Triheptanoin for Glucose Transporter Type I Deficiency (G1D) Modulation of Human Ictogenesis, Cerebral Metabolic Rate, and Cognitive Indices by a Food Supplement
Triheptanoin for Glucose Transporter Type I Deficiency (G1D) Modulation of Human Ictogenesis, Cerebral Metabolic Rate, and Cognitive Indices by a Food Supplement
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DOI：
10.1001/jamaneurol.2014.1584
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发表时间：
2014-10-01
期刊：
影响因子：
29
通讯作者：
Lu, Hanzhang
中科院分区：
文献类型：
--
作者：
Pascual, Juan M.;Liu, Peiying;Lu, Hanzhang
脑代谢障碍的机制和表现形式多种多样，其中许多仍然没有得到充分的理解，因此也被类似地治疗。葡萄糖转运蛋白I型缺陷（G1D）通常与癫痫发作和电图棘波有关。G1D综合征长期以来被认为是能量（即三磷酸腺苷合成）衰竭，如三羧酸（TCA）循环中间体耗竭。事实上，葡萄糖和其他底物通过回补产生TCA。然而，TCA被保存在小鼠G1D，使能源故障的推断过早，并提出了不同的假设，也基于我们的工作，即消费的替代TCA前体的刺激，可能是有害的。其次，常见的生酮饮食导致治疗上违反直觉的血糖降低，可用于G1D大脑，并证明在三分之一的患者中无效。（而不是减少）血糖浓度和刺激TCA循环，包括回补，在G1D中使用中链，食品级甘油三酯三庚酸甘油酯。和参与者在学术环境中进行的非申办的开放标签病例系列。14名儿童和成人G1D谁没有收到生酮饮食被选中，先到先登记的基础上。干预补充的常规饮食与食品级triheptanoin.Main结果和措施首先，我们表明，无论脑电图棘波，大多数癫痫发作是很少可见的，这样的病人或其他人的看法是不足以治疗评估。因此，我们使用定量脑电图，神经心理学，血液分析和磁共振成像脑代谢率measurements.Results一个参与者（7%）没有表现出尖峰波，然而，尖峰波迅速减少70%（P = .001），在其他参与者消费后的triheptanoin。此外，大多数患者的神经心理学表现和脑代谢率增加。11名患者（78%）在长期使用三庚酸甘油酯后没有不良反应。三名患者（21%）出现胃肠道症状，1（7%）停止使用triheptanoin.Conclusions和相关性Triheptanoin可以有利地影响G1D神经功能的主要方面。此外，我们的结果措施构成了一个重要的框架，用于评估与中间代谢受损相关的脑病的治疗。
IMPORTANCE Disorders of brain metabolism are multiform in their mechanisms and manifestations, many of which remain insufficiently understood and are thus similarly treated. Glucose transporter type I deficiency (G1D) is commonly associated with seizures and with electrographic spike-waves. The G1D syndrome has long been attributed to energy (ie, adenosine triphosphate synthetic) failure such as that consequent to tricarboxylic acid (TCA) cycle intermediate depletion. Indeed, glucose and other substrates generate TCAs via anaplerosis. However, TCAs are preserved in murine G1D, rendering energy-failure inferences premature and suggesting a different hypothesis, also grounded on our work, that consumption of alternate TCA precursors is stimulated and may be detrimental. Second, common ketogenic diets lead to a therapeutically counterintuitive reduction in blood glucose available to the G1D brain and prove ineffective in one-third of patients.OBJECTIVE To identify the most helpful outcomes for treatment evaluation and to uphold (rather than diminish) blood glucose concentration and stimulate the TCA cycle, including anaplerosis, in G1D using the medium-chain, food-grade triglyceride triheptanoin.DESIGN, SETTING, AND PARTICIPANTS Unsponsored, open-label cases series conducted in an academic setting. Fourteen children and adults with G1D who were not receiving a ketogenic diet were selected on a first-come, first-enrolled basis.INTERVENTION Supplementation of the regular diet with food-grade triheptanoin.MAIN OUTCOMES AND MEASURES First, we show that, regardless of electroencephalographic spike-waves, most seizures are rarely visible, such that perceptions by patients or others are inadequate for treatment evaluation. Thus, we used quantitative electroencephalographic, neuropsychological, blood analytical, and magnetic resonance imaging cerebral metabolic rate measurements.RESULTS One participant (7%) did not manifest spike-waves; however, spike-waves promptly decreased by 70%(P = .001) in the other participants after consumption of triheptanoin. In addition, the neuropsychological performance and cerebral metabolic rate increased in most patients. Eleven patients (78%) had no adverse effects after prolonged use of triheptanoin. Three patients (21%) experienced gastrointestinal symptoms, and 1 (7%) discontinued the use of triheptanoin.CONCLUSIONS AND RELEVANCE Triheptanoin can favorably influence cardinal aspects of neural function in G1D. In addition, our outcome measures constitute an important framework for the evaluation of therapies for encephalopathies associated with impaired intermediary metabolism.