Energy metabolism, adenosine, and glutamate signaling reprogramming by decanoic acid in Glut1 disorder syndrome

Glut1 deficiency syndrome (Glut1DS) leads to neurological and cognitive symptoms and is primarily treated using carbohydrate-restricted ketogenic diets. However, a recent clinical trial of a less restrictive, non-ketogenic, medium chain triglyceride (MCT) diet with a high decanoic acid content suggests efficacy in Glut1DS treatment. Here, we employ human Glut1DS-derived iPSCs to investigate a role for these medium chain fatty acids in the regulation of gene expression as a proxy for metabolic reprogramming. We show that the new high decanoic blend reproduces many therapeutic changes in energy metabolism-related gene expression seen during glucose-restricted ketogenic diets, including enhanced expression of β-oxidation, TCA cycle, and oxidative phosphorylation-related genes, but under high glucose conditions. These treatments also unexpectedly regulate transcription of adenosine signaling and synaptic transmission-related genes. This study thus identifies potential molecular mechanisms of decanoic acid that may underlie its clinical benefit in Glut1DS and expands its role to other genetic epilepsies. PLAIN LANGUAGE SUMMARY: Ketogenic diets provide the first-choice treatment for glucose transporter type 1 deficiency syndrome (Glut1DS), where reduced carbohydrate intake triggers the production of ketones as the therapeutic mechanism. Alternatively, a new, flexible medium chain triglyceride diet has been developed that does not involve reduced carbohydrate restriction nor ketone production. This study investigates the metabolic mechanisms underlying this diet in Glut1DS patient-derived stem cells. Interestingly, the diet mimicked the beneficial effects of ketogenic diets to improve energy metabolism, and surprisingly indicated new ways that the diet may provide therapeutic benefit in Glut1DS treatment.