Genetic Etiologies, Diagnosis, and Treatment of Tuberous Sclerosis Complex

Annu Rev Genomics Hum Genet. 2019 Aug 31;20:217-240. doi: 10.1146/annurev-genom-083118-015354. Epub 2019 Apr 24.

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems due to an inactivating variant in either TSC1 or TSC2, resulting in the hyperactivation of the mechanistic target of rapamycin (mTOR) pathway. Dysregulated mTOR signaling results in increased cell growth and proliferation. Clinically, TSC patients exhibit great phenotypic variability, but the neurologic and neuropsychiatric manifestations of the disease have the greatest morbidity and mortality. TSC-associated epilepsy occurs in nearly all patients and is often difficult to treat because it is refractory to multiple antiseizure medications. The advent of mTOR inhibitors offers great promise in the treatment of TSC-associated epilepsy and other neurodevelopmental manifestations of the disease; however, the optimal timing of therapeutic intervention is not yet fully understood.

Keywords: epilepsy; genetics; mTOR; rapamycin; tuberous sclerosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Everolimus / therapeutic use
  • Gene Expression Regulation
  • Genotype
  • Humans
  • Mental Disorders / diagnosis
  • Mental Disorders / drug therapy
  • Mental Disorders / genetics*
  • Mental Disorders / metabolism
  • Mutation
  • Neurogenesis / drug effects
  • Neurogenesis / genetics
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / therapeutic use
  • Phenotype
  • Severity of Illness Index
  • Signal Transduction
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / genetics*
  • TOR Serine-Threonine Kinases / metabolism
  • Tuberous Sclerosis / diagnosis
  • Tuberous Sclerosis / drug therapy
  • Tuberous Sclerosis / genetics*
  • Tuberous Sclerosis / metabolism
  • Tuberous Sclerosis Complex 1 Protein / genetics*
  • Tuberous Sclerosis Complex 1 Protein / metabolism
  • Tuberous Sclerosis Complex 2 Protein / genetics*
  • Tuberous Sclerosis Complex 2 Protein / metabolism
  • Vigabatrin / therapeutic use

Substances

  • Neuroprotective Agents
  • TSC1 protein, human
  • TSC2 protein, human
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Everolimus
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Vigabatrin