Abstract

To estimate the incidence of Aicardi-Goutières syndrome (AGS) and potassium sodium-activated channel subfamily T member 1 (KCNT1)-related epilepsy in Denmark and to characterize the patients diagnosed with AGS and KCNT1-related epilepsy.AGS and KCNT1-related epilepsy are 2 distinct rare genetic disorders. Due to the rarity of AGS and KCNT1-related epilepsy, the epidemiology remains unclear. The incidences for these diseases or the carriers with disease-related genetic variants remain unknown.This is a retrospective, non-interventional, population-based study using aggregate data from the Danish population register and hospital-based patient-level data in Denmark to identify persons with genetically confirmed AGS between January 2010 to December 2020 and KCNT1-related epilepsies between January 2012 to December 2020. Cases of these disorders were identified from in-hospital databases, and pathogenic variants were identified and confirmed by Sanger and/or whole exome (panel-based) sequencing. The incidence of AGS and KCNT1-related epilepsy were estimated in separate statistical analyses.A total of 7 AGS patients were identified. The mean age at AGS diagnosis was 19.4 months (median age 14 months). TREX1 (n < 5) and RNASEH2B (n = 5) genes were reported with confirmed pathogenic variants. The birth incidence of AGS was <0.7600 per 100,000 live births. The average annual incidence rate was calculated as 0.0539 (95% CI: 0.0217-0.1111) per 100,000 persons per year in the total population < 18 years (n = 7); the average annual incidence rate was <0.7538 per 100,000 persons per year (n < 5) in the population < 12 months, and the average annual incidence rate in the population = 12 months and < 18 years was <0.0406 per 100,000 persons per year (n < 5). A total of 14 KCNT1-related epilepsy cases were identified during the study period (n = 5 in 2016, remaining 9 cases in 2013 and 2015). The mean age at diagnosis was 20.6 years (median 19 years) for KCNT1 cases. A total of 8 cases (57.1%) were = 18 years, and 6 (42.9%) were < 18 years at diagnosis. The phenotype autosomal dominant or sporadic sleep-related hypermotor epilepsy (ADSHE) (n = 10, 71.4%) was most reported; the remaining 4 cases had either epilepsy of infancy with migrating focal seizures (EIMFS) or an unclassifiable developmental and epileptic encephalopathy (DEE). The birth incidence of KCNT1-related epilepsy was =1.1205 per 100,000 live births. The average annual incidence rates per 100,000 persons per year during the study period were 0.0431 (95% confidence interval [CI]: 0.0236-0.0723; n = 14) in the overall population = 50 years, 0.0568 (95% CI: 0.0209-0.1237; n = 6) in the population < 18 years, and 0.0365 (95% CI: 0.0157-0.0718; n = 8) in the population = 18 and = 50 years. There were 3 families with at least 2 cases diagnosed with KCNT1-related epilepsies (on average 3.3 cases per family), indicating 10 cases in total within the 3 families. All KCNT1 cases of ADSHE phenotype came from the 3 families. The higher incidence of older ages and ADSHE cases compared with previous KCNT1 studies is likely due to the capture of prevalent and familial previously undiagnosed cases. Excluding these family cases, the average annual incidence was 0.0123 (95% CI: 0.0034-0.0315, n = 4) per 100,000 persons per year in the population = 50 years during 2012-2020.AGS and KCNT1-related epilepsy are particularly rare diseases. The annual average incidence rate of AGS was 0.0539 per 100,000 persons per year in the population < 18 years and birth incidence was <0.7600 per 100,000 live births during 2010-2020. The average annual incidence rate of KCNT1-related epilepsy was 0.0431 per 100,000 persons per year in the population = 50 years and the birth incidence was =1.1205 per 100,000 live births during 2012-2020. Given similar healthcare systems and genetic pools, these findings may provide insight on the incidence of these rare diseases in the Nordics.

View details for DOI 10.1016/j.ymgmr.2022.100924

View details for PubMedID 36262748

View details for PubMedCentralID PMC9574483