Longitudinal changes of outcome measures in spinal and bulbar muscular atrophy
Longitudinal changes of outcome measures in spinal and bulbar muscular atrophy
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DOI：
10.1093/brain/aws170
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发表时间：
2012-09-01
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：
Hashizume, Atsushi;Katsuno, Masahisa;Sobue, Gen
脊髓和球性肌萎缩症是一种成人发病的遗传性运动神经元疾病，由编码雄激素受体的基因中CAG重复序列的三核苷酸扩增引起。迄今为止，在这种疾病的动物模型中，已有几种药物被证明可以预防或减缓疾病进展。对于这些药物的转化研究，有必要对自然史进行详细的分析，定量的结果测量，并在临床试验中建立敏感和有效的疾病特异性终点。为此，我们对34名基因确诊的日本脊髓和球性肌萎缩症患者进行了为期3年的疾病进展的前瞻性观察，采用了定量结果测量，包括功能和血液参数。基线评估显示雄激素受体基因CAG重复长度不仅与发病年龄有关，而且与日常生活活动发生重大变化的时间有关。多元回归分析表明，血清肌酐水平是反映脊髓和球性肌萎缩症运动功能障碍严重程度的最有用的血液参数。在3年的前瞻性分析中，我们检查的大多数结果测量都证实了缓慢但稳定的进展。在使用随机系数模型将个体数据汇总成一条代表性线的分析中，疾病进展不受CAG重复序列长度或发病年龄的影响。这些模型显示出较大的个体间差异，这也与CAG重复大小的差异无关。使用这些模型的分析还表明，在早期或临床前阶段，细微的神经功能缺陷更容易通过客观运动功能测试（如6分钟步行测试、握力或血清肌酐水平）检测出来，而不是通过功能评定量表（如修订的肌萎缩侧索硬化症功能评定量表或修订的诺里斯量表）检测出来。使用因子分析对临床表型进行分类显示，上肢功能与球功能密切相关，但与基线时的下肢功能无关，而发病部位对疾病进展没有实质性影响。这些结果表明，脊髓和球性肌萎缩患者随着时间的推移表现出缓慢但稳定的运动功能障碍进展，这与CAG重复序列长度或临床表型无关，并且客观的结果测量可用于评估疾病早期的严重程度。
Spinal and bulbar muscular atrophy is an adult-onset, hereditary motor neuron disease caused by the expansion of a trinucleotide CAG repeat within the gene encoding the androgen receptor. To date, several agents have been shown to prevent or slow disease progression in animal models of this disease. For the translational research of these agents, it is necessary to perform the detailed analysis of natural history with quantitative outcome measures and to establish sensitive and validated disease-specific endpoints in the clinical trials. To this end, we performed a prospective observation of disease progression over 3 years in 34 genetically confirmed Japanese patients with spinal and bulbar muscular atrophy by using quantitative outcome measures, including functional and blood parameters. The baseline evaluation revealed that CAG repeat length in the androgen receptor gene correlated not only with the age of onset but also with the timing of substantial changes in activity of daily living. Multiple regression analyses indicated that the serum level of creatinine is the most useful blood parameter that reflects the severity of motor dysfunction in spinal and bulbar muscular atrophy. In 3-year prospective analyses, a slow but steady progression was affirmed in most of the outcome measures we examined. In the analyses using random coefficient models that summarize the individual data into a representative line, disease progression was not affected by CAG repeat length or onset age. These models showed large interindividual variation, which was also independent of the differences of CAG repeat size. Analyses using these models also demonstrated that the subtle neurological deficits at an early or preclinical stage were more likely to be detected by objective motor functional tests such as the 6-min walk test and grip power or serum creatinine levels than by functional rating scales, such as the revised amyotrophic lateral sclerosis functional rating scale or modified Norris scale. Categorization of the clinical phenotypes using factor analysis showed that upper limb function is closely related to bulbar function, but not to lower limb function at baseline, whereas the site of onset had no substantial effects on disease progression. These results suggest that patients with spinal and bulbar muscular atrophy show a slow but steady progression of motor dysfunction over time that is independent of CAG repeat length or clinical phenotype, and that objective outcome measures may be used to evaluate disease severity at an early stage of this disease.