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DISEASE GENETICS

Linking brain tumors and epileptic seizures

Nature Medicine volume 24, pages 1638–1639 (2018)Cite this article

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Mutationally activated BRAF-V600E influences the behavior of different types of cells in the brain and leads to promotion of seizures as well as brain tumors, indicating how both can be pharmacologically targeted in the clinic.

Intractable epilepsy is an important medical challenge about which there is poor understanding—it is not known why 25% of patients with epilepsy fail to respond to combinations of antiepileptic drugs (AEDs)1. Patients with intractable epilepsy are at an increased risk of early death, trauma, and psychosocial difficulties, and their overall quality of life is poor. These patients frequently require invasive therapies, such as neuromodulation or surgery that attempts to control synaptic transmissions or remove the underlying cause of the seizures2. The underlying cause of epilepsy in many such patients is a brain tumor; this phenomenon is known as a long-term epilepsy–associated tumor (LEAT) and results in complications for therapy for both the seizures and the tumor. One approach to address intractable epilepsy is to customize the combination of AEDs used for the various types of epilepsy1. Alternatively, understanding the underlying cause of these seizures may lead to new and improved therapeutic interventions. For example, activation of the PI3K–mTORC pathway by mutations is associated with cortical malformations (but interestingly, not tumor formation)3, which has led to successful clinical deployment of everolimus, an mTORC1 inhibitor, for the treatment of epilepsy in a molecularly defined subset of patients, with relatively modest side-effects4. In this issue of Nature Medicine, Koh et al.5 report a mechanistic link between the activity of the BRAF-V600E-mutant oncoprotein kinase, commonly expressed in gangliogliomas (GGs), and intractable epilepsy and show evidence that BRAF-V600E could be a therapeutic target for epilepsy.

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Fig. 1: The role of BRAF-V600E signaling and REST in GG-associated intractable epilepsy.

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Authors and Affiliations

  1. Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children’s Hospital Colorado and University of Colorado, Denver, CO, USA

    Jean M. Mulcahy Levy

  2. Huntsman Cancer Institute and Department of Dermatology, University of Utah, Salt Lake City, UT, USA

    Martin McMahon

Authors
  1. Jean M. Mulcahy Levy
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  2. Martin McMahon
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Correspondence to Jean M. Mulcahy Levy or Martin McMahon.

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The authors declare no competing interests.

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Mulcahy Levy, J.M., McMahon, M. Linking brain tumors and epileptic seizures. Nat Med 24, 1638–1639 (2018). https://doi.org/10.1038/s41591-018-0249-6

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  • DOI: https://doi.org/10.1038/s41591-018-0249-6

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