Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders: From Concept to Clinical Practice

Abstract

Tuberous sclerosis complex-associated neuropsychiatric disorders (TAND) affect up to 90% of individuals with tuberous sclerosis complex and are a major contributor to reduced quality of life, yet they remain widely under-recognized and undertreated. This narrative review describes how the field evolved from scattered behavioral observations to a defined and increasingly actionable component of clinical care. We trace the development of the original six-level TAND framework and the subsequent identification of seven data-driven natural clusters of co-occurring difficulties, which provide a practical alternative to viewing manifestations in isolation. We then summarize the clinical landscape, including prevalence, developmental trajectories, and relationships among genotype, intellectual ability, and epilepsy. We also review the biological rationale for targeting mechanistic target of rapamycin signaling, the limited neuropsychiatric benefits reported in trials involving older children, and the emerging interest in early presymptomatic intervention. Finally, an illustrative clinical vignette demonstrates how the 2023 international consensus rec-ommendations—organized around the natural clusters and summarized as ‘screen, act, repeat’— can support individualized assessment and care.