Still considered a rare disease, partial deficiency of the brain glucose transporter type I (G1D) is diagnosed in a broad variety of encephalopathies with increasing frequency. Its most common form – and that with the greatest public health impact – is a childhood-onset epilepsy associated (in all epilepsy cases) with neuropsychological impairment, which is refractory to antiseizure drugs and has consequently remained almost inextricably linked to the ketogenic diet therapy for 25 years. No clinical trials have been conducted for G1D, but the carbohydrate- restricted ketogenic diet (recommended in G1D-associated epilepsy to maximize ketosis and nourish the brain) leads to a physiological - and intuitively counterproductive - decrease in blood glucose available to the brain. Our primary objective is to evaluate whether partial dietary replacement with triheptanoin (C7, a widely available food-grade synthetic triglyceride extensively used in small quantities in human consumption applications) can safely modulate neuropsychological performance (specifically, attention scores) in G1D epilepsy. To support this objective, our published data inform this and other outcome measures chosen here. The scientific motivation is to account for two aspects of brain glucose metabolism: (1) Full degradation of glucose by the tricarboxylic acid (TCA) cycle into CO2 and water; and (2) Stimulation of the TCA cycle (by another glucose fraction amounting to about 20% of all brain glucose) by the refilling of natural TCA precursor loss via carbon-donor reactions collectively termed anaplerosis. In this context, another limitation of ketogenic diets is that their constitutive fatty acids and derivative ketone bodies, are devoid of anaplerotic capacity, and are thus consumed as in (1) without contributing to (2). Results from our and from two other laboratories indicate that C7 metabolites are anaplerotic in rodents, fulfilling both (1) and (2). C7 metabolism also favorably impacts neuronal excitability and convulsions in epileptic mouse models, including G1D. This is the mechanistic framework in which C7 will be examined. Thus, our main hypothesis is that C7 supplementation of a regular diet impacts (and this is key in a rare disease) widely-available outcome measures of G1D encephalopathy. An additional hypothesis, prerequisite for future combined- or comparative-therapy research, is that the addition of C7 to the ketogenic diet does not interfere with it analytically or clinically. These expectations will be tested in G1D patients who are already receiving (i.e., prior to enrollment) either a regular diet or a ketogenic diet. The proposal is significant because its go/no-go perspective and criteria will address whether C7 can be developed as a medical food treatment for G1D. Particularly innovative is the investigation of brain anaplerotic therapy, which can be expanded to disorders associated with deficient brain glucose states such as those identified by fludeoxyglucose-PET scan (for example, head trauma, dementia and lesional epilepsy). The ethical dimensions and projection of this research are underscored by its use of a broadly verifiable (i.e., accessible and reproducible) food-grade intervention for a severe, hardly treatable disease. If successful, this work may thus catalyze a medical practice transformation.

Intellectual impairment, epilepsy and other forms of severe neurological disability caused by mutation of the glucose transporter type I gene, which encodes a key protein situated at the doorstep of brain metabolism, are generally refractory to medication. Glucose transporter type I deficiency (G1D) is associated with a normal lifespan, but can only be alleviated by prolonged, continuous daily interventions such as the ketogenic diet, which can ultimately lead to poor tolerance and incomplete restoration of neural function, and thus constitutes an important health problem. Treatment development for G1D and, potentially, related disorders, fulfills the mission of the NIH by uncovering new fundamental aspects of brain function and by facilitating the development of potential medical food (such as triheptanoin) and other therapies aimed to restore brain metabolism, excitability and neuropsychological performance.