Correlation of clinical and molecular features in spinal bulbar muscular atrophy
Correlation of clinical and molecular features in spinal bulbar muscular atrophy
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DOI：
10.1212/wnl.0000000000000507
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发表时间：
2014-06-10
期刊：
影响因子：
9.9
通讯作者：
Hanna, Michael G.
中科院分区：
文献类型：
--
作者：
Fratta, Pietro;Nirmalananthan, Niranjanan;Hanna, Michael G.
目的：描述脊髓球性肌萎缩症（SBMA）的临床和遗传特征，SBMA是一种罕见的神经退行性疾病，由雄激素受体基因第一外显子CAG重复扩增引起。方法：我们在英国建立了SBMA的国家登记册，并在2005年至2013年期间招募了61名患者。在我们的横断面研究中，我们通过直接询问，评估了日常生活活动障碍（ADL）里程碑、功能评级和主观疾病影响，并进行了CAG重复大小和体细胞嵌合程度的相关性。10例患者死亡，46例患者参与研究，5例患者下降。结果：受试者的平均发病年龄为43.4岁，下肢最常出现无力发作（87%）。活动能力受损是患者最常报告的问题，其次是球功能障碍。与日本的一项研究相比，ADL里程碑损伤的年龄分布有显著的重叠。我们已经确定了CAG重复次数与发病年龄和ADL里程碑之间的显著相关性。体细胞嵌合现象也与CAG扩张大小和发病年龄相关。结论：在不同遗传背景的人群中，SBMA的临床特征有很大的重叠。这一发现具有重要意义，因为在未来的临床试验中需要多中心试验来获得足够的力量。SBMA的临床-遗传相关性很强，应该为这种情况下的任何临床研究策略提供信息。
Objectives: To characterize the clinical and genetic features of spinal bulbar muscular atrophy (SBMA), a rare neurodegenerative disorder caused by the expansion of a CAG repeat in the first exon of the androgen receptor gene, in the United Kingdom.Methods: We created a national register for SBMA in the United Kingdom and recruited 61 patients between 2005 and 2013. In our cross-sectional study, we assessed, by direct questioning, impairment of activities of daily living (ADL) milestones, functional rating, and subjective disease impact, and performed correlations with both CAG repeat size and degree of somatic mosaicism. Ten patients were deceased, 46 patients participated in the study, and 5 declined.Results: Subjects had an average age at onset of 43.4 years, and weakness onset most frequently occurred in the lower limbs (87%). Impaired mobility was the most frequently reported problem by patients, followed by bulbar dysfunction. Age distribution of the impairment of ADL milestones showed remarkable overlap with a Japanese study. We have identified a significant correlation between the number of CAG repeats and both age at onset and ADL milestones. Somatic mosaicism also showed a correlation with CAG expansion size and age at onset.Conclusions: Clinical features in SBMA show a substantial overlap when comparing populations with different genetic backgrounds. This finding has major implications, because multicenter trials will be necessary to obtain sufficient power in future clinical trials. Clinical-genetic correlations are strong in SBMA and should inform any clinical research strategy in this condition.