Ventriculomegaly and hydrocephalus are associated with loss of function of glycine decarboxylase (Gldc) in mice and in humans suffering from non-ketotic hyperglycinemia (NKH), a neurometabolic disorder characterized by accumulation of excess glycine. Here, we showed that ventriculomegaly in Gldc-deficient mice is preceded by stenosis of the Sylvian aqueduct and malformation or absence of the subcommissural organ and pineal gland. Gldc functions in the glycine cleavage system, a mitochondrial component of folate metabolism, whose malfunction results in accumulation of glycine and diminished supply of glycine-derived 1-carbon units to the folate cycle. We showed that inadequate 1-carbon supply, as opposed to excess glycine, is the cause of hydrocephalus associated with loss of function of the glycine cleavage system. Maternal supplementation with formate prevented both ventriculomegaly, as assessed at prenatal stages, and postnatal development of hydrocephalus in Gldc-deficient mice. Furthermore, ventriculomegaly was rescued by genetic ablation of 5,10-methylene tetrahydrofolate reductase (Mthfr), which results in retention of 1-carbon groups in the folate cycle at the expense of transfer to the methylation cycle. In conclusion, a defect in folate metabolism can lead to prenatal aqueduct stenosis and resultant hydrocephalus. These defects are preventable by maternal supplementation with formate, which acts as a 1-carbon donor.

中文翻译：

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叶酸1-碳代谢受损导致甘氨酸脱羧酶缺乏症小鼠甲酸可预防的脑积水

脑室肥大和脑积水与小鼠和患有非酮症高血糖症（NKH）的人的甘氨酸脱羧酶（Gldc）功能丧失有关，后者是一种以代谢性甘氨酸过多为特征的神经代谢疾病。在这里，我们显示，在Gldc缺陷型小鼠中，脑室肥大之前是Sylvian导水管狭窄，连合下器官和松果体畸形或缺失。Gldc在甘氨酸裂解系统中发挥功能，该系统是叶酸代谢的线粒体成分，其故障会导致甘氨酸蓄积并减少叶酸循环中甘氨酸衍生的1碳单元的供应。我们表明，与过量的甘氨酸相反，不足的1碳供应是导致脑积水的原因，而脑积水与甘氨酸裂解系统的功能丧失有关。产妇补充甲酸盐可预防Gldc缺陷小鼠的脑室肥大，如在产前阶段评估的那样，以及脑积水的出生后发展。此外，通过基因消融5,10-亚甲基四氢叶酸还原酶（Mthfr）挽救了脑室肥大，这导致叶酸循环中保留1-碳基团，但以转移至甲基化循环为代价。总之，叶酸代谢缺陷可导致产前导水管狭窄并导致脑积水。这些缺陷可以通过孕妇补充甲酸酯（作为1碳供体）来预防。10-亚甲基四氢叶酸还原酶（Mthfr），其导致叶酸循环中保留1个碳基团，但以转移至甲基化循环为代价。总之，叶酸代谢缺陷可导致产前导水管狭窄并导致脑积水。这些缺陷可以通过孕妇补充甲酸酯（作为1碳供体）来预防。10-亚甲基四氢叶酸还原酶（Mthfr），其导致叶酸循环中保留1个碳基团，但以转移至甲基化循环为代价。总之，叶酸代谢缺陷可导致产前导水管狭窄并导致脑积水。这些缺陷可以通过孕妇补充甲酸酯（作为1碳供体）来预防。