Vonsattel Jean Paul G, Keller Christian, Cortes Ramirez Etty Paola
Department of Pathology, Presbyterian Hospital and Columbia University, New York, NY 10032, USA.
Handb Clin Neurol. 2011;100:83-100. doi: 10.1016/B978-0-444-52014-2.00004-5.
An expansion of a trinucleotide CAG repeat on chromosome 4 causes Huntington disease. The abnormal elongation of the CAG increases the polyglutamine stretch of huntingtin, which becomes proportionally toxic. The mutated huntingtin is ubiquitous in somatic tissues, yet the pathologic changes are apparently restricted to the brain. The degree of the abnormal expansion of the CAG repeats governs the gradually diffuse atrophy of the brain. However, the brunt of the degenerative process involves the striatum. The onset of symptoms is insidious, but the longer the CAG expansion, the earlier their occurrence. They include psychiatric, motor, and cognitive disorders. Patients with adult onset of symptoms are more prone to exhibit choreic movements whereas those with juvenile onset tend to develop parkinsonism or rigidity. Brains from patients with juvenile onset are usually more atrophic than those with adult onset. Brains from patients with late onset of symptoms might show changes occurring in usual aging in addition to those characteristically observed in Huntington disease. Despite recent important discoveries, the pathogenesis of Huntington disease is still not elucidated. Many possible mechanisms underlying the relative selective vulnerability of neurons are being explored. In particular, factors promoting apoptosis, and phenomena causing the toxic aggregation of proteins, or the blockage of trophic factors, or mitochondria dysfunction, and excitoxicity have been studied.
4号染色体上三核苷酸CAG重复序列的扩增会导致亨廷顿病。CAG的异常延长增加了亨廷顿蛋白的多聚谷氨酰胺延伸，这会产生相应的毒性。突变的亨廷顿蛋白在体细胞组织中普遍存在，但病理变化显然仅限于大脑。CAG重复序列异常扩增的程度决定了大脑逐渐弥漫性萎缩。然而，退化过程主要累及纹状体。症状的发作很隐匿，但CAG扩增越长，症状出现得越早。症状包括精神、运动和认知障碍。成年起病的患者更容易出现舞蹈样动作，而青少年起病的患者则倾向于发展为帕金森症或僵硬。青少年起病患者的大脑通常比成年起病患者的大脑萎缩更严重。症状晚发患者的大脑除了具有亨廷顿病的典型特征外，可能还会出现与正常衰老相关的变化。尽管最近有重要发现，但亨廷顿病的发病机制仍未阐明。目前正在探索许多可能导致神经元相对选择性易损性的机制。特别是，促进细胞凋亡的因素、导致蛋白质毒性聚集的现象、营养因子的阻断、线粒体功能障碍和兴奋性毒性都已得到研究。
