This is an area that is still being developed and investigated in TSC, but, in all patients who develop epilepsy at an early age, the best QOL outcomes are generally observed in children who have a low burden of disease. Specifically with regard to TSC, the type of gene mutation that the child or adolescent has may also influence QOL, with the more severe mutations being associated with more developmental impairments and poorer QOL. Those with single nucleotide polymorphisms, for instance, generally do better than those who have a complete truncation of 1 of the 2 TSC proteins. And, of the 2 TSC proteins, early evidence suggests that TSC2 pathogenic variants are linked to a more severe clinical phenotype than mosaic TSC2 or TSC1 variants in infants with TSC.

In addition to the epilepsy burden and the specific genetic variants involved, the tuber burden in the brain can have important implications. One of the questions that I often ask radiologists is: “How much of the brain is involved with the cortical tubers?” It is often true that the greater the tuber load (ie, volume of abnormal brain), the greater the likelihood of poor developmental outcomes and reduced QOL. Conversely, smaller tuber loads and smaller tuber sizes are associated with a better likelihood of achieving seizure control and having better developmental and QOL outcomes; however, there are certainly exceptions.

TSC is a disease in which understanding the disease burden can help in trying to predict long-term outcomes, but there can be a great deal of variability. We all have patients in our practice in whom there is a sizable tuber load but who are still doing quite well developmentally. We also see examples of the opposite (eg, a patient with a single small tuber who is not doing as well developmentally as we would expect). We do not yet understand all of the reasons for this discordance between the disease burden manifested by tuber load and outcomes. The bottom line is that early seizure control and less disease burden will be linked to better outcomes and better QOL.