Genetics of tuberous sclerosis complex: implications for clinical practice

Abstract

Tuberous sclerosis complex (TSC) is a multisystem disorder that results from heterozygous mutations in either TSC1 or TSC2. The primary organ systems that are affected include the brain, skin, lung, kidney, and heart, all with variable frequency, penetrance, and severity. Neurological features include epilepsy, autism, and intellectual disability. There are more than 1,500 known pathogenic variants for TSC1 and TSC2, including deletion, nonsense, and missense mutations, and all pathogenic mutations are inactivating, leading to loss of function effects on the encoded proteins TSC1 and TSC2. These proteins form a complex to constitutively inhibit mechanistic target of rapamycin (mTOR) signaling cascade, and as a consequence, mTOR signaling is constitutively active within all TSC-associated lesions. The mTOR inhibitors rapamycin (sirolimus) and everolimus have been shown to reduce the size of renal and brain lesions and improve pulmonary function in TSC, and these compounds may also decrease seizure frequency. The clinical application of mTOR inhibitors in TSC has provided one of the first examples of precision medicine in a neurodevelopmental disorder.

Scalp EEG spikes predict impending epilepsy in TSC infants: A longitudinal observational study

“…[1][2][3] Epilepsy affects about 80% of individuals with TSC, 4 mostly starting in the first 2 years of life. [1][2][3] Epilepsy affects about 80% of individuals with TSC, 4 mostly starting in the first 2 years of life.…”

Novel mutations and phenotypes of epilepsy‐associated genes in epileptic encephalopathies

“…SMEB refers to children who meet most of the diagnostic criteria but lack several key features of SMEI such as myoclonic seizures or generalized spike‐wave activity but shares the same course and the same outcome as the patients with SMEI . Tuberous sclerosis complex was also included, considering that its presentation is similar to other forms of epileptic encephalopathy in refractory epilepsy and intellectual disability and that genetic causes other than TSC1 and TSC2 are possible . Patients who lack characteristics of a specific epilepsy syndrome were classified as unclassified epileptic encephalopathies.…”

A Study on Neurocutaneous Syndromes in a Rural Teaching Institute- A South Indian Study

“…Sturge-Weber syndrome is a sporadic disease, but familial cases have been described. [5] Port-wine stain generally represents progressive ectasia of superficial vascular plexus which stains pink in infancy, but becomes darker in the postnatal age. [6] It has an incidence of about 1: 50,000 live births.…”

“…[4] encompassing the clinical triad of tuberous sclerosis (Epi: epilepsy, Loi: low intelligence, A: adenoma sebaceum. [5] No pathognomonic clinical signs for TSC complex are seen. TSC is caused by a mutation of either of two genes, TSC1 and TSC2, which code for the proteins hamartin and tuberin, respectively.…”