Approximately 1 in 200 children in Ireland have epilepsy of whom 20 – 30 % do not have their seizures controlled by available medication. Poor seizure control has devastating consequences for children, increasing risk of physical harm and neurodevelopmental delay. Ketogenic diet therapies (KDT) represent one of the most effective treatments for refractory epilepsy in children. The diet forces the body to use fats rather than carbohydrates for energy, producing ketone bodies and altering brain metabolism. KDT can reduce seizures by as much as 90% but about half of children fail to show any improvement. The identification of a predictor of KDT efficacy would enable clinicians to select those patients who will benefit most, while avoiding children having to adhere to KDT unnecessarily. Despite various efforts, reliable predictors of KDT response have not been found. Important roles have recently emerged for microRNAs in the pathophysiology of epilepsy. These small endogenous noncoding RNAs function by sequence-specific binding to target messenger RNAs resulting in lower protein levels. MicroRNAs are also present in various biofluids due to passive and active release, including from damaged cells. Their stability in biofluids and select expression in particular brain cell types mean they have strong biomarker (diagnostic) potential. In pilot work we have identified a microRNA signature in blood for epilepsy and we show the KDT alters brain levels of these molecules. The proposed research will discover and validate microRNA biomarkers in children with epilepsy and explore their predictive value for seizure control on KDT. We will also explore novel biofluid sources which could avoid unnecessary blood sampling (venipuncture). These studies will help predict the efficacy and understand the mechanism of this important alternative treatment for refractory epilepsy in children.