Children facing epilepsy: deciphering the underlying genetic mystery

Sami Lina, 3rd year PhD, Sorbonne Université

BACKGROUND:

​

From my early years, a fascination with science, combined with a love for exploration, has been my guiding force. After completing high school in Morocco, I chose to delve into the world of biology in Paris. Commencing with a general undergraduate program, I later specialized in neuroscience through a master's degree. My final internship in a laboratory dedicated to the genetics and pathophysiology of epilepsy deepened my appreciation for the field, prompting my commitment to stay and pursue a Ph.D.

​

In providing a concise background, the brain, the most intricate organ in our body, can face disruption in its precision due to abnormal electrical activity, resulting in unexpected and recurrent epileptic seizures. Epilepsy, a neurological disorder, impacts up to 700,000 people in France and 50 million worldwide, causing significant suffering for patients and their families.

​

My PhD project centers on patients with pharmaco-resistant epilepsy associated with malformations of cortical development (MCD). Their only potential for effective treatment involves a surgical intervention, removing the affected brain area. With the consent of their families, this pathological brain tissue becomes a crucial resource for advancing genetic research on epilepsy.

​

MCDs manifest during the second trimester of pregnancy, a critical period in neurodevelopment. The histopathological hallmarks of this disease primarily involve cortical dyslamination. Research has shown that some MCDs result from either germline (inherited) and/or brain-specific somatic mutations (appearing spontaneously in a fraction of cells, known as somatic mosaicism), which is the focal point of my study. While certain genes, mainly in the mTOR pathway or linked to glycosylation, have been associated with MCDs, some patients still lack a genetic diagnosis. Thus, my PhD aims to unravel the genetic mystery surrounding these cases.

​

​

METHODOLOGY:

​

In the initial two years of my PhD, I explored brain somatic mosaicism using cutting-edge genetic analysis techniques, including high-depth whole-exome and genome sequencing, on over 60 brain-derived DNA samples from MCD patients. This led to the identification of highly promising candidate genes, one of which I am currently developing an animal model for.

Employing a technique known as in utero electroporation, I introduce the candidate gene at embryonic day E14.5 into the specific brain region of interest—in this case, the cortex. This approach creates a focal and mosaic animal model for this gene. The objective is to validate this new gene as disease-causing, ultimately enhancing genetic diagnostics and contributing to the development of personalized medicine.

​

RESULTS and FUTURE WORK: 

​

Below is a NeuN staining, illustrating cortical dyslamination in a typical cortex versus that of a patient with MCD - 

​

​

​

​

​

​

​

​

​

​

​

​

​

​

​

The workflow for the animal model involves two pivotal aspects. Firstly, an exploration of histopathology will be conducted to ascertain whether it faithfully replicates the cortical dyslamination observed in MCD patients. Secondly, the research will progress to the implementation of electrodes within the cortex to facilitate the recording of electroencephalogram signals. The objective is to detect the presence of seizures, mirroring the observed clinical manifestations in patients.