National Institute of Child Health and Human Development, NIH, Building 10 Room 10N313, 10 Center Drive MSC 1853, Bethesda, MD 20892-1853, USA.
Nat Rev Neurol. 2011 Jan;7(1):15-29. doi: 10.1038/nrneurol.2010.180.
This Review summarizes recent advances in understanding copper-transporting ATPase 1 (ATP7A), and examines the neurological phenotypes associated with dysfunction of this protein. Involvement of ATP7A in axonal outgrowth, synapse integrity and neuronal activation underscores the fundamental importance of copper metabolism to neurological function. Defects in ATP7A cause Menkes disease, an infantile-onset, lethal condition. Neonatal diagnosis and early treatment with copper injections enhance survival in patients with this disease, and can normalize clinical outcomes if mutant ATP7A molecules retain small amounts of residual activity. Gene replacement rescues a mouse model of Menkes disease, suggesting a potential therapeutic approach for patients with complete loss-of-function ATP7A mutations. Remarkably, a newly discovered ATP7A disorder-isolated distal motor neuropathy-has none of the characteristic clinical or biochemical abnormalities of Menkes disease or its milder allelic variant occipital horn syndrome (OHS), instead resembling Charcot-Marie-Tooth disease type 2. These findings indicate that ATP7A has a crucial but previously unappreciated role in motor neuron maintenance, and that the mechanism underlying ATP7A-related distal motor neuropathy is distinct from Menkes disease and OHS pathophysiology. Collectively, these insights refine our knowledge of the neurology of ATP7A-related copper transport diseases and pave the way for further progress in understanding ATP7A function.
本文综述了人们对铜转运 ATP 酶 1（ATP7A）的最新认识，并探讨了该蛋白功能障碍与神经表型的关联。ATP7A 参与轴突生长、突触完整性和神经元激活，这凸显了铜代谢对神经功能的重要性。ATP7A 的缺陷会导致 Menkes 病，这是一种婴儿期发病、致命的疾病。新生儿诊断并早期采用铜注射治疗可提高此类患者的存活率，如果突变 ATP7A 分子保留少量残余活性，则可使临床结局正常化。基因替代可挽救 Menkes 病的小鼠模型，提示针对完全丧失功能的 ATP7A 突变患者可能具有治疗方法。值得注意的是，新发现的 ATP7A 疾病孤立性远端运动神经病与 Menkes 病或其轻度等位基因变异枕骨角综合征（OHS）均无特征性的临床或生化异常，反而类似于腓骨肌萎缩症 2 型。这些发现表明，ATP7A 在运动神经元维持中具有关键但以前未被认识到的作用，并且 ATP7A 相关远端运动神经病的发病机制与 Menkes 病和 OHS 病理生理学不同。总之，这些认识完善了我们对 ATP7A 相关铜转运疾病神经学的了解，并为进一步深入研究 ATP7A 功能铺平了道路。
