Department of Anatomy and Neurobiology, Medical University of Gdansk, 1 Debinki Street, 80-211 Gdańsk, Poland.
Department of Clinical Anatomy, Pomeranian University in Slupsk, Poland.
Folia Morphol (Warsz). 2020;79(2):191-197. doi: 10.5603/FM.a2020.0020. Epub 2020 Feb 19.
The main source of energy for brain and other organs is glucose. To obtain energy for all tissue, glucose has to come through glycolysis; then as pyruvate it is converted to acetyl-CoA by pyruvate dehydrogenase complex (PDC) and finally enters citric acid cycle. What happens when one of these stages become disturb? Mutation in genes encoding subunits of PDC leads to pyruvate dehydrogenase deficiency. Abnormalities in PDC activity result in severe metabolic and brain malformations. For better understanding the development and mechanism of pyruvate dehydrogenase deficiency the murine model of this disease has been created. Studies on a murine model showed similar malformation in brain structures as in the patients suffered from pyruvate dehydrogenase deficiency such as reduced neuronal density, heterotopias of grey matter, reduced size of corpus callosum and pyramids. There is still no effective cure for PDC-deficiency. Promising therapy seemed to be ketogenic diet, which substitutes glucose to ketone bodies as a source of energy. Studies have shown that ketogenic diet decreases lactic acidosis and inhibits brain malformations, but not the mortality in early childhood. The newest reports say that phenylbutyrate increases the level of PDC in the brain, because it reduces the level of inactive form of PDH. Experiments on human fibroblast and zebra fish PDC-deficiency model showed that phenylbutyrate is promising cure to PDC-deficiency. This review summarizes the most important findings on the metabolic and morphological effects of PDC-deficiency and research for treatment therapy.
大脑和其他器官的主要能源物质是葡萄糖。为了给所有组织提供能量，葡萄糖必须通过糖酵解途径获取；然后作为丙酮酸，它被丙酮酸脱氢酶复合物（PDC）转化为乙酰辅酶 A，最后进入柠檬酸循环。如果这些阶段中的任何一个出现问题会怎样？PDC 编码亚基的基因突变导致丙酮酸脱氢酶缺乏。PDC 活性的异常会导致严重的代谢和脑畸形。为了更好地理解丙酮酸脱氢酶缺乏症的发展和机制，已经建立了这种疾病的小鼠模型。对小鼠模型的研究表明，大脑结构的畸形与丙酮酸脱氢酶缺乏症患者相似，如神经元密度降低、灰质异位、胼胝体和锥体体积减小。目前仍然没有针对 PDC 缺乏症的有效治疗方法。有前途的治疗方法似乎是生酮饮食，它用酮体替代葡萄糖作为能量来源。研究表明，生酮饮食可以减少乳酸酸中毒并抑制脑畸形，但不能降低儿童早期的死亡率。最新的报告称，苯丁酸钠可以增加大脑中 PDC 的水平，因为它可以降低 PDH 的无活性形式的水平。在人类成纤维细胞和斑马鱼 PDC 缺乏模型上的实验表明，苯丁酸钠是治疗 PDC 缺乏症的一种很有前途的药物。本文综述了 PDC 缺乏症的代谢和形态学影响以及治疗研究的最重要发现。
