Tuberous Sclerosis

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General Information


Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by germline loss of function mutations in the TSC1 or TSC2 gene. TSC can affect both adults and children with an estimated 2 million people affected by the disease worldwide. TSC affects multiple organ systems and causes benign tumors of the brain, heart, skin, kidneys (angiomyolipomas) and lungs (lymphangioleiomyomatosis [LAM]).  In addition to these tumors, the majority of individuals with TSC have neurologic manifestations which can include seizures, autism, and cognitive disability.  While the manifestations of TSC1 and TSC2-associated disease are essentially identical, in general individuals with TSC2 mutations are more severely affected in the kidney and the lung.  

LAM occurs in up to 80% of women with tuberous sclerosis complex (TSC) and was the leading cause of death in adult women with TSC (median age at death 44 yrs) in a cohort followed at the University of Cincinnati (n=702). LAM is an incurable destructive lung disease that affects almost exclusively women.  LAM is characterized by cystic lung destruction and distinctive microscopic nodules of smooth muscle like LAM cells.  The typical initial symptoms of LAM are pneumothorax (lung collapse) and/or shortness of breath. LAM can lead to oxygen dependence and lung failure. LAM also occurs in a sporadic setting, in women who do not have TSC (sporadic LAM [S-LAM]).

In both S-LAM and TSC-LAM, bi-allelic inactivation of the TSC2 or TSC1 gene occurs in LAM cells.  The TSC protein complex (which includes TSC1, TSC2, and TBC1D7) integrates signals from the cellular environment, including growth factors and nutrients to regulate the activity of mechanistic/mammalian target of rapamycin complex 1 (mTORC1).  mTORC1 controls numerous essential metabolic processes, including protein, nucleotide, and lipid synthesis, glycolysis, and autophagy.   Hyperactivation of mTORC1 is a hallmark of LAM and TSC.

A landmark clinical trial demonstrated that the mTORC1 inhibitor, rapamycin (sirolimus), stabilizes lung function in most LAM patients, but lung function continues to decline upon treatment cessation. Pivotal clinical trials have also demonstrated benefit of the rapamycin analog everolimus for the treatment of several other manifestations of TSC. 

Although LAM is found almost exclusively in women, there have been rare cases reported in men with TSC.  LAM progresses more rapidly in premenopausal women, and mouse models have suggested that estrogen promotes the survival of TSC2-defienct LAM cells, but the reasons for the striking female predominance of LAM and the mechanisms underlying cystic lung destruction in LAM remain incompletely understood.  The cell-of-origin of LAM cells is also a source of ongoing investigation.  Recent evidence from human specimens and from mouse models suggests that LAM cells may arise in the uterus and metastasize to the lungs. 

Elizabeth P. Henske, MD, Gregory P. Downey, MD, ATSF

Four Facts About Tuberous Sclerosis

  1. TSC is a genetic disorder affecting 50,000 in the USA and 1 million worldwide.
  1. TSC causes tumors to form in the vital organs, primarily in the brain, eyes, heart, kidneys, skin, and lungs.
  1. Lymphangioleiomyomatosis (LAM) occurs in up to 49% of women with TSC (Muzykewicz et al, 2009; Adriansen et al, 2011; Cudzilo et al, 2013).
  1. TSC affects no two people alike, not even identical twins.