Dietary treatment of Glucose Transporter Type 1 Deficiency (G1D)

大脑葡萄糖转运蛋白I型(G1D)部分缺乏症仍然被认为是一种罕见的疾病，在各种脑病中被诊断出的频率越来越高。其最常见的形式--也是对公共卫生影响最大的形式--是一种儿童发作性癫痫，(在所有癫痫病例中)与神经心理损害有关，这种疾病对抗癫痫药物无效，因此25年来一直与生酮饮食疗法几乎密不可分。目前还没有针对G1D的临床试验，但限制碳水化合物的生酮饮食(在G1D相关的癫痫中推荐，以最大化酮症和滋养大脑)会导致大脑可用血糖的生理性--以及直觉上适得其反的--下降。我们的主要目标是评估用三庚酸(C7，一种广泛存在的食品级合成甘油三酯，在人类消费应用中被广泛使用)部分饮食替代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，我们公布的数据为这一指标和此处选择的其他结果指标提供了参考。科学动机是为了解释大脑葡萄糖代谢的两个方面：(1)三羧酸(TCA)循环将葡萄糖完全降解为二氧化碳和水；(2)通过碳供体反应补充天然TCA前体损失，刺激TCA循环(通过另一个葡萄糖部分，约占所有大脑葡萄糖的20%)。 统称为再生障碍症。在这种情况下，生酮饮食的另一个限制是它们的组成脂肪酸和衍生的酮体缺乏性欲能力，因此像(1)中那样被消耗，而不会导致(2)。我们和另外两个实验室的结果表明，C7代谢物在啮齿类动物中是无性的，同时满足(1)和(2)。C7代谢也有利于影响癫痫小鼠模型的神经元兴奋性和惊厥，包括G1D。这是对C7进行研究的机械框架。因此，我们的主要假设是，规律饮食的C7补充剂影响(这是一种罕见疾病的关键)广泛可用的G1D脑病预后指标。另一个假设是，未来联合疗法或比较疗法研究的先决条件是，在生酮饮食中添加C7在分析或临床上不会干扰它。这些期望将在已经接受(即在登记之前)常规饮食或生酮饮食的G1D患者中进行测试。这项提议意义重大，因为它的通过/不通过的观点和标准将解决C7是否可以被开发为治疗G1D的医疗食品。特别具有创新性的是对脑性失眠疗法的研究，这种疗法可以扩展到与大脑葡萄糖缺乏状态相关的疾病，例如通过氟脱氧葡萄糖-正电子发射计算机断层扫描确定的疾病(例如，头部创伤、痴呆症和癫痫)。这项研究使用了一种广泛可验证的(即，可获得和可重复的)食品级干预措施来治疗一种严重的、难以治愈的疾病，这突显了这项研究的伦理层面和预测。如果成功，这项工作可能会因此催化医疗实践的转变。

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.