Familial clustering of ALS in a population-based resource

Abstract

Objective: To determine the extent of an inherited contribution to amyotrophic lateral sclerosis (ALS) mortality.

Methods: Death certificates (DCs) from 1904 to 2009 were analyzed from patients with at least 3 generations recorded in the Utah Population Database, a genealogic and medical database of more than 2 million Utah residents. Among probands whose DCs listed ALS, the relative risk (RR) of death with ALS was determined among spouses and first- through fifth-degree relatives, using birth year-, sex-, and birthplace-matched cohorts.

Results: Eight hundred seventy-three patients with ALS met the inclusion criteria. Among 3,531 deceased first-degree relatives of probands, the RR of dying with ALS was increased compared with control cohorts (RR = 4.91, 95% confidence interval 3.36, 6.94). The RR of dying with ALS was also increased among 9,386 deceased second-degree relatives (RR = 2.85, 95% confidence interval 2.06, 3.84). The RR of dying with ALS was not increased among third- through fifth-degree relatives. More affected first-degree relatives were male (p = 0.014). No cases of conjugal ALS were observed.

Conclusions: This study is suggestive of familial clustering in excess of expected for ALS. Our results confirm the results of prior studies of familial ALS, suggesting applicability of our findings to other mixed European populations. Furthermore, this work expands on previous studies by quantifying the RR of ALS among more distant relatives. The use of mortality data obtained from DCs reduces the ascertainment and recall bias of many previous studies. Finally, the excess of ALS among second-degree relatives and lack of conjugal ALS are strongly supportive of a genetic contribution.

Figure 1. RR of death with ALS divided into sex and relationship from the proband

Square = male; circle = female; triangle = not sex-specific; red = significant; blue = nonsignificant or not estimable; black = proband; n = number of relatives. ALS = amyotrophic lateral sclerosis; CI = confidence interval; OD = observed death; RR = relative risk.