Journal
NEUROLOGY-GENETICS
Volume 4, Issue 3, Pages -Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/NXG.0000000000000239
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Funding
- Science Foundation Ireland [15/SPP/3244, 16/ERCD/3854]
- Health Research Board including Joint Programme in Neurodegeneration, Research Motor Neurone, and Science Foundation Ireland
- Motor Neurone Disease Association (MNDA)
- Science Foundation Ireland (SFI) [15/SPP/3244, 16/ERCD/3854] Funding Source: Science Foundation Ireland (SFI)
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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.
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