Opherk Christian, Peters Nils, Herzog Jürgen, Luedtke Rainer, Dichgans Martin
Department of Neurology, Klinikum Grosshadern, Ludwig Maximilians University, Munich, Germany.
Brain. 2004 Nov;127(Pt 11):2533-9. doi: 10.1093/brain/awh282. Epub 2004 Sep 13.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary angiopathy caused by mutations in the NOTCH3 gene. The clinical course is highly variable. Little is known about the long-term prognosis and the causes of death in CADASIL patients. Likewise, the impact of gender and NOTCH3 genotype on disease progression remains largely unexplored. We identified 411 subjects (196 men, 215 women) with a definite diagnosis of CADASIL. Age at onset for stroke, immobilization and death as well as the causes of death and clinical status at onset of the cause of death were determined systematically. Weibull regression models were used to calculate times to event, with gender and NOTCH3 genotype as covariates. At the time of the study, 73 patients had died. The median age at onset for stroke was 50.7 years [95% confidence interval (CI) = 48.2-53.1 years] in men and 52.5 years (95% CI = 50.0-54.9 years) in women (P = n.s.). The median ages at onset for inability to walk without assistance [men 58.9 years (95% CI = 56.6-61.3 years); women 62.1 years (59.7-64.4 years)], bedriddenness [men 62.1 years (59.6-64.7 years), women 66.5 years (63.9-69.1 years); and death [men 64.6 years (61.7-67.6 years); women 70.7 years (67.6-73.9 years)] were significantly lower in men than in women (all P < or = 0.01). The median survival time of men was significantly shorter than expected from German life tables (64.6 versus 69.3 years, P = 0.01). In contrast, the median survival time of women was not significantly reduced (70.7 versus 72.2 years). The C117F mutation was associated with a lower age at death and the C174Y mutation with a lower age at onset for stroke, immobilization and death (adjusted P values <0.05). At onset of the cause of death, 78% of the subjects were completely dependent. Sixty-three per cent were confined to bed. Pneumonia was the most frequent cause of death (38%), followed by sudden unexpected death (26%) and asphyxia (12%). We conclude that male sex is a risk factor for early immobilization and death in CADASIL. Our findings suggest possible genotype-phenotype correlations with regard to disease progression. The data presented may serve as source material for counselling CADASIL patients and for designing future interventional trials.
伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）是一种由NOTCH3基因突变引起的遗传性血管病。其临床病程差异很大。关于CADASIL患者的长期预后和死亡原因知之甚少。同样，性别和NOTCH3基因型对疾病进展的影响在很大程度上仍未得到探索。我们确定了411例确诊为CADASIL的受试者（196例男性，215例女性）。系统地确定了中风、行动不便和死亡的发病年龄以及死亡原因和死亡原因出现时的临床状况。使用威布尔回归模型计算事件发生时间，将性别和NOTCH3基因型作为协变量。在研究时，73例患者已经死亡。男性中风的中位发病年龄为50.7岁[95%置信区间（CI）=48.2 - 53.1岁]，女性为52.5岁（95%CI = 50.0 - 54.9岁）（P =无显著差异）。男性无辅助行走能力丧失的中位发病年龄[58.9岁（95%CI = 56.6 - 61.3岁）；女性62.1岁（59.7 - 64.4岁）]、卧床不起的中位发病年龄[男性62.1岁（59.6 - 64.7岁），女性66.5岁（63.9 - 69.1岁）]以及死亡的中位发病年龄[男性64.6岁（61.7 - 67.6岁）；女性70.7岁（67.6 - 73.9岁）]均显著低于女性（所有P≤0.01）。男性的中位生存时间显著短于德国生命表预期（64.6岁对69.3岁，P = 0.01）。相比之下，女性的中位生存时间没有显著缩短（70.7岁对72.2岁）。C117F突变与较低的死亡年龄相关，C174Y突变与中风、行动不便和死亡的较低发病年龄相关（校正P值<0.05）。在死亡原因出现时，78%的受试者完全依赖他人。63%的人卧床不起。肺炎是最常见的死亡原因（38%），其次是猝死（26%）和窒息（12%）。我们得出结论，男性是CADASIL患者早期行动不便和死亡的危险因素。我们的研究结果表明在疾病进展方面可能存在基因型 -表型相关性。所呈现的数据可作为为CADASIL患者提供咨询和设计未来干预试验的源材料。
