Folate Receptor Alpha Defect Causes Cerebral Folate Transport Deficiency: A Treatable Neurodegenerative Disorder Associated with Disturbed Myelin Metabolism
Folate Receptor Alpha Defect Causes Cerebral Folate Transport Deficiency: A Treatable Neurodegenerative Disorder Associated with Disturbed Myelin Metabolism
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DOI：
10.1016/j.ajhg.2009.08.005
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发表时间：
2009-09-11
影响因子：
9.8
通讯作者：
Gaertner, Jutta
中科院分区：
文献类型：
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作者：
Steinfeld, Robert;Grapp, Marcel;Gaertner, Jutta
充足的叶酸补充对于多种生物过程和不同的器官系统是必不可少的。目前已知至少有五种不同的遗传性叶酸运输和代谢障碍，所有这些都会导致全身性叶酸缺乏。我们发现了一种遗传性的脑特异性叶酸转运缺陷，这种缺陷是由叶酸受体1(FOLR1)基因编码叶酸受体α(FRα)的突变引起的。三名携带FOLR1突变的患者出现进行性运动障碍、精神运动障碍和癫痫，并显示脑脊液(CSF)中叶酸浓度严重降低。脑磁共振成像(MRI)显示严重的髓鞘减少，基于MR的体内代谢物分析表明白质胆碱和肌醇共同耗竭。用逆转录病毒转染法将FRα或FRβ基因导入患者细胞，可以挽救叶酸结合。此外，脑脊液叶酸浓度，以及神经胶质胆碱和肌醇耗竭，通过叶酸治疗恢复，并在临床改善之前。我们的研究不仅描述了一种以前未知的可治疗的儿童早期疾病，还为参与出生后髓鞘形成和脑发育的叶酸代谢途径提供了新的见解。
Sufficient folate supplementation is essential for a multitude of biological processes and diverse organ systems. At least five distinct inherited disorders of folate transport and metabolism are presently known, all of which cause systemic folate deficiency. We identified an inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 (FOLR1) gene coding for folate receptor alpha (FR alpha). Three patients carrying FOLR1 mutations developed progressive movement disturbance, psychomotor decline, and epilepsy and showed severely reduced folate concentrations in the cerebrospinal fluid (CSF). Brain magnetic resonance imaging (MRI) demonstrated profound hypomyelination, and MR-based in vivo metabolite analysis indicated a combined depletion of white-matter choline and inositol. Retroviral transfection of patient cells with either FR alpha or FR beta could rescue folate binding. Furthermore, CSF folate concentrations, as well as glial choline and inositol depletion, were restored by folinic acid therapy and preceded clinical improvements. Our studies not only characterize a previously unknown and treatable disorder of early childhood, but also provide new insights into the folate metabolic pathways involved in postnatal myelination and brain development.