Liu Lin Thio, MD, PhD – Washington University in St. Louis
Joel R. Garbow, PhD – Washington University in St. Louis
$150,000 TWO YEAR RESEARCH AWARD
Co-funded with JAM for Dravet
Children with Dravet syndrome have drug-resistant epilepsy characterized by different seizure types along with developmental regression and intellectual impairment. Dravet syndrome is genetic with the typical cause being a mutation in a subunit of the neuronal, voltage-gated sodium channel. Ion channels mediate the electrical communication between neurons in the brain, and mutations in ion channels are obvious candidates for causing epilepsy, which is characterized by abnormal electrical activity in the brain. However, several clinical observations including the success of the ketogenic diet (KD) in treating various forms of epilepsy suggest that abnormal metabolism also contributes to the disease process. Although an ion channel mutation causes Dravet syndrome, the often good response to the KD seen in patients and results from animal models of Dravet syndrome indicate that disordered metabolism has a role in this epilepsy syndrome. We hypothesize that Dravet syndrome affects two major metabolic pathways involved in energy production – glycolysis and the tricarboxylic acid (TCA) cycle – and that the KD alters the function of these pathways in Dravet syndrome. We will assess these metabolic pathways in commonly used, genetic mouse model of Dravet syndrome with a magnetic resonance imaging (MRI) based technique. We will use this non-invasive method to compare glycolysis and TCA cycle flux in control and Dravet mice when fed a regular diet and when fed a KD diet. The findings will be directly applicable to patients with Dravet syndrome since the same MRI based technique can be used clinically.