Autism Spectrum Disorders in Tuberous Sclerosis

Abstract

Tuberous sclerosis complex (TSC) is a genetic, multisystem disorder that affects the skin, kidneys, heart, and lungs, and, in the vast majority of cases, the brain. It is caused by mutations of either the TSC1 or TSC2 gene. These genes function as inhibitors of the mTOR Complex 1 (mTORC1) pathway, a master regulator in the cell that integrates growth factor, energy, and nutrient signals to control cellular growth and protein translation. The TSC/mTORC1 pathway is also involved in various steps of neuronal development and maturation, such as neuronal polarization, axon guidance, synaptic plasticity, and myelination. A loss-of-function mutation in either of the TSC genes results in constitutive overactivation of mTORC1 and a loss of control over downstream events.

Neurological symptoms of TSC can include epilepsy, cognitive disabilities, and behavioral abnormalities such as attention deficit hyperactivity disorder (ADHD), autism, and autism spectrum disorders (ASD). About 50 % of TSC patients are diagnosed with ASD, with a male-to-female ratio of 1:1. How TSC causes this phenomenon is not yet clear. It was originally thought that the benign hamartomas called cortical tubers were responsible for autism and other neurological symptoms of this disorder. However, research from the past decade, including rodent models with learning deficits and abnormal social approach behavior in the absence of a tuber-like brain pathology, indicates that microstructural abnormalities such as axon connectivity and myelination, as well as altered glutamate and GABAergic neurotransmission, render individuals with TSC highly susceptible to autism.