迟发性GM2神经节剂量,包括晚发性泰-萨克斯和桑霍夫病,是罕见的,慢慢进步,神经遗传性疾病主要以神经源性虚弱为特征,共济失调,和构音障碍.这项纵向研究的目的是使用许多临床结果评估来表征迟发性GM2神经节剂量的自然史,以衡量疾病负担和随时间进展的不同方面。包括神经学,功能,和生活质量,为未来临床介入试验的设计提供信息。2015年至2019年参加美国国家泰萨克斯和相关疾病家庭会议的患者接受了年度临床结果评估。目前,没有经过验证的临床结果评估来评估迟发性GM2神经节剂量;因此,用于或设计用于具有类似特征的疾病的仪器,或解决临床表现的各个方面,被使用。临床结果评估包括Friedreich的共济失调评定量表,9孔钉试验,以及构音障碍言语的清晰度评估。23名患者参加了至少一次会议访问(晚发性Tay-Sachs,n=19;迟发性桑霍夫,n=4)。患者在基线时的疾病负担很高,不同临床结局评估的评分普遍低于一般人群的预期.纵向分析显示缓慢,但具有统计学意义,神经系统进展,如9孔钉测试评分恶化(2.68%/年,95%CI:0.13-5.29;p=0.04)和Friedreich共济失调评定量表神经系统检查(1.31分/年,95%CI:0.26-2.35;p=0.02)。从诊断到进入研究的时间与9孔钉测试的评分恶化相关(r=0.728;p<0.001),Friedreich的共济失调评定量表神经学检查(r=0.727;p<0.001),和构音障碍言语清晰度的清晰度评估(r=-0.654;p=0.001)。总之,晚发性GM2神经节剂量组患者的疾病负担高且疾病进展缓慢.适用于临床试验的几种临床结果评估显示,在4年内仅有很小的变化和标准化的效果大小(变化/变化的标准偏差)。这些纵向自然史研究结果说明了在罕见的临床试验中确定响应性终点的挑战,慢慢进步,神经退行性疾病的治疗目标可以说是停止或降低下降速度,而不是改善临床状态。此外,为这样的研究提供动力将需要大的样本量和/或长的研究持续时间,对于没有可用治疗的超罕见疾病,这两种方法都不是一个有吸引力的选择。这些发现支持开发潜在更敏感的迟发性GM2神经节剂量特异性评级仪器和/或替代终点,用于未来的临床试验。
The late-onset GM2 gangliosidoses, comprising late-onset Tay-Sachs and Sandhoff diseases, are rare, slowly progressive, neurogenetic disorders primarily characterized by neurogenic weakness, ataxia, and dysarthria. The aim of this longitudinal study was to characterize the natural history of late-onset GM2 gangliosidoses using a number of clinical outcome assessments to measure different aspects of disease burden and progression over time, including neurological, functional, and quality of life, to inform the design of future clinical interventional trials. Patients attending the United States National Tay-Sachs & Allied Diseases Family Conference between 2015 and 2019 underwent annual clinical outcome assessments. Currently, there are no clinical outcome assessments validated to assess late-onset GM2 gangliosidoses; therefore, instruments used or designed for diseases with similar features, or to address various aspects of the clinical presentations, were used. Clinical outcome assessments included the Friedreich\'s Ataxia Rating Scale, the 9-Hole Peg Test, and the Assessment of Intelligibility of Dysarthric Speech. Twenty-three patients participated in at least one meeting visit (late-onset Tay-Sachs, n = 19; late-onset Sandhoff, n = 4). Patients had high disease burden at baseline, and scores for the different clinical outcome assessments were generally lower than would be expected for the general population. Longitudinal analyses showed slow, but statistically significant, neurological progression as evidenced by worsening scores on the 9-Hole Peg Test (2.68%/year, 95% CI: 0.13-5.29; p = 0.04) and the Friedreich\'s Ataxia Rating Scale neurological examination (1.31 points/year, 95% CI: 0.26-2.35; p = 0.02). Time since diagnosis to study entry correlated with worsening scores on the 9-Hole Peg Test (r = 0.728; p < 0.001), Friedreich\'s Ataxia Rating Scale neurological examination (r = 0.727; p < 0.001), and Assessment of Intelligibility of Dysarthric Speech intelligibility (r = -0.654; p = 0.001). In summary, patients with late-onset GM2 gangliosidoses had high disease burden and slow disease progression. Several clinical outcome assessments suitable for clinical trials showed only small changes and standardized effect sizes (change/standard deviation of change) over 4 years. These longitudinal natural history study results illustrate the challenge of identifying responsive endpoints for clinical trials in rare, slowly progressive, neurogenerative disorders where arguably the treatment goal is to halt or decrease the rate of decline rather than improve clinical status. Furthermore, powering such a study would require a large sample size and/or a long study duration, neither of which is an attractive option for an ultra-rare disease with no available treatment. These findings support the development of potentially more sensitive late-onset GM2 gangliosidoses-specific rating instruments and/or surrogate endpoints for use in future clinical trials.