Schiefermeier M, Kollegger H, Madl C, Polli C, Oder W, Kühn H, Berr F, Ferenci P
Department of Clinical Neurology, University of Vienna, Vienna, Austria.
Brain. 2000 Mar;123 Pt 3:585-90. doi: 10.1093/brain/123.3.585.
Wilson's disease is a disorder of biliary copper excretion that may result in severe neurological symptoms and advanced liver disease. The wide variation of phenotypic disease expression cannot be fully explained by the different mutations of the Wilson disease gene. In neurological disorders, such as Alzheimer's disease, temporal lobe epilepsy and cerebral trauma, the presence of the apolipoprotein E (ApoE) allele epsilon4 is associated with an increased vulnerability of the brain to the effects of the disease, whereas the presence of the ApoE genotype epsilon3/3 appears to provide moderate neuroprotection. We examined whether this hypothesis holds true for the development of neurological symptoms in patients with Wilson's disease. The ApoE genotype and the H1069Q mutation (the most common in Wilson's disease) status were determined by polymerase chain reaction-based mutation assays in 121 well-characterized, symptomatic index patients with Wilson's disease. An investigation profile was established in which the patients were grouped according to the clinical symptoms at presentation, the ApoE genotypes and the status of the H1069Q mutation. Fifty-nine per cent of the 121 patients had the allele combination ApoE epsilon3/3 (21% ApoE epsilon3/4, 19% ApoE epsilon3/2, 1% ApoE epsilon4/2). The distribution of ApoE genotypes did not deviate from known distributions in healthy European subjects. Within the group of 40 H1069Q-homozygous patients, the onset of symptoms was significantly delayed in patients with the ApoE epsilon3/3 genotype (25 +/- 6 years at presentation) compared with patients with the ApoE epsilon3/4 genotype (20 +/- 3 years at presentation). In this study, the ApoE genotype was established as an important factor delaying the onset of neurological and hepatic symptoms, but not modifying phenotypic disease expression in a homogeneous group of patients with Wilson's disease (all H1069Q-homozygotes, similar genetic background). The presence of ApoE epsilon3/3 attenuates clinical manifestations in Wilson's disease by mechanisms which might involve the antioxidant and membrane-stabilizing properties of the ApoE 3 protein.
威尔逊病是一种胆汁铜排泄障碍疾病，可能导致严重的神经症状和晚期肝病。威尔逊病基因的不同突变并不能完全解释该疾病表型表达的广泛差异。在神经疾病中，如阿尔茨海默病、颞叶癫痫和脑外伤，载脂蛋白E（ApoE）ε4等位基因的存在与大脑对疾病影响的易感性增加有关，而ApoE基因型ε3/3的存在似乎能提供一定程度的神经保护作用。我们研究了这一假设在威尔逊病患者神经症状发展中是否成立。通过基于聚合酶链反应的突变分析，对121例特征明确、有症状的威尔逊病索引患者确定了ApoE基因型和H1069Q突变（威尔逊病中最常见的突变）状态。建立了一个调查概况，根据患者就诊时的临床症状、ApoE基因型和H1069Q突变状态对患者进行分组。121例患者中，59%具有ApoE ε3/3等位基因组合（21%为ApoE ε3/4，19%为ApoE ε3/2，1%为ApoE ε4/2）。ApoE基因型的分布与健康欧洲受试者的已知分布没有偏差。在40例H1069Q纯合子患者组中，与ApoE ε3/4基因型患者（就诊时20±3岁）相比，ApoE ε3/3基因型患者的症状出现明显延迟（就诊时25±6岁）。在本研究中，ApoE基因型被确定为延迟威尔逊病患者神经和肝脏症状出现的一个重要因素，但在一组具有相同遗传背景的威尔逊病患者（所有H1069Q纯合子）中，它不会改变疾病的表型表达。ApoE ε3/3的存在通过可能涉及ApoE 3蛋白抗氧化和膜稳定特性的机制减轻了威尔逊病的临床表现。
