Tuberous Sclerosis Complex Review Highlights mTOR Pathway Breakthroughs and Treatment Gaps

Tuberous sclerosis complex represents a paradigm for understanding how single genetic defects can cascade into complex multi-system diseases. This Nature Reviews primer synthesizes current knowledge about TSC, a condition affecting approximately 1 in 6,000 births worldwide.

TSC results from mutations in TSC1 or TSC2 genes, which normally form a protein complex that restrains the mTOR signaling pathway. When this brake fails, cells grow uncontrollably, forming characteristic benign tumors called hamartomas throughout the body. These appear in brain, kidneys, lungs, heart, skin, and eyes.

The most devastating aspects involve the nervous system. Up to 90% of patients develop epilepsy, often beginning in infancy and proving difficult to control. Additionally, TSC-associated neuropsychiatric disorders (TAND) including intellectual disability and autism affect the majority of patients, profoundly impacting quality of life.

Treatment advances have followed directly from understanding mTOR's central role. Rapamycin and related mTOR inhibitors now successfully treat several TSC manifestations including brain tumors, kidney lesions, lung disease, and facial growths. Some patients also experience seizure reduction.

However, critical treatment gaps persist. Current therapies inadequately address the neuropsychiatric features that most severely impact patients and families. Despite available medical and surgical options, many patients continue experiencing uncontrolled seizures and developmental challenges, underscoring the need for novel therapeutic approaches targeting the underlying neurodevelopmental aspects of this complex condition.