Focal epilepsies are localized in a limited area of the brain. As they are often resistant to antiepileptic drugs, surgical resection of the epileptogenic zone – brain area responsible for seizures – is the only therapeutic solution for patients. Focal epilepsies may be associated with brain malformations, in particular focal cortical dysplasia (FCD). Scientists from Stéphanie Baulac’s team searched for mutations in the resected brain tissue of patients with focal epilepsies and FCD. They discovered several mutations in the MTOR gene, only present in the dysplasia. These researches open the way to the development of new therapeutic targets for the treatment of epilepsy, focusing on the mTOR cellular signaling pathway. These results are published in Neurology: genetics.
Focal epilepsies, which emerge in a restricted brain area, are the most frequent type of epilepsy, affecting about 2/3 of patients. Focal epilepsies may be associated to focal cortical dysplasias (FCD).
FCD are brain malformations appearing during brain development. They are characterized by morphological modifications of the cells (enlarged and dysmorphic cells) and bydisorganization of the cerebral cortex. Patients with severe focal epilepsy and resistant to drug therapies, can be operated to remove the epileptogenic zone (brain area in which seizures emerge). Scientists from Stéphanie Baulac’s team searched for mutations in DNA from post-operative tissues and blood in a cohort of patients with focal epilepsy and FCD.
Their results show that 1/3 of patients from the cohort present a mutation in the MTOR gene within the DNA of the brain lesion. These mutations, called somatic, are detected only in a small proportion of the cells of the brain and are absent from the blood DNA (i.e. they are not present in the entire organism). Moreover, these mutations are recurrent, meaning that the same mutation is found in several patients.
mTOR signaling pathway, which involves MTOR gene among others, controls cell growth and proliferation. It regulates brain development by controlling the production of numerous proteins as well as the migration or the size of neuronal cells. The researchers then showed a hyperactivation of mTOR pathway in enlarged and dysmorphic cells localized in the resected brain tissue of patients, confirming the involvement of the pathway in the pathogenic mechanism. A mutation in MTOR gene in neuronal cells could explain cortical dysplasia outbreak during development.
In collaboration with other European scientists, the team also identified germline mutations (in every cells of the organism) in MTOR, in patients with focal epilepsy with or without brain malformation. Surprisingly, somatic mutations lead to more severe malformations than germline mutations. Thus, a mutation affecting only a few cells of the organism could cause more damages than a constitutive mutation present in every cells of the organism.
Overall, these discoveries support the emerging concept of a mosaic brain, each cell of the brain having its own, unique DNA.
Stéphanie Baulac’s team now tackles the single cell sequencing of DNA and RNA, from post-operative tissues of patients. This will allow to confirm the presence of somatic mutations in cytomegalic cells. The second step is to pair this genetic study with the study of electrophysiological properties of neurons, to highlight the effects of mTOR pathway hyperactivation on neurons function.
A better understanding of mutations responsible for certain cases of epilepsy and of the mechanisms involving the mTOR pathway, open new therapeutic perspectives for the treatment of epilepsy.
Référence : Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy. Rikke S. Møller PhD; Sarah Weckhuysen MD, PhD; Mathilde Chipaux MD, PhD; Elise Marsan; Valerie Taly PhD; E. Martina Bebin MD, MPA; Susan M. Hiatt PhD; Jeremy W Prokop PhD, Kevin M. Bowling PhD; Davide Mei MSc; Valerio Conti PhD; Pierre de la Grange PhD; Sarah Ferrand-Sorbets MD; Georg Dorfmüller MD; Virginie Lambrecq MD, PhD; Line HG Larsen; Eric Leguern MD, PhD; Renzo Guerrini MD, FRCP; Guido Rubboli MD,; Gregory M. Cooper PhD and Stéphanie Baulac PhD.