Two centuries of mortality in ten large families with Huntington disease: A rising impact of gene carriership

To estimate the impact of the Huntington gene on mortality, we studied ten families with Huntington disease, whose records started before 1800. We investigated mortality from 1800 to 1997 in 257 carriers of the Huntington gene and 474 potential carriers. Follow-up extended from age 20 years to the date of death or end-of-study date. The observed deaths were compared with those expected on the basis of the general population, adjusted for sex, age, and calendar time. To study the influence of the family and parental transmission, we calculated hazard ratios adjusted for sex, probability of carrying the gene, and year of birth. In 25,013 person-years, 420 deaths occurred, whereas 278 deaths were expected [standardized mortality ratio = 1.5; 95% confidence interval (CI) = 1.4-1.7]. Excess mortality was confined to ages 40-70 years (standardized mortality ratio = 2.2; 95% CI = 1.9-2.4). To study the evolution of mortality over time in this age group, we calculated absolute mortality rates per calendar period. From 1800 onward, mortality rates in the general population continuously declined, but among the families with Huntington disease this decline was absent. There were only small differences in risk between families, and the relative risk for paternal over maternal transmission was 1.2 (95% CI = 0.9-1.5). Our main finding is that persons who carry the Huntington gene and reach middle age have not benefited from advances in medical care and overall increase in life expectancy.