Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Brain. 2012 Sep;135(Pt 9):2838-48. doi: 10.1093/brain/aws170. Epub 2012 Jul 6.
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.
脊髓延髓肌肉萎缩症是一种成人发病的遗传性运动神经元病，由雄激素受体基因内编码三核苷酸 CAG 重复扩展引起。迄今为止，已经有几种药物在这种疾病的动物模型中被证明可以预防或减缓疾病进展。为了将这些药物进行转化研究，有必要使用定量结果测量方法对其自然病史进行详细分析，并在临床试验中建立敏感和有效的疾病特异性终点。为此，我们使用定量结果测量方法，对 34 名经基因证实的日本脊髓延髓肌肉萎缩症患者进行了为期 3 年的前瞻性疾病进展观察，包括功能和血液参数。基线评估显示，雄激素受体基因中的 CAG 重复长度不仅与发病年龄相关，还与日常生活活动能力实质性变化的时间相关。多元回归分析表明，血清肌酐水平是反映脊髓延髓肌肉萎缩症运动功能障碍严重程度最有用的血液参数。在 3 年的前瞻性分析中，我们检查的大多数结果指标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为代表性线的分析中，疾病进展不受 CAG 重复长度或发病年龄的影响。这些模型显示出很大的个体间差异，并且与 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的细微神经功能缺陷更有可能通过客观的运动功能测试（如 6 分钟步行测试和握力或血清肌酐水平）而不是通过功能评定量表（如修订版肌萎缩侧索硬化功能评定量表或改良诺里斯量表）来检测到。使用因子分析对临床表型进行分类表明，上肢功能与延髓功能密切相关，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，脊髓延髓肌肉萎缩症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，与 CAG 重复长度或临床表型无关，并且客观的结果测量可能用于评估该疾病早期的疾病严重程度。
