A Unifying Theory for Autism: The Pathogenetic Triad as a Theoretical Framework

This paper presents a unifying theory for autism by applying the framework of a pathogenetic triad to the scientific literature. It proposes a deconstruction of autism into three contributing features (an autistic personality dimension, cognitive compensation, and neuropathological risk factors), and delineates how they interact to cause a maladaptive behavioral phenotype that may require a clinical diagnosis. The autistic personality represents a common core condition, which induces a set of behavioral issues when pronounced. These issues are compensated for by cognitive mechanisms, allowing the individual to remain adaptive and functional. Risk factors, both exogenous and endogenous ones, show pathophysiological convergence through their negative effects on neurodevelopment. This secondarily affects cognitive compensation, which disinhibits a maladaptive behavioral phenotype. The triad is operationalized and methods for quantification are presented. With respect to the breadth of findings in the literature that it can incorporate, it is the most comprehensive model yet for autism. Its main implications are that (1) it presents the broader autism phenotype as a non-pathological core personality domain, which is shared across the population and uncoupled from associated features such as low cognitive ability and immune dysfunction, (2) it proposes that common genetic variants underly the personality domain, and that rare variants act as risk factors through negative effects on neurodevelopment, (3) it outlines a common pathophysiological mechanism, through inhibition of neurodevelopment and cognitive dysfunction, by which a wide range of endogenous and exogenous risk factors lead to autism, and (4) it suggests that contributing risk factors, and findings of immune and autonomic dysfunction are clinically ascertained rather than part of the core autism construct.