Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium3Department of Neurology and Memory Clinic, Hospital Network Antwerp Middelheim and Hoge Beuken, Antwerp, Belgium4Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
Center for Molecular Neurology, VIB, Antwerp, Belgium2Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
JAMA Neurol. 2017 Apr 1;74(4):445-452. doi: 10.1001/jamaneurol.2016.4847.
Patients carrying a C9orf72 repeat expansion leading to frontotemporal dementia and/or amyotrophic lateral sclerosis have highly variable ages at onset of disease, suggesting the presence of modifying factors.
To provide clinical-based evidence for disease anticipation in families carrying a C9orf72 repeat expansion by analyzing age at onset, disease duration, and age at death in successive generations.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study was performed from June 16, 2000, to June 1, 2016, in 36 extended Belgian families in which a C9orf72 repeat expansion was segregating. The generational effect on age at onset, disease duration, and age at death was estimated using a mixed effects Cox proportional hazards regression model, including random-effects terms for within-family correlation and kinship. Time until disease onset or last examination, time from disease onset until death or last examination, or age at death was collected for for 244 individuals (132 proven or obligate C9orf72 carriers), of whom 147 were clinically affected (89 proven or obligate C9orf72 carriers).
Generational effect on age at onset, disease duration, and age at death.
Among the 111 individuals with age at onset available (66 men and 45 women; mean [SD] age, 57.2 [9.1] years), the mean (SD) age at onset per generation (from earliest-born to latest-born generation) was 62.5 (8.3), 57.1 (8.2), 54.6 (10.2), and 49.3 (7.5) years. Censored regression analysis on all affected and unaffected at-risk relatives confirmed a decrease in age at onset in successive generations (P < .001). No generational effect was observed for disease duration or age at death.
The clinical data provide supportive evidence for the occurrence of disease anticipation in families carrying a C9orf72 repeat expansion by means of a decrease in age at onset across successive generations. This finding may help clinicians decide from which age onward it may be relevant to clinically follow presymptomatic individuals who carry a C9orf72 repeat expansion.
携带 C9orf72 重复扩展导致额颞叶痴呆和/或肌萎缩侧索硬化症的患者发病年龄差异很大，提示存在修饰因素。
通过分析连续几代人的发病年龄、疾病持续时间和死亡年龄，为携带 C9orf72 重复扩展的家族中疾病的预期提供临床依据。
设计、地点和参与者：这项队列研究于 2000 年 6 月 16 日至 2016 年 6 月 1 日在 36 个比利时扩展家族中进行，这些家族中存在 C9orf72 重复扩展。使用混合效应 Cox 比例风险回归模型估计代际效应对发病年龄、疾病持续时间和死亡年龄的影响，该模型包括用于家族内相关性和亲缘关系的随机效应项。收集了 244 个人（132 名已知或推定 C9orf72 携带者）的发病时间或最后一次检查时间、发病时间到死亡或最后一次检查时间或死亡年龄，其中 147 人患有临床疾病（89 名已知或推定 C9orf72 携带者）。
代际效应对发病年龄、疾病持续时间和死亡年龄的影响。
在可获得发病年龄的 111 名个体中（66 名男性和 45 名女性；平均[标准差]年龄为 57.2[9.1]岁），每一代（从最早出生到最晚出生的一代）的平均（标准差）发病年龄为 62.5（8.3）、57.1（8.2）、54.6（10.2）和 49.3（7.5）岁。对所有受影响和未受影响的高危亲属进行的校正回归分析证实，发病年龄在连续几代人中呈下降趋势（P < .001）。未观察到疾病持续时间或死亡年龄的代际效应。
临床数据为携带 C9orf72 重复扩展的家族中发生疾病预期提供了支持性证据，表现为连续几代人的发病年龄下降。这一发现可能有助于临床医生确定从哪个年龄开始，对携带 C9orf72 重复扩展的有临床意义的个体进行临床随访可能是相关的。
