Defining SOD1 ALS natural history to guide therapeutic clinical trial design.
Defining SOD1 ALS natural history to guide therapeutic clinical trial design.
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DOI：
10.1136/jnnp-2016-313521
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发表时间：
2017-02
期刊：
影响因子：
--
通讯作者：
Miller TM
中科院分区：
文献类型：
--
作者：
Bali T;Self W;Liu J;Siddique T;Wang LH;Bird TD;Ratti E;Atassi N;Boylan KB;Glass JD;Maragakis NJ;Caress JB;McCluskey LF;Appel SH;Wymer JP;Gibson S;Zinman L;Mozaffar T;Callaghan B;McVey AL;Jockel-Balsarotti J;Allred P;Fisher ER;Lopate G;Pestronk A;Cudkowicz ME;Miller TM
了解SOD1突变引起的家族性肌萎缩侧索硬化症(ALS)的自然病史将为优化这一患者群体的临床试验提供关键信息。建立ALSSOD1的最新自然历史。来自北美15个医疗中心的回溯性队列研究评估了175名ALS患者的记录，这些患者的基因确认为SOD1突变，在2000年后得到治疗。分析患者的发病年龄、生存期、ALS功能评定量表(ALS-FRS)评分和呼吸功能。A4V(ALA-Val)SOD1突变患者(SOD1A4V)是北美最大的突变人群，具有侵袭性的疾病进展，我们将其与其他SOD1突变患者(SOD1non-A4V)区分开来进行分析。所有SOD1患者的平均发病年龄为49.7±12.3岁(平均±SD)，SOD1A4V与SOD1Non-A4V之间无统计学意义(p=0.72，Kruskal-Wallis)。SOD1患者的中位生存期为2.7年。所有病例的平均病程为4.6±6.0年，SOD1A4V为1.4±0.7年。SOD1A4V的生存概率(中位生存期1.2年)显著低于SOD1Non-A4V(中位生存期6.8年；p<；0.0001，对数列)。与SOD1Non-A4V组相比，SOD1A4V组ALS-FRS下降显著增加(p=0.02)，SOD1A4V组ALS强迫肺活量下降比SOD1Non-A4V组显著增加(p=0.02)。SOD1A4V是一种侵袭性的ALS，但相对同质。这些特定于肌萎缩侧索硬化症患者的自然病史数据将对设计和实施ALSSOD1患者群体的临床试验非常重要。
Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALSSOD1) will provide key information for optimising clinical trials in this patient population. To establish an updated natural history of ALSSOD1. Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000. Age of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1A4V), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1non-A4V) for analysis. Mean age of disease onset was 49.7 ±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1A4V and SOD1non-A4V (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1A4V. SOD1A4V survival probability (median survival 1.2 years) was significantly decreased compared with SOD1non-A4V (median survival 6.8 years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1A4V compared with SOD1non-A4V participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1A4V compared with SOD1non-A4V (p=0.02). SOD1A4V is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALSSOD1 patient population.
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