Turning genetic discoveries into answers for children with epilepsy

For some children with severe epileptic encephalopathies, every seizure is a mystery. Despite decades of research, uncovering the root cause of these seizures — and how to prevent them — remains one of the most elusive challenges in pediatric neurology.

Developmental and epileptic encephalopathies (DEEs) are severe neurological disorders affecting thousands of children worldwide. These conditions are characterized by frequent and severe seizures, developmental delays, and cognitive impairments. While some cases have identifiable triggers or underlying conditions, a significant number of children with DEEs have no known cause, making diagnosis and treatment particularly challenging.

Heather Mefford, MD, PhD, St. Jude Pediatric Translational Neuroscience Initiative, Center for Pediatric Neurological Disease Research and Department of Cell & Molecular Biology, is a clinician-scientist specializing in genetic epilepsies. Her work focuses on uncovering the genetic changes that may lead to seizures and understanding how these mutations cause epilepsy. 

“Understanding what goes wrong to cause disease helps us understand what needs to go right to be healthy and provides potential new targets for treating disease,” said Mefford.

The diagnostic landscape

DEEs are highly heterogeneous disorders with various underlying causes, making them difficult to pinpoint, diagnose and treat. Genetic testing allows scientists to determine if DNA is driving these disorders. 

“DEEs are severe conditions that present soon after birth; these are features that led us to believe these epilepsies might have a genetic basis. It turns out we were right,” Mefford explains. “We found that many genetic mutations can lead to severe forms of epilepsy, and we’ve continued to build on that work ever since.”

By identifying the genetic causes of pediatric DEEs, Mefford and her team aim to improve diagnostics, develop accurate disease models for scientific study and pave the way for more effective, personalized treatments.

However, getting there will require surmounting some remaining challenges, particularly fully understanding the complexities of genetic variations.

Pushing the boundaries of genetic diagnosis

Despite significant progress in genetic testing and sequencing technologies, diagnosing pediatric seizure disorders remains arduous. While 50% of children with severe early-onset epilepsy have a confirmed genetic cause, the underlying cause remains elusive in the remaining half of cases. The difficulty lies in reading the DNA sequence and determining which subtle or previously unknown change, if any, might be driving the disease.

“Interpreting DNA in epilepsy is challenging because many genetic mutations are not fully understood, and some may have subtle effects or involve complex interactions that are difficult to pinpoint as the cause of the disease,” explained Mefford.

The nuance involved in interpreting and analyzing genetic changes poses a significant hurdle. Historically, the focus has been on sequencing just a few genes in a child with epilepsy, but this has been ineffective. Mefford and her team are working to improve this situation by utilizing robust high-throughput sequencing technologies such as whole-exome and whole-genome sequencing. Now, they sequence both parents’ entire genome and DNA to identify new or inherited mutations that may be driving the disorder. With these technologies, they hope to improve the interpretation of genetic data to understand what goes wrong when a child has a genetic change that causes epilepsy. 

“We often compare the child’s DNA to their parents’ to find changes,” explained Mefford. “Many severe cases involve new mutations not found in either parent or a combination of inherited changes that only cause problems when they come together.”

Through this work, the team has discovered several genes previously not known to be linked to DEEs. Mefford and her team are taking the work further, using epigenetic tools to identify disease-specific patterns related to how genes are turned on and off (DNA methylation) to uncover the causes of previously unsolved epileptic neurological disorders.

Leveraging innovative models to understand neurological disorders

Directly investigating underlying neurological disorders’ cellular and molecular mechanisms is extremely challenging because, unlike muscle or skin tissue samples, which can be obtained through biopsies and studied in the laboratory, it is often too invasive to take brain tissue samples.

To overcome this, researchers use patient-derived cell lines, reprogramming skin cells into stem cells that can then be differentiated into neurons or other neuron-like cells. This approach allows Mefford’s team to study how genetic mutations affect cell growth, electrical activity and signaling pathways.

Mefford’s team has also employed cortical organoids, three-dimensional brain models derived from patient cells, to deepen their investigation of neurological disorders and explore potential therapeutic options. These organoids closely replicate the human brain’s structure and function, offering a more accurate and physiologically relevant model for studying neurological diseases compared to traditional two-dimensional cell cultures.

“By identifying the genetic changes responsible for epilepsy, studying them in patient-derived cells and modeling them, we can better understand the disease and use that knowledge to design more precise therapies,” said Mefford.

Bridging the gap between diagnosis and treatment

While identifying the genetic causes of epilepsy is a critical first step toward precision medicine, it is only part of the journey. In some cases, even when a genetic diagnosis is made, a specific treatment is often not yet available. This gap between diagnosis and treatment creates a major hurdle not only for families eager for solutions once a cause is identified but also for clinicians and researchers striving to translate these discoveries into targeted therapies.

“Most current treatments for kids with epilepsy aim to control the seizures, but they often fall short and rarely address the developmental delays these children experience,” said Mefford. “Our goal is to pinpoint the most promising genetic targets so we can develop truly targeted and effective therapies. Then, we hope to apply those insights more broadly to help as many children as possible.

“We want to be able to go all the way — from identifying the mutation to delivering a personalized treatment that truly makes a difference,” Mefford continued.

Achieving that ideal — moving from mutation to treatment — requires more than just lab work; it demands close collaboration with patients, families and other institutions. This is where the Pediatric Translational Neuroscience Initiative, with its research, clinical and partnership pillars, helps. 

“We work closely with advocacy groups focused on specific genetic epilepsies to connect with families, enroll patients in our research and better understand the condition,” Mefford said. “This kind of clinical research, combined with other collaborations, plays a vital role in moving our work forward.”

The connection with patients and their families remains a driving force behind the research, providing essential clinical insights and a reminder of the real-world impact and urgency behind the work.