Metz J
Department of Hematology, South African Institute for Medical Research, Johannesburg.
Annu Rev Nutr. 1992;12:59-79. doi: 10.1146/annurev.nu.12.070192.000423.
Neuropathy commonly complicates cobalamin (Cb1) deficiency in humans, monkeys, fruit bats, and pigs. The neuropathy is characterized by demyelination of the posterolateral columns of the spinal cord (subacute combined degeneration). The lesion was thought to arise primarily from impairment of the adenosylcobalamin-dependent methylmalonyl CoA mutase reaction, leading to the formation of abnormal odd-chain and branched-chain fatty acids and their incorporation into myelin with resultant demyelination. Data from recently developed animal models of the Cb1 neuropathy induced by exposure to nitrous oxide do not substantiate this hypothesis, but rather identify impairment of the methylcobalamin-dependent methionine synthetase reaction as the more important basic defect. The key evidence for this hypothesis is the ability of methionine to delay the onset of Cb1 neuropathy in experimental Cb1 deficiency. In the Cb1-deficient pig, adenosylhomocysteine accumulates in neural tissue, presumably owing to the inability to recycle homocysteine via the defective methionine synthetase reaction. Accumulation of adenosylhomocysteine results in a fall in the adenosylmethionine:adenosylhomocysteine methylation ratio, and this change is believed to cause defective methylation and demyelination in the nervous system. However, in the Cb1 neuropathy in the fruit bat, adenosylhomocysteine does not accumulate in the nervous system, the methylation ratio does not change, and no defect can be demonstrated in the methylation of myelin lipid or basic protein. Although a central role for methionine in the pathogenesis of the Cb1 neuropathy has been established, defective methylation attendant upon impairment of the methionine synthetase reaction may not be the universal defect underlying the Cb1 neuropathy. This would suggest that the methionine effect could be mediated via its role in formate metabolism or polyamine synthesis, or by some as yet unidentified pathway.
在人类、猴子、果蝠和猪中，神经病变常使钴胺素（Cb1）缺乏症复杂化。这种神经病变的特征是脊髓后外侧柱脱髓鞘（亚急性联合变性）。该病变曾被认为主要源于腺苷钴胺素依赖性甲基丙二酰辅酶A变位酶反应受损，导致异常奇数链和支链脂肪酸的形成，并将其掺入髓磷脂中，从而导致脱髓鞘。最近通过暴露于氧化亚氮诱导的Cb1神经病变动物模型的数据并未证实这一假设，而是确定甲基钴胺素依赖性甲硫氨酸合成酶反应受损是更重要的基本缺陷。这一假设的关键证据是甲硫氨酸能够延缓实验性Cb1缺乏症中Cb1神经病变的发作。在Cb1缺乏的猪中，腺苷同型半胱氨酸在神经组织中积累，这可能是由于通过有缺陷的甲硫氨酸合成酶反应无法使同型半胱氨酸再循环。腺苷同型半胱氨酸的积累导致腺苷甲硫氨酸：腺苷同型半胱氨酸甲基化比率下降，并且这种变化被认为会导致神经系统中的甲基化缺陷和脱髓鞘。然而，在果蝠的Cb1神经病变中，腺苷同型半胱氨酸在神经系统中不积累，甲基化比率不变，并且在髓磷脂脂质或碱性蛋白的甲基化中未发现缺陷。尽管甲硫氨酸在Cb1神经病变发病机制中的核心作用已经确立，但甲硫氨酸合成酶反应受损伴随的甲基化缺陷可能不是Cb1神经病变潜在的普遍缺陷。这表明甲硫氨酸的作用可能是通过其在甲酸代谢或多胺合成中的作用，或通过一些尚未确定的途径介导的。
