The role of somatic mutational events in the pathogenesis of epilepsy

There has been rapid progress in defining novel causative gene variants responsible for a large spectrum of human epilepsy syndromes and subtypes. Of particular interest is the discovery that somatic mutations, for example, noninherited mutations occurring in neuroglial progenitor cells during embryonic brain development, are highly linked to malformations of cortical development (MCD) such as focal cortical dysplasia (FCD) type II and hemimegalencephaly.

Somatic gene variants have been identified in genes encoding regulatory proteins within the mechanistic target of rapamycin (mTOR) signaling cascade and have thus comprised the group classified as mTORopathies. FCD II and hemimegalencephaly often result from mutations in identical genes suggesting that these are spectrum disorders. An exciting recent development has been the identification of somatic mutations causing both FCD Ia and nonlesional neocortical epilepsy.

Defining somatic gene mutations in brain tissue specimens has shed new light on how MCD form and the mechanisms of epileptogenesis associated with MCD. Trials of mTOR inhibitors in tuberous sclerosis complex have demonstrated that inhibition of mTOR activation in mTORopathies can reduce seizure frequency. New somatic mutations found for a variety of epilepsy syndromes may provide new targets for clinical therapeutics.