Tuberous sclerosis complex: genetic basis and management strategies

Victoria Tsai, Peter B Crino

PENN Epilepsy Center, PENN Tuberous Sclerosis Clinic, Department of Neurology and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Abstract: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that results from mutations in the TSC1 or TSC2 genes. TSC is a multisystem hamartoma syndrome with manifestations in the brain, heart, lungs, kidney, skin, and eyes. Neurologically, TSC patients may exhibit severe epilepsy, cognitive disabilities, and autism spectrum disorders. Many TSC patients also present with renal angiomyolipomas, polycystic kidney disease, skin lesions, and lymphangiomyomatosis. TSC1 and TSC2 proteins form a heterodimeric complex that serves to inhibit mammalian target of rapamycin (mTOR) signaling pathway through Ras homolog enriched in brain (Rheb). TSC1 and TSC2 receive activating or inhibitory signals from multiple inputs including growth factors, insulin signaling, energy and amino acid levels, and proinflammatory pathways, which are then integrated to regulate the activity of the mTOR pathway. mTOR signaling plays a critical role in regulating cell growth, transcription, translation, and autophagy. Animal models have shed light on certain features of TSC, but failed to recapitulate the disease completely and currently further research is under way to better understand this devastating disorder. Clinical trials with mTOR inhibitors have shown promising results for some features of TSC, but further research needs to be conducted to establish full indications for therapeutic treatment.

Keywords: tuberous sclerosis complex, TSC, TSC1, TSC2