Dietary treatment of Glucose Transporter Type 1 Deficiency (G1D)

脑葡萄糖转运体I型部分缺乏症（G1D）仍然被认为是一种罕见的疾病，在各种脑病中被诊断出来的频率越来越高。其最常见的形式——也是对公共卫生影响最大的形式——是儿童期发作的癫痫，（在所有癫痫病例中）伴有神经心理损伤，抗癫痫药物对其难以治愈，因此25年来几乎一直与生酮饮食疗法密不可分。目前还没有针对G1D的临床试验，但是限制碳水化合物的生酮饮食（推荐用于与G1D相关的癫痫，以最大限度地发挥酮症作用并滋养大脑）会导致大脑可用血糖的生理-直觉上适得其反-降低。我们的主要目的是评估用三庚烷酸（C7，一种广泛使用的食品级合成甘油三酯，广泛用于少量人类消费应用）替代部分膳食是否可以安全地调节G1D癫痫患者的神经心理表现（特别是注意力评分）。为了支持这一目标，我们公布的数据为本文选择的这一结果和其他结果提供了依据。科学动机是考虑脑葡萄糖代谢的两个方面：(1)葡萄糖通过三羧酸（TCA）循环完全降解为二氧化碳和水；(2)通过碳供体反应重新填充天然TCA前体损失，刺激TCA循环（由约占所有脑葡萄糖的20%的另一葡萄糖部分）

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.