Margolis R L, O'Hearn E, Rosenblatt A, Willour V, Holmes S E, Franz M L, Callahan C, Hwang H S, Troncoso J C, Ross C A
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Ann Neurol. 2001 Dec;50(6):373-80. doi: 10.1002/ana.1312.
Huntington's disease (HD) is an autosomal dominant disorder characterized by abnormalities of movement, cognition, and emotion and selective atrophy of the striatum and cerebral cortex. While the etiology of HD is known to be a CAG trinucleotide repeat expansion, the pathways by which this mutation causes HD pathology remain unclear. We now report a large pedigree with an autosomal dominant disorder that is clinically similar to HD and that arises from a different CAG expansion mutation. The disorder is characterized by onset in the fourth decade, involuntary movements and abnormalities of voluntary movement, psychiatric symptoms, weight loss, dementia, and a relentless course with death about 20 years after disease onset. Brain magnetic resonance imaging scans and an autopsy revealed marked striatal atrophy and moderate cortical atrophy, with striatal neurodegeneration in a dorsal to ventral gradient and occasional intranuclear inclusions. All tested affected individuals, and no tested unaffecteds, have a CAG trinucleotide repeat expansion of 50 to 60 triplets, as determined by the repeat expansion detection assay. Tests for the HD expansion, for all other known CAG expansion mutations, and for linkage to chromosomes 20p and 4p were negative, indicating that this mutation is novel. Cloning the causative CAG expansion mutation for this new disease, which we have termed Huntington's disease-like 2, may yield valuable insight into the pathogenesis of HD and related disorders.
亨廷顿舞蹈病（HD）是一种常染色体显性疾病，其特征为运动、认知和情感异常，以及纹状体和大脑皮质的选择性萎缩。虽然已知HD的病因是CAG三核苷酸重复序列扩增，但这种突变导致HD病理改变的途径仍不清楚。我们现在报告一个常染色体显性疾病的大家系，该疾病在临床上与HD相似，且由不同的CAG扩增突变引起。该疾病的特征为发病于40岁左右，有不自主运动和自主运动异常、精神症状、体重减轻、痴呆，病程呈进行性，发病后约20年死亡。脑磁共振成像扫描和尸检显示纹状体明显萎缩和中度皮质萎缩，纹状体神经变性呈背侧至腹侧梯度，并有偶尔的核内包涵体。通过重复序列扩增检测试验确定，所有检测的患病个体均有50至60个三联体的CAG三核苷酸重复序列扩增，而所有检测的未患病个体均无此扩增。对HD扩增、所有其他已知的CAG扩增突变以及与20号染色体短臂和4号染色体短臂的连锁分析均为阴性，表明该突变是新的。克隆这种我们称为亨廷顿舞蹈病样2型的新疾病的致病CAG扩增突变，可能会为HD及相关疾病的发病机制提供有价值的见解。
