Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
Curr Gene Ther. 2018;18(2):68-89. doi: 10.2174/1566523218666180404162622.
Tay-Sachs disease, caused by impaired β-N-acetylhexosaminidase activity, was the first GM2 gangliosidosis to be studied and one of the most severe and earliest lysosomal diseases to be described. The condition, associated with the pathological build-up of GM2 ganglioside, has acquired almost iconic status and serves as a paradigm in the study of lysosomal storage diseases. Inherited as a classical autosomal recessive disorder, this global disease of the nervous system induces developmental arrest with regression of attained milestones; neurodegeneration progresses rapidly to cause premature death in young children. There is no effective treatment beyond palliative care, and while the genetic basis of GM2 gangliosidosis is well established, the molecular and cellular events, from diseasecausing mutations and glycosphingolipid storage to disease manifestations, remain to be fully delineated. Several therapeutic approaches have been attempted in patients, including enzymatic augmentation, bone marrow transplantation, enzyme enhancement, and substrate reduction therapy. Hitherto, none of these stratagems has materially altered the course of the disease. Authentic animal models of GM2 gangliodidosis have facilitated in-depth evaluation of innovative applications such as gene transfer, which in contrast to other interventions, shows great promise. This review outlines current knowledge pertaining the pathobiology as well as potential innovative treatments for the GM2 gangliosidoses.
泰萨二氏病，由β-N-乙酰己糖胺酶活性缺陷引起，是首例被研究的 GM2 神经节苷脂贮积症，也是最早被描述的严重溶酶体贮积症之一。这种与 GM2 神经节苷脂病理性堆积相关的疾病几乎已成标志性病症，为溶酶体贮积症的研究提供了范例。作为一种经典的常染色体隐性遗传病，这种全球性的神经系统疾病会导致发育停滞和已获得的发育里程碑倒退；神经退行性变迅速进展，导致幼儿早亡。除了姑息治疗外，尚无有效治疗方法，尽管 GM2 神经节苷脂贮积症的遗传基础已得到充分确立，但从致病突变和糖脂贮积到疾病表现的分子和细胞事件仍有待充分描述。已经在患者中尝试了几种治疗方法，包括酶增强、骨髓移植、酶增强和底物减少疗法。迄今为止，这些策略都没有实质性地改变疾病进程。GM2 神经节苷脂贮积症的真实动物模型促进了基因转移等创新应用的深入评估，与其他干预措施相比，基因转移显示出巨大的前景。这篇综述概述了 GM2 神经节苷脂贮积症的病理生物学以及潜在的创新治疗方法。
