New Gene Linked to Severe, Treatment-Resistant Epilepsy Discovered by Montreal Researchers

A team of researchers in Montreal has pinpointed a new gene potentially responsible for a rare and severe form of epilepsy. This discovery, stemming from work at the Research Centre of the Montreal University Health Centre (CRCHUM), offers a crucial step toward diagnosing the condition in patients where the cause has remained elusive. The findings, currently available on Medrxiv while awaiting publication in a peer-reviewed journal, could significantly impact families navigating the complexities of treatment-resistant epilepsy.

Understanding Treatment-Resistant Epilepsy

Professor Eric Samarut, who led the research, describes the form of epilepsy under investigation as particularly challenging. “We’re talking about very severe cases of epilepsy that are often resistant to available anti-epileptic treatments,” he explained. These epilepsies frequently manifest in early childhood and persist into adulthood, profoundly affecting patients’ quality of life. A significant hurdle in addressing these cases is the unknown cause – in up to 50% of instances, the underlying reason for the seizures remains unidentified. Without knowing the root cause, determining the appropriate course of treatment becomes exceptionally difficult.

The breakthrough came through a collaboration with the mother of two young girls diagnosed with Lennox-Gastaut syndrome, a severe form of childhood epilepsy. Recognizing a potential genetic link, Professor Samarut and his colleagues focused on the THAP12 gene. Their research suggests this gene is responsible for an “autosomal recessive” form of epilepsy – meaning the disease develops only when both copies of the gene, one inherited from each parent, are defective.

The Role of THAP12 and Genetic Investigation

The family’s situation – two sisters both affected – strongly indicated a genetic component. “The fact that there were two sisters really made us suspect a genetic cause,” Samarut noted. Interestingly, the parents had chosen to have a second child despite the first daughter’s illness, as initial assessments hadn’t pointed to a genetic disorder. Although, a comparative analysis of the girls’ genomes, alongside their parents’, revealed two genetic variants.

To understand the impact of these variants, the researchers replicated them in both mice and zebrafish – a species sharing approximately 80% of our genes. The results were striking. The genetic mutations significantly reduced the production of a protein, the function of which was previously unknown. The consequences were severe: early mortality, major disruptions in brain development, abnormal neuronal activity, and increased susceptibility to seizures. Le Journal de Montréal reported on these findings.

Prior to this research, the THAP12 gene hadn’t been linked to neurological diseases, and its function remained a mystery. Now, scientists understand it plays a critical role in the very early stages of embryonic development and in the survival of progenitor cells that eventually become nerve cells. When the gene doesn’t function correctly, brain development is compromised, leading to abnormal brain activity and a heightened risk of epileptic seizures.

Implications for Diagnosis and Future Treatments

Professor Samarut acknowledged the challenges of proving a link to a gene with an unknown function. “How do you prove there’s a problem with the function of something whose function you don’t understand? It’s a bit of a circle.” However, the converging evidence now strongly suggests these mutations cause a loss of function within the gene.

While the development of new treatments, particularly gene therapies, is a potential long-term outcome, the immediate impact of this discovery lies in improved diagnostics. A genetic diagnosis can be a pivotal step for families seeking answers and navigating treatment options. “Genetic diagnosis is really an essential first step in their therapeutic odyssey,” Samarut emphasized. “And often it makes them feel better to position a name, to put a cause, even if it doesn’t change their daily lives right away, it establishes the credibility of their illness and really helps them move forward.”

Expanding the Genetic Landscape

The THAP12 gene is one of eleven “siblings” within its gene family, suggesting the potential for uncovering new functions within this group, particularly concerning the central nervous system. This opens avenues for further research into related genetic factors influencing neurological health.

The researchers have made their findings available on Medrxiv to benefit other undiagnosed patients while awaiting formal publication in a scientific journal – a process that can take up to two years. This proactive approach underscores the urgency of sharing knowledge to improve patient care.

What’s Next: Refining Understanding and Exploring Therapies

The identification of THAP12 as a key gene in this specific form of epilepsy is not the end of the story, but rather a crucial starting point. Further research will focus on fully elucidating the protein’s normal function and how its disruption leads to the observed neurological effects. This deeper understanding is essential for developing targeted therapies. Clinical trials exploring potential gene therapies or other interventions aimed at restoring THAP12 function are likely several years away, but this discovery provides a clear target for those efforts. Ongoing genomic surveillance and data sharing will be vital to identify additional cases and refine our understanding of the genetic landscape of epilepsy.