Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients
Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients
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DOI：
10.1093/brain/awl096
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发表时间：
2006-06-01
期刊：
影响因子：
14.5
通讯作者：
Sobue, Gen
中科院分区：
文献类型：
--
作者：
Atsuta, Naoki;Watanabe, Hirohisa;Sobue, Gen
脊髓和球部肌萎缩症(SBMA)是一种成人起病的运动神经元疾病，由雄激素受体(AR)基因CAG重复扩增引起，目前尚无根治方法。然而，由于最近的研究可能为治疗提供机会，有关SBMA自然病史的信息将有助于计划未来的临床试验。我们调查了223例日本SBMA患者(数据收集时平均年龄为55.2岁；范围为30-87岁)的9个日常生活活动(ADL)里程碑评估的自然病程，时间为1~20年。所有患者均经基因分析确诊。手部震颤是一种早期事件，中位年龄为33岁。肌肉无力主要发生在下肢，注意到的中位年龄为44岁，其次是上楼需要扶手49岁，构音困难50岁，吞咽困难54岁，使用拐杖59岁，使用轮椅61岁。其中21名患者在中位年龄62岁时患上肺炎，其中15人在中位年龄65岁时死亡。这些病例中最常见的死亡原因是肺炎和呼吸衰竭。每个ADL里程碑开始时的年龄与AR基因中CAG重复的长度密切相关。然而，CAG重复长度与每个ADL里程碑之间的时间间隔不相关，这表明尽管每个ADL里程碑的开始年龄取决于AR基因中的CAG重复长度，但疾病进展速度并不相关。血清睾酮水平是多谷氨酰胺介导的运动神经元变性的重要触发因素，即使在高龄时也保持在相对较高的水平。这些结果为未来的临床治疗试验提供了有益的信息，尽管还需要进一步的详细前瞻性研究。
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motoneuron disease caused by a CAG-repeat expansion in the androgen receptor (AR) gene and for which no curative therapy exists. However, since recent research may provide opportunities for medical treatment, information concerning the natural history of SBMA would be beneficial in planning future clinical trials. We investigated the natural course of SBMA as assessed by nine activities of daily living (ADL) milestones in 223 Japanese SBMA patients (mean age at data collection = 55.2 years; range = 30-87 years) followed from 1 to 20 years. All the patients were diagnosed by genetic analysis. Hand tremor was an early event that was noticed at a median age of 33 years. Muscular weakness occurred predominantly in the lower limbs, and was noticed at a median age of 44 years, followed by the requirement of a handrail to ascend stairs at 49, dysarthria at 50, dysphagia at 54, use of a cane at 59 and a wheelchair at 61 years. Twenty-one of the patients developed pneumonia at a median age of 62 and 15 of them died at a median age of 65 years. The most common cause of death in these cases was pneumonia and respiratory failure. The ages at onset of each ADL milestone were strongly correlated with the length of CAG repeats in the AR gene. However CAG-repeat length did not correlate with the time intervals between each ADL milestone, suggesting that although the onset age of each ADL milestone depends on the CAG-repeat length in the AR gene, the rate of disease progression does not. The levels of serum testosterone, an important triggering factor for polyglutamine-mediated motoneuron degeneration, were maintained at relatively high levels even at advanced ages. These results provide beneficial information for future clinical therapeutic trials, although further detailed prospective studies are also needed.