Department of Pediatric Neurology, Academic Medical Center, PO Box 22660, 1000 AZ, Amsterdam, The Netherlands,
J Inherit Metab Dis. 2013 Nov;36(6):967-72. doi: 10.1007/s10545-013-9590-6. Epub 2013 Feb 8.
Rett syndrome is a neurodevelopmental disorder characterized by cognitive and locomotor regression and stereotypic hand movements. The disorder is caused by mutations in the X chromosomal MECP2 a gene encoding methyl CpG-binding protein. It has been associated with disturbances of cerebral folate homeostasis, as well as with speculations on a compromised DNA-methylation. Folinic acid is the stable form of folate. Its derived intermediate 5-MTHF supports the conversion of homocysteine to methionine, the precursor of S-adenosylmethionine (SAM). This in turn donates its methyl group to various acceptors, including DNA, thereby being converted to S-adenosylhomocysteine (SAH). The SAM/SAH ratio reflects the methylation potential. The goal of our study was to influence DNA methylation processes and ameliorate the clinical symptoms in Rett syndrome. Therefore we examined the hypothesis that folinic acid supplementation, besides increasing cerebrospinal fluid (CSF) 5-MTHF (p = 0.003), influences SAM and SAH and their ratio. In our randomized, double-blind crossover study on folinic acid supplementation, ten female Rett patients received both folinic acid and placebo for 1 year each. It was shown that both SAM and SAH levels in the CSF remained unchanged following folinic acid administration (p = 0.202 and p = 0.097, respectively) in spite of a rise of plasma SAM and SAH (p = 0.007; p = 0.009). There was no significant change in the SAM/SAH ratio either in plasma or CSF. The apparent inability of Rett patients to upregulate SAM and SAH levels in the CSF may contribute to the biochemical anomalies of the Rett syndrome. Our studies warrant further attempts to promote DNA methylation in the true region of interest, i.e. the brain.
雷特综合征是一种神经发育障碍，其特征为认知和运动倒退以及刻板的手部运动。该疾病是由 X 染色体 MECP2a 基因编码的甲基 CpG 结合蛋白的突变引起的。它与脑叶酸稳态的紊乱有关，也与 DNA 甲基化受损有关。叶酸是叶酸的稳定形式。其衍生的中间产物 5-MTHF 支持同型半胱氨酸转化为蛋氨酸，蛋氨酸是 S-腺苷甲硫氨酸（SAM）的前体。SAM 反过来将其甲基供体转移到各种受体上，包括 DNA，从而转化为 S-腺苷同型半胱氨酸（SAH）。SAM/SAH 比值反映了甲基化潜能。我们研究的目的是影响 DNA 甲基化过程并改善雷特综合征的临床症状。因此，我们检验了以下假设：叶酸补充剂除了增加脑脊液（CSF）5-MTHF（p = 0.003）外，还会影响 SAM 和 SAH 及其比值。在我们的叶酸补充剂随机、双盲交叉研究中，10 名女性雷特综合征患者每人分别接受了叶酸和安慰剂治疗 1 年。结果表明，尽管血浆 SAM 和 SAH 升高（p = 0.007；p = 0.009），但在给予叶酸后，CSF 中的 SAM 和 SAH 水平仍保持不变（p = 0.202 和 p = 0.097）。血浆或 CSF 中的 SAM/SAH 比值也没有明显变化。雷特综合征患者似乎无法上调 CSF 中的 SAM 和 SAH 水平，这可能导致雷特综合征的生化异常。我们的研究进一步证明，需要进一步尝试促进真正的感兴趣区域（即大脑）的 DNA 甲基化。
