A deuterium MRS study of the effect of the ketogenic diet on β-hydroxybutyrate metabolism in a mouse model of Dravet syndrome

Motivation: Children with Dravet syndrome, a drug-resistant epilepsy, often show a positive response to the ketogenic diet (KD) where the TCA cycle is driven mainly by ketones. Goal(s): To monitor TCA cycle metabolism of ketone body β-hydroxybutyrate in wild-type and Dravet mouse models comparing normal diet (ND) vs. KD. Approach: Deuterium (2H) single-voxel brain MRS is applied to wild-type and Dravet mouse models following subcutaneous administration of [3,4,4,4-2H4]β-hydroxybutyrate. Results: Mice on KD vs. ND show enhanced brain uptake of β-hydroxybutyrate (p < 0.001) with subsequent increase in glutamine+glutamate (“Glx”) production (p < 0.002), evidence that the KD upregulates brain monocarboxylate transporters. Impact: Deuterium metabolic imaging quantification of TCA cycle flux in individual Dravet patients may (i) assess metabolic dysfunction, (ii) assist in selecting the best treatment option, and (iii) allow optimization of the diet. Hence development of a personalized treatment plan.