Childhood developmental disorders: an academic and clinical convergence point for psychiatry, neurology, psychology and pediatrics

Abstract

Background: Significant advances in understanding brain development and behavior have not been accompanied by revisions of traditional academic structure. Disciplinary isolation and a lack of meaningful interdisciplinary opportunities are persistent barriers in academic medicine. To enhance clinical practice, research, and training for the next generation, academic centers will need to take bold steps that challenge traditional departmental boundaries. Such change is not only desirable but, in fact, necessary to bring about a truly innovative and more effective approach to treating disorders of the developing brain.

Methods: I focus on developmental disorders as a convergence point for transcending traditional academic boundaries. First, the current taxonomy of developmental disorders is described with emphasis on how current diagnostic systems inadvertently hinder research progress. Second, I describe the clinical features of autism, a phenomenologically defined condition, and Rett and fragile X syndromes, neurogenetic diseases that are risk factors for autism. Finally, I describe how the fields of psychiatry, psychology, neurology, and pediatrics now have an unprecedented opportunity to promote an interdisciplinary approach to training, research, and clinical practice and, thus, advance a deeper understanding of developmental disorders.

Results: Research focused on autism is increasingly demonstrating the heterogeneity of individuals diagnosed by DSM criteria. This heterogeneity hinders the ability of investigators to replicate research results as well as progress towards more effective, etiology-specific interventions. In contrast, fragile X and Rett syndromes are 'real' diseases for which advances in research are rapidly accelerating towards more disease-specific human treatment trials.

Conclusions: A major paradigm shift is required to improve our ability to diagnose and treat individuals with developmental disorders. This paradigm shift must take place at all levels - training, research and clinical activity. As clinicians and scientists who are currently constrained by disciplinary-specific history and training, we must move towards redefining ourselves as clinical neuroscientists with shared interests and expertise that permit a more cohesive and effective approach to improving the lives of patients.

Figure 1

A conceptualization of the current state of phenomenologically defined (e.g., DSM or ICD) disorders. In the center is a DSM-IV defined diagnosis, here shown with autism as the example. Multiple biological and environmental factors (shown around the periphery) modify risk for the development of aberrant ‘neural pathways’ during brain development. Some of these risk factors are of moderate or greater influence (e.g., MeCP2 mutations that lead to Rett syndrome shown here), and thus are able to increase the likelihood of brain dysfunction with relatively less influence from other genetic or environmental factors. Other factors, such as FMR1 mutations associated with fragile X syndrome (also shown in the figure), may contribute moderately increased risk for autistic behavior. However, this risk can be moderated by measurable environmental factors related to the home and school (Hessl et al., 2001). ‘Neural pathways’ leading to manifestations of DSM defined disorders (shown as the intermediate step between risk factors and diagnosis) also would be expected to vary for a given DSM diagnosis, even though they might result in a (somewhat) similar phenotype. Examples of neural pathways influenced by FMR1 mutations are shown in the figure (mGluR-metabotropic glutamate receptor, Ach-Acetylcholine system, GABA-gamma-aminobutyic acid). Given the lack of scientific precision of such phenomenologically based diagnostic taxonomies, alternatives to the DSM should be strongly considered for future research studies focused on elucidating the pathogenesis of (currently) idiopathic developmental disorders

Figure 2

The genetic basis for the fragile X full mutation. FMR1 gene from X chromosome shown on left under typical conditions. Modal trinucleotide (CGG) repeat length is 29–30. Significantly expanded CGG repeats in the FMR1 full mutation (right) lead to hypermethylation (CH₃), transcriptional repression and reduced levels of FMRP. Reduced levels of FMRP lead to neurobiological dysfunction and the cognitive-behavioral phenotype (also see Figure 3)

Figure 3

A hierarchical model for planning treatment strategies in fragile X syndrome. The left-hand side of the diagram shows the genetic and neurobiological mechanisms leading to brain dysfunction in this condition. Specifically, the FMR1 mutation causes reduction in FMRP, leading to transcriptional dysregulation of FMRP mRNA targets (involved in synapse maturation and function). Other (non-FMR1 related) genetic and environmental factors interact with this genetic-neurobiological pathway, ultimately culminating in the cognitive-behavioral phenotype associated with fragile X. The right-hand side of the diagram shows potential treatment approaches matched to the corresponding genetic and pathophysiological level on the left. Given that gene therapy approaches are not feasible at the present time, the most promising current approaches are at the level of pathways ‘downstream’ to reduced levels of FMRP (shown under the category of ‘FMRP-specific Biological Interventions). Abbreviations: FraX: fragile X syndrome; FMRP: fragile X mental retardation protein; mGlurR: metabotropic glutamate receptor; GABA: gammaaminobutyric acid. Asterisks (*) next to treatment approaches indicate ongoing trials in the Center for Interdisciplinary Brain Sciences Research at Stanford University