Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
Medical & Science, Novo Nordisk A/S, Søborg, Denmark.
Acta Neurol Scand. 2022 May;145(5):529-540. doi: 10.1111/ane.13578. Epub 2022 Jan 8.
Chromosome 3-linked frontotemporal dementia (FTD-3) is caused by a c.532-1G > C mutation in the CHMP2B gene. It is extensively studied in a Danish family comprising one of the largest families with an autosomal dominantly inherited frontotemporal dementia (FTD). This retrospective cohort study utilizes demographics to identify risk factors for onset, progression, life expectancy, and death in CHMP2B-mediated FTD. The pedigree of 528 individuals in six generations is provided, and clinical descriptions are presented. Choices of genetic testing are evaluated.
Demographic and lifestyle factors were assessed in survival analysis in all identified CHMP2B mutation carriers (44 clinically affected FTD-3 patients and 16 presymptomatic CHMP2B mutation carriers). Predictors of onset and progression included sex, parental disease course, education, and vascular risk factors. Life expectancy was established by matching CHMP2B mutation carriers with average life expectancies in Denmark.
Disease course was not correlated to parental disease course and seemed unmodified by lifestyle factors. Diagnosis was recognized at an earlier age in members with higher levels of education, probably reflecting an early dysexecutive syndrome, unmasked earlier in people with higher work-related requirements. Carriers of the CHMP2B mutation had a significant reduction in life expectancy of 13 years. Predictive genetic testing was chosen by 20% of at-risk family members.
CHMP2B-mediated FTD is substantiated as an autosomal dominantly inherited disease of complete penetrance. The clinical phenotype is a behavioral variant FTD. The disease course is unpredictable, and life expectancy is reduced. The findings may be applicable to other genetic FTD subtypes.
染色体 3 连锁额颞叶痴呆（FTD-3）是由 CHMP2B 基因中的 c.532-1G>C 突变引起的。在一个丹麦家族中对此进行了广泛研究，该家族由一个常染色体显性遗传额颞叶痴呆（FTD）的最大家族之一组成。本回顾性队列研究利用人口统计学数据来确定 CHMP2B 介导的 FTD 发病、进展、预期寿命和死亡的危险因素。提供了六代 528 人的谱系，并介绍了临床描述。评估了遗传检测的选择。
在所有鉴定的 CHMP2B 突变携带者（44 例临床受累 FTD-3 患者和 16 例无症状 CHMP2B 突变携带者）的生存分析中评估了人口统计学和生活方式因素。发病和进展的预测因素包括性别、父母疾病病程、教育程度和血管危险因素。通过与丹麦的平均预期寿命相匹配来确定预期寿命。
疾病病程与父母疾病病程无关，并且似乎不受生活方式因素的影响。教育程度较高的成员的诊断年龄更早，这可能反映了早期执行功能障碍综合征，在工作相关要求较高的人群中更早被揭示。CHMP2B 突变携带者的预期寿命显著缩短了 13 年。20%的高危家族成员选择了预测性遗传检测。
CHMP2B 介导的 FTD 被证实为完全外显率的常染色体显性遗传疾病。临床表型为行为变异型 FTD。病程不可预测，预期寿命缩短。这些发现可能适用于其他遗传 FTD 亚型。
