脊髓延髓肌萎缩症临床及分子生物学的研究进展

Research progress of clinical and molecular biology of spinal and bulbar muscular atrophy

Kennedy病又称脊髓延髓肌萎缩症,是一种X-连锁隐形遗传的晚发性运动神经元病,该病的主要临床症状为肌肉无力、萎缩及男性雄激素不敏感,一般仅有男性受累。作为第一个被发现的多聚谷氨酰胺疾病,Kennedy病同其他Poly Q疾病类似,其发病机制为位于X染色体的雄激素受体基因1号外显子三核苷酸(CAG)序列重复数目异常增加。目前认为,Kennedy病的发病机制既包含了正常的雄激素受体功能的缺失,又包含了异常的AR蛋白会对运动神经元产生毒性作用。随着近年来对Kennedy病分子致病机制的进一步研究,一些关键的途径和机制成为新的治疗靶点,目前的治疗策略可以分为以下四类:雄激素剥夺疗法;基因沉默疗法;增加蛋白质降解和控制蛋白质质量;调节雄激素受体功能。本文拟针对Kennedy病的临床及分子生物学的最新研究进展进行回顾。

Kennedy disease, also known as spinal and bulbar muscular atrophy, is an X-linked recessive, late-onset neuromuscular disease. Phenotypically, patients present with weakness and atrophy of muscle and male androgen insensitivity. The disease exclusively affects adult males. Kennedy disease, which is the first polyglutamine disease discovered, is caused by an expanded CAG repeat in the androgen receptor gene on the X chromosome. The mutant androgen receptor protein causes both a loss and gain of androgen receptor function. Over the past decade, the deeper understanding of the pathomechanisms that play a role in Kennedy disease has increased dramatically. Some of the key pathomechanisms become the new therapeutic strategies, which can be divided into the following four categories： androgen deprivation; gene silencing; increased protein degradation and protein quality control; modulation of androgen receptor function. This paper discusses the recent advances in clinical and molecular biology of Kennedy disease.