Determining the incidence of familiality in ALS: A study of temporal trends in Ireland from 1994 to 2016

Abstract

Objective: To assess temporal trends in familial amyotrophic lateral sclerosis (FALS) incidence rates in an Irish population and to determine factors influencing FALS ascertainment.

Methods: Population-based data collected over 23 years, using the Irish amyotrophic lateral sclerosis (ALS) register and DNA biobank, were analyzed and age-standardized rates of FALS and associated familial neuropsychiatric endophenotypes were identified.

Results: Between 1994 and 2016, 269 patients with a family history of ALS from 197 unique families were included on the register. Using stringent diagnostic criteria for FALS, the mean age-standardized FALS incidence rate for the study period was 11.1% (95% confidence interval [CI], 8.8-13.4). The FALS incidence rate increased steadily from 5.2% in 1994 to 19.1% in 2016, an annual increase of 0.7% (95% CI, 0.5-0.9, p < 0.0001). Inclusion of the presence of neuropsychiatric endophenotypes within kindreds increased the FALS incidence rate to 30%. The incidence of FALS in newly diagnosed individuals from known families increased significantly with time, accounting for 50% of all FALS diagnoses by 2016. The mean annual rate of recategorization from "sporadic ALS" to "FALS" was 3% (95% CI, 2.6-3.8).

Conclusions: The true population-based rate of FALS is at least 20%. Inclusion of extended endophenotypes within kindreds increases the rate of FALS to 30%. Cross-sectional analysis of clinic-based cohorts and stringent definitions of FALS underestimate the true rate of familial disease. This has implications for genetic counseling and in the recognition of presymptomatic stages of ALS.

Figure 1. Byrne criteria for familial amyotrophic lateral sclerosis (FALS)

Figure 2. Flow chart of patients who met the inclusion/exclusion criteria for the study

(A) All patients with ALS registered with the Irish ALS register from 1994 to 2016 who reported a history of suspected or confirmed ALS or FTD in at least 1 relative were identified. All patients with an established, highly penetrant ALS variant (C9orf72 89, TARDBP 1, FUS 2, SOD1 1, and SQSTM1 1) were identified from the DNA database. (B) Thirty-five patients with a family history suspicious for ALS or FTD in whom it was not possible to confirm the relatives' diagnoses and 9 patients with Kennedy disease were excluded. Five C9orf72-positive patients with a family history suspicious for ALS or FTD in whom it was not possible to confirm the relatives' diagnoses were recategorized into gene-positive only category. ALS = amyotrophic lateral sclerosis; FTD = frontotemporal lobar dementia.

Figure 3. Temporal trends in FALS incidence

Temporal trends in age-standardized FALS incidence for total FALS (A), definite FALS (B), probable ALS (C), and possible FALS (D). Temporal trends in age-standardized FALS incidence for total FALS compared with definite and probable FALS (E). ALS = amyotrophic lateral sclerosis; FALS = familial ALS.

Figure 4. Binomial probability distribution

For the number of relatives with schizophrenia (A) or dementia (B) against the kindred size. p < 0.05 is highlighted in blue.