Familial aggregation of amyotrophic lateral sclerosis

Abstract

Objective: To assess the relative risk for amyotrophic lateral sclerosis (ALS) in families of ALS patients.

Methods: We conducted a cohort study based on the Swedish Multi-Generation Register in 1961 to 2005. Among 6,671 probands (first ALS case in the family), 1,909 full siblings, 13,947 children, and 5,405 spouses were identified (exposed group). Other persons in the Multi-Generation Register, who were siblings, children, or spouses to persons without ALS, served as the reference group. Relative risks for ALS among the exposed group, compared with the reference group, were calculated from Poisson regression models. Concurrence of ALS within twins was assessed in 86,441 twin pairs registered in the Swedish Twin Register.

Results: Nine cases of ALS were noted among the siblings and 37 cases among the children of the probands, giving a 17-fold risk among the siblings (95% confidence interval, 8.1-30.4) and a 9-fold risk among the children (95% confidence interval, 6.2-12.0), compared with the reference group. Siblings and children had a greater excess risk if the proband was diagnosed at a younger age, and the excess risks decreased with increasing age at diagnosis of the proband (p < 0.001). Spouses had no significantly increased risk (p = 0.27). Two cases were identified among the cotwins of ALS probands, giving a relative risk of 32 (95% confidence interval, 5.2-102.6).

Interpretation: The siblings and children of ALS patients have an about 10-fold risk for ALS compared with the reference group. The excess risks vary with both age and kinship, indicating a major genetic role in familial ALS. Ann Neurol 2009;66:94-99.

Fig

Incidence rates (IR, per 100,000 person-years; among the first degree relatives of ALS probands and the reference group, respectively) and relative risks (RR; among the first degree relatives of ALS probands, compared to the reference group) of ALS, by attained age at follow-up. Gray dashed line with circles = IR Reference. Black dashed line with circles = IR Exposed. Solid black line with squares = RR.