Tuberous sclerosis complex (TSC)

Tuberous sclerosis complex (TSC) is a genetic disorder affecting many different organs, including the eyes, heart, kidney, skin, lungs and the brain. While the severity of the symptoms of individual patients varies strongly, TSC symptoms associated with the brain tend to have the strongest effect on the quality of life. Most patients develop seizures, developmental delay, intellectual disability, and autism. Estimates indicate that one in 6,000 children born is affected by TSC. However, many cases remain undiagnosed as a result of mild symptoms and some TSC patients remain unnoticed until a more severely affected sibling is diagnosed with TSC. One third of patients inherit the genetic mutation from a (mildly affected) parent, while the other two thirds develop the mutation 'de novo' meaning the mutation arises spontaneously in the fetus.

TSC is caused by a mutation in either the TSC1 or the TSC2 gene, which encode the proteins hamartin and tuberin, respectively. These proteins work together to regulate the activity of the mTOR enzyme. A mutation in either gene causes the absence or malfunctioning of the respective protein. This causes mTOR to be hyperactive, which affects several crucial functions in an affected neuron.

In the lab, we are in particular interested in understanding the brain-related symptoms of TSC. In principle, we follow two main lines of research; one focusing on the causative mechanisms of TSC related epilepsy and the other on understanding why the severity of the disease is so diverse.

Epilepsy research.

To study the epileptic brain in a physiological environment, we use a mouse-model of TSC. Our research focuses particularly on understanding how loss of a functional TSC gene causes the development of epilepsy, a process called epileptogenesis. Analyzing the electric currents in single neurons will help us to comprehend this process. The advantage of our model system lays in a genetic trick, that the TSC-causing gene TSC1 can be deleted at a desired point in time. Hence, this allows us to precisely study the cellular and molecular changes that are induced by the loss of the TSC gene, and eventually cause epilepsy. By understanding this process, we hope to develop better drugs. We also use these mice to test which anti-epileptic drugs work best for treating TSC related epilepsy (Koene, Annals of Clinical and Translational Neurology, 2019).

Discordance of TSC severity..

In general, TSC patients with a mutation in the TSC2 gene show more severe symptoms than those lacking TSC1. However, even when the same mutation is inherited from parent to child, their symptoms may still strongly diverge. Understanding the underlying causes for these differences may allow us to develop new treatments. To study this we cannot use mice, as they are all genetically identical and do not show such variability. Hence, we utilize induced pluripotent stem (iPS) cells. These stem cells are generated from reprogrammed blood cells donated by patients of such discordant family members. The major benefit of such iPS cells is that we can differentiate these cells into human neurons, which enables us to study human (patient) neurons in a dish. With this approach we hope to decipher factors that cause the variation in severity. These might help predict the severity of TSC for specific patients early on, enable assessment of potential treatment options, and in the long run improve disease severity and quality of life.

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