Pathways from Genes to Symptoms in Tourette Syndrome

Abstract

Abstract Tourette syndrome (TS) is not a unitary condition but, rather, heterogeneous in clinical presentation, course, treatment response, and longitudinal outcomes. This chapter offers a critical commentary on the varying phenotypic presentations and the associated etiological underpinnings. Potential endophenotypes linking the genetic architecture with the clinical phenotypes are described. Gender-dependent differences in the phenotypic expression as well as the presence of commonly encountered comorbidities such as obsessive–compulsive behavior/disorder and attention-deficit/hyperactivity disorder may indicate different etiological pathways and pathogenesis. Additional factors that may influence the phenotypic expression of TS include prenatal and perinatal difficulties and immunological factors. The clinical phenotype and the severity of symptoms, as well as the associated psychopathology observed in TS, may be influenced by the nature and extent of involvement of the cortico-striato-thalamo-cortical circuitry and the unique contribution of both the genetic and nongenetic factors at play as well as the timing of events during the developmental period. Thus, there may be shared molecular genetic pathways affecting development across diagnostic boundaries mediated through neurodevelopmental genes, but the clinical phenotypic expression may be further shaped by other nongenetic factors. This chapter focuses on the pathogenetic pathways of the distinct and overlapping phenotypes of TS. Currently understood etiologies and phenotypes are discussed, as are underexplored factors in the pathogenesis. Endophenotypes are considered with respect to how they may mediate between genotype and phenotype. The chapter considers the reasons for etiological ambiguity and suggests future research directions to meet some of these challenges.