ALDH1L2, a mitochondrial enzyme in folate metabolism, converts 10-formyl-THF (10-formyltetrahydrofolate) to THF (tetrahydrofolate) and CO₂. At the cellular level, deficiency of this NADP⁺-dependent reaction results in marked reduction in NADPH/NADP⁺ ratio and reduced mitochondrial ATP. Thus far, a single patient with biallelic ALDH1L2 variants and the phenotype of a neurodevelopmental disorder has been reported. Here, we describe another patient with a neurodevelopmental disorder associated with a novel homozygous missense variant in ALDH1L2, Pro133His. The variant caused marked reduction in the ALDH1L2 enzyme activity in skin fibroblasts derived from the patient as probed by 10-FDDF, a stable synthetic analog of 10-formyl-THF. Additional associated abnormalities in these fibroblasts include reduced NADPH/NADP⁺ ratio and pool of mitochondrial ATP, upregulated autophagy and dramatically altered metabolomic profile. Overall, our study further supports a link between ALDH1L2 deficiency and abnormal neurodevelopment in humans.

中文翻译：

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进一步描述 ALDH1L2 相关神经发育障碍的表型和代谢组学特征

ALDH1L2 是叶酸代谢中的一种线粒体酶，可将 10-甲酰基-THF（10-甲酰四氢叶酸）转化为 THF（四氢叶酸）和 CO ₂。在细胞水平上，这种 NADP ^{+依赖性反应的缺乏会导致 NADPH/NADP +}比率显着降低和线粒体 ATP 减少。迄今为止，已报道了一名患有双等位基因ALDH1L2变异和神经发育障碍表型的患者。在这里，我们描述了另一位患有神经发育障碍的患者，该障碍与ALDH1L2中的新型纯合错义变异（Pro133His）相关。通过 10-FDDF（10-甲酰基-THF 的稳定合成类似物）检测，该变异导致患者皮肤成纤维细胞中 ALDH1L2 酶活性显着降低。这些成纤维细胞中其他相关的异常包括 NADPH/NADP ⁺比率和线粒体 ATP 库降低、自噬上调以及代谢组学特征显着改变。总体而言，我们的研究进一步支持 ALDH1L2 缺陷与人类神经发育异常之间的联系。