Changing the outcome in genetic brain disorders.

Tuberous sclerosis complex (TSC) has historically been seen as a hopeless and devastating disease against which little could be offered except symptomatic treatment. This is embodied in the classic view that the inevitable hallmarks of TSC are Vogt's triad: intellectual disability, intractable epilepsy, and facial angiofibromas. Even today this perspective is encountered in patients referred for specialist treatment.

In actual fact the majority of people with TSC have a normal full‐scale IQ, can have effective control or even freedom from seizures, and live healthy full lives with aggressive and appropriate management of the wide variety of symptoms to which an individual may be subject. For TSC results from hyperactivation of mammalian target of rapamycin (mTOR), a protein kinase that is critical for the growth and development of every organ and tissue in a person's body. Finally, approved mechanistic therapies exist for the most significant manifestations of TSC in the mTOR inhibitors rapamycin and everolimus.

It is axiomatic that the earlier one intervenes in a chronic disorder such as TSC, the greater the impact on the acute and long‐term outcome of the disease. Zhang et al. show that, in addition to renal and cardiac involvement, there is a higher risk of perinatal adversity both in infants who have TSC and in pregnant females with TSC, whether their unborn child is affected or not. Wang et al. report improved outcomes in infants with TSC following prenatal or early postnatal diagnosis, apparently as result of subsequent intervention with vigabatrin and/or rapamycin (sirolimus).

Given the critical role of mTOR in fetal and placental development, the findings of increased risk of perinatal adversity are unsurprising and highlight how early the challenges began for children with TSC. Interestingly, this increased adversity did not correlate with worse developmental outcomes. Perhaps because developmental delay and autism are more closely related to the advent of seizures or epileptiform activity on electroencephalogram. A straightforward example of TSC‐related perinatal adversity is hemodynamically significant cardiac rhabdomyomas which can cause substantial perinatal morbidity and death. Increasingly, mTOR inhibitors administered to the mother during the last trimester, or shortly after birth, have caused regression of cardiac rhabdomyomas, preventing or minimizing this infrequent but serious clinical problem. Based on multiple case reports, this has been well‐tolerated. Treatment can be short term, with no evidence of lesion regrowth.

Zhang et al. report that prenatal or early postnatal diagnosis, followed by treatment with vigabatrin and/or sirolimus, appears to improve developmental outcomes, decrease seizure frequency as well as the incidence of intractable epilepsy. Postnatal treatment was often presymptomatic, i.e. before the onset of clinical seizures or developmental delay. This was not a prospective clinical trial, but a retrospective analysis of what has become widespread practice in China. It nonetheless provides important circumstantial evidence that early and presymptomatic treatment of epilepsy in TSC is associated with improved long‐term outcomes and seizure control. This finding is being evaluated prospectively in three randomized clinical trials currently ongoing in the United States and Europe.

These findings offer hope, not only for patients with TSC, but for those with other genetic diseases affecting development. Despite the complexity of the mTOR pathway and much less brain development, these studies typify the promise of proactive and presymptomatic therapy of supposedly ‘untreatable’ conditions through mechanism‐based insights and genetic diagnosis.