Is prenatal myo-inositol deficiency a mechanism of CNS injury in galactosemia?
Is prenatal myo-inositol deficiency a mechanism of CNS injury in galactosemia?
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DOI：
10.1007/s10545-010-9260-x
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发表时间：
2011-04-01
影响因子：
4.2
通讯作者：
Berry, Gerard T.
中科院分区：
文献类型：
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作者：
Berry, Gerard T.
由于半乳糖-1-磷酸尿苷酰转移酶（GALT）缺乏引起的典型半乳糖血症与明显的非饮食依赖性并发症相关，包括认知障碍、学习问题和言语缺陷。尽管母体无乳糖饮食，但脐带血红细胞和羊水中的半乳糖-1-磷酸和半乳糖醇均可能升高，因此内源性半乳糖产生可能是导致胎儿半乳糖代谢产物升高以及出生后CNS并发症的原因。由于半乳糖-1-磷酸和半乳糖醇的积累而导致的产前肌醇缺乏可能在出生后CNS功能障碍的产生中起作用。两种独立的机制可能导致胎儿肌醇缺乏症：竞争性抑制肌醇单磷酸酶1（IMPA 1）介导的肌醇单磷酸水解高半乳糖-1-磷酸水平，导致细胞肌醇作为肌醇单磷酸和半乳糖醇诱导的SMIT 1介导的肌醇转运减少螯合。胎儿脑细胞内肌醇的随后减少可导致肌醇缺乏，导致钙和蛋白激酶C信号传导、AKT/mTOR/细胞生长和发育途径、细胞迁移、胰岛素敏感性、血管运输、内吞作用和胞吐作用、肌动蛋白细胞骨架重塑、核代谢、mRNA输出和核孔复合物调节、磷脂酰肌醇锚定蛋白、蛋白磷酸化和/或内源性铁"螯合"。使用基因敲除动物模型，我们已经表明，在子宫内肌醇的显着不足是致命的，但表型可以通过补充怀孕小鼠的饮用水来挽救。如果发现肌醇缺乏症存在于GALT缺乏的胎儿大脑中，则可以考虑通过口服补充孕妇来使用肌醇治疗胎儿。
Classic Galactosemia due to galactose-1-phosphate uridyltransferase (GALT) deficiency is associated with apparent diet-independent complications including cognitive impairment, learning problems and speech defects. As both galactose-1-phosphate and galactitol may be elevated in cord blood erythrocytes and amniotic fluid despite a maternal lactose-free diet, endogenous production of galactose may be responsible for the elevated fetal galactose metabolites, as well as postnatal CNS complications. A prenatal deficiency of myo-inositol due to an accumulation of both galactose-1- phosphate and galactitol may play a role in the production of the postnatal CNS dysfunction. Two independent mechanisms may result in fetal myo-inositol deficiency: competitive inhibition of the inositol monophosphatase1 (IMPA1)-mediated hydrolysis of inositol monophosphate by high galactose-1- phosphate levels leading to a sequestration of cellular myo-inositol as inositol monophosphate and galactitol-induced reduction in SMIT1-mediated myo-inositol transport. The subsequent reduction of myo-inositol within fetal brain cells could lead to inositide deficiencies with resultant perturbations in calcium and protein kinase C signaling, the AKT/mTOR/ cell growth and development pathway, cell migration, insulin sensitivity, vescular trafficking, endocytosis and exocytosis, actin cytoskeletal remodeling, nuclear metabolism, mRNA export and nuclear pore complex regulation, phosphatidylinositol-anchored proteins, protein phosphorylation and/or endogenous iron "chelation". Using a knockout animal model we have shown that a marked deficiency of myo-inositol in utero is lethal but the phenotype can be rescued by supplementing the drinking water of the pregnant mouse. If myo-inositol deficiency is found to exist in the GALT-deficient fetal brain, then the use of myo-inositol to treat the fetus via oral supplementation of the pregnant female may warrant consideration.