New Findings in Genetic Focal Epilepsies: The GATOR1 Complex as a Hub for Idiopathic/Genetic and Structural Focal Epilepsies

Background: The GATOR1 complex incudes the genes DEPDC5, NPRL2, NPRL3. This complex again regulates the mTOR complex, which, among other genes, includes TSC1 and TSC2. Both are known to be responsible for the tuberous sclerosis complex (TSC).

Purpose: To give an update, on clinically relevant genetic findings in the genetics of focal epilepsies and their relevance for potential treatment options.

Methods: Literature summary and presentation of own data.

Results: In “autosomal dominant epilepsy with variable foci” two independent groups succeeded to disclose mutations in DEPDC5 in several families, and in up to 12% of individuals of families with idiopathic focal epilepsy. A Canadian group showed that in ~5% of families with idiopathic focal epilepsies in general, DEPDC5 defects can be detected. In a group of 207 patients with typical and atypical Rolandic epilepsy we identified truncating and missense mutations in DEPDC5 in ~1.5%. This makes DEPDC5 currently the most relevant gene in focal idiopathic epilepsies.

Conclusion: Surprisingly, in some of the DEPDC5 mutation carriers of larger families cortical dysplasias type IIB, like “bottom of sulcus” dysplasia and focal band heterotopia, were detected. In one child, a heterozygous somatic mutation and an additional mutation in brain tissue was disclosed, possibly encompassing a double hit mechanism like in TSC. Additional prove that GATOR1 plays a pivotal role in focal cortical dysplasia comes from the finding that also both other members of the GATOR 1 complex, NPRL2, NPRL3, were identifies as a genetic cause in other DEPDC5 negative families and individuals with FCD IIb. MTOR activity may be influenced by mTOR inhibitors like everolimus and newer still experimental drugs. Current data will be presented.