treatments for Fragile X syndrome are continuing (Oral Abstracts 2015). We may also be able to apply advances in disorders with similar mechanisms, such as Freidreich's ataxia (Invited Speakers 2015). Despite preclinical advances and their potential applications, treatments available to clinicians to address the core features and difficulties associated with genetic intellectual disability syndromes remain limited. Whilst better pre-clinical understanding opens up the possibility of more avenues for intervention, until a better understanding of how our genes and our environment interact, leading to the disorders that are clinically seen, as well as a better understanding of phenotypic expression and how to accurately measure it, the advances will remain for the most part confined to the bench. An important key to further progress and translation into clinical practice is to establish a closer relationship between pre-clinical ‘bench’ research and research that can be applied clinically. The 18th symposium of the SSBP is therefore aiming to explicitly link specific biological processes and phenomenological outcomes across preclinical and human research studies. Pre-clinical research that will be presented include animal model research (Invited Speakers 2015; Oral Abstracts 2015), research focused on better understanding of genetic risk and mechanisms (Oral Abstracts 2015) and associated cellular processes (Oral Abstracts 2015). A key issue is to ensure that behavioural and other assays are comparable to allow better alignment of research in animal models and in humans. It is encouraging that this symposium includes work from several groups attempting to link explicitly human and animal behavioural as well as neuroimaging assays (Invited Speakers 2015; Oral Abstracts 2015). At the clinical end, researchers are leveraging advanced, high-resolution neuroimaging to understand brain process and reveal changes in circuitry (Invited Speakers 2015; Oral Abstracts 2015); developing assessment tools and conducting detailed phenotype studies of CNVs such as those at the 16p11.2 locus (Oral Abstracts 2015; Maillard et al. 2015), and exploring behavioural differences between syndromes (Dimitriou et al. 2015; Oral Abstracts 2015) as well as attempting to understand early predictors of within-syndrome heterogeneity in clinical outcomes (Invited Speakers 2015; Oral Abstracts 2015). This will be assisted with the development of international disease registries, such as for methyl CpG binding protein 2 (MCPG2) duplication syndrome (Oral Abstracts 2015) and TSC (Oral Abstracts 2015). The ultimate aim of intervention is improvement in individual function and to alter the trajectory and otherwise poor outcomes so often associated with developmental disabilities, and progress is also being made with developing targeted interventions that can be tested in clinical trials (Oral Abstracts 2015) and used in clinics (Invited Speakers 2015). The symposium will also consider changes and developments in our understanding of clinical syndromes. Most recent updates to the autism diagnostic criteria appeared in Diagnostic and Statistical Manual 5. Field testing of International Classification of Diseases 11 criteria are currently underway. By understanding the spectrum of presentation of autism and other cognitive and behavioural phenotypes, and by linking this variability with underlying mechanisms and biology, allows clinicians and researchers to work together to improve the lives of those presenting with these disorders. Yet as our knowledge of disorders increase and our ability to intervene and prolong life continues, new challenges come to the fore. In an ageing population, dementia is increasing. The relationship between developmental trajectories and the ageing of the human brain, and the impact of improved survival in a variety of disorders is also now beginning to be explored (Invited Speakers 2015). By supporting a translational approach, it is hoped that the SSBP symposium will be a forum where researchers and clinicians can mutually enrich their work and knowledge by taking lessons from laboratory and animal research through to clinical application, and conversely by informing ‘bench’-based research through detailed clinical observation.

Journal of intellectual disability research : JIDR, 2015 · doi:10.1111/jir.12211