First of its kind study identifies metabolic defects in Dravet Syndrome

New research from the University of Colorado Anschutz Medical Campus is the first to identify defects related to metabolism (how the body processes and uses energy) in lymphoblast cell lines (LCLs) derived from blood samples of children with Dravet syndrome.

Dravet syndrome is a severe form of epilepsy, usually diagnosed in infancy, that is associated with developmental delays and severe seizures. It has long been recognized for its neurological symptoms but its underlying metabolic issues, especially at the cellular level (specifically mitochondrial function), have not been extensively explored until this study.

The findings from this study were published today in Epilepsia.

“It’s been proven that some children with Dravet syndrome respond to ketogenic diets, which suggests that energy metabolism is somehow involved in the condition. Our goal was to explore this connection further to gain a deeper understanding of its role in managing the syndrome,” said the paper’s senior author Manisha Patel, PhD, Associate Dean for Research at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences.

The pilot study looked at the blood-derived immune cells of eight children with Davet syndrome with known mutations in their sodium channels to create LCLs. They then compared them to age- and sex-matched control LCLs to explore whether the cells from children with the condition exhibit different energy metabolism characteristics.

“By using the LCLs, we’re able to look at patients with a variety of mutations in a non-invasive way. This gets us closer to a full picture of what’s happening in their bodies and phenotype that may be causing their seizures and severe symptoms,” said co-author Kelly Knupp, MD, an associate professor of pediatrics and neurology at the University of Colorado School of Medicine and a pediatric epileptologist at Children’s Hospital Colorado.

In children with Dravet syndrome, the researchers found significant mitochondrial dysfunction in their LCLs. These cells had lower energy production, with particular problems in mitochondrial respiration. To compensate, the cells shifted towards using fatty acids for energy. Despite this, other aspects of the cells, such as glucose metabolism and mitochondrial structure, appeared normal. This study suggests that mitochondrial defects play a role in the metabolic dysfunction observed in Dravet syndrome. These metabolic alterations could help explain the neurological symptoms of Dravet syndrome, like seizures and developmental delays, which require large amounts of energy in the brain.

“This opens the door for further research into the role of mitochondrial dysfunction in epilepsy and other neurological disorders. Understanding these defects could lead to new treatment options aimed at improving cellular energy production, potentially benefiting children and adults with Dravet syndrome or have a similar condition,” adds Patel.

This research was made possible through a collaborative research approach between the CU Skaggs School of Pharmacy and Children’s Hospital Colorado with funding from the Dravet Syndrome Foundation. The paper's first author Anna G. Figueroa is a 4th year PharmD student embarking on a PhD degree in the CU Skaggs School of Pharmacy and Pharmaceutical Sciences. She helped lead the study and is planning to conduct her PhD thesis on the impact of metabolic defects in Dravet syndrome.

About the University of Colorado Anschutz Medical Campus

The University of Colorado Anschutz Medical Campus is a world-class medical destination at the forefront of transformative science, medicine, education and patient care. The campus encompasses the University of Colorado health professional schools, more than 60 centers and institutes and two nationally ranked independent hospitals - UCHealth University of Colorado Hospital and Children's Hospital Colorado – which see more than two million adult and pediatric patient visits yearly. Innovative, interconnected and highly collaborative, the CU Anschutz Medical Campus delivers life-changing treatments, patient care and professional training and conducts world-renowned research fueled by $910 million in annual research funding, including $757 million in sponsored awards and $153 million in philanthropic gifts.