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(Abst. 1.39), 2019

ERGENT: Early Recognition of Genetic Epilepsy in Neonates
Authors: #N/A, Children's National Medical Center; John J. Millichap, Lurie Children's Hospital; Gerry Nesbitt, Clirinx, Inc.; Nishtha Joshi, Baylor College of Medicine; Rebecca Luke, Cook Children's Hospital; Jill Marks, Children's Colorado; Jan Martin, Children's Colorado; Laurel R. McGarry, Children's Colorado; Natanya Mishal, Neuro Network Partners/Nicklaus Children; Andrea Pardo, Lurie Children's Hospital; Jennifer M. Thomas, University of Texas Southwestern; Edward C. Cooper, Baylor College of Medicine
Content: Rationale: Although the majority of neonatal seizures are provoked by acute or structural causes (e.g., hypoxia-ischemia, infection, stroke, metabolic abnormalities, brain malformations), for some patients, neonatal seizures are heralding signs of genetic epilepsy. Recent studies provide evidence that pathogenic variants (PVs) in KCNQ2 account for the largest subgroup of the neonatal-onset genetic epilepsies. PVs in other known genes (including SCN2A, KCNQ3, KCNT1, ARX, and STXBP1) make up many of the remaining subgroup. The identification of neonatal-onset epilepsy genes has led to strategies for targeted therapies. If specific diagnosis of these genetic epilepsies were made as early as possible, benefits from targeted therapies may be enhanced. Methods: This is a prospective observational cohort study (Fig. 1). Neonates were screened prospectively for study eligibility using an anonymous online questionnaire submitted by referring caregivers. Eligibility required (1) EEG-proven seizure(s) requiring ongoing seizure medication; (2) neonatal seizure onset ≤14 days post term; (3) application within 30 days of seizure onset; (4) negative standard-of-care diagnostic evaluation for acute causes of neonatal seizures. After parental informed consent, eligible patients, underwent sponsored CLIA-certified next generation sequencing (187 epilepsy-associated genes). Primary outcomes were: fraction of tests performed with positive results, time to events, and correlation of screening sub-criteria with genetic test results. Results: Over 8 months (Aug. 2018 - Mar. 2019), referring providers submitted applications via the website for 20 neonates. Five patients (25%) were judged ineligible due to evidence on the application of structural or metabolic causes for seizures. Three were eligible but discharged and lost to follow-up before testing, and 1 test is pending. Of 11 proband genetic tests completed, 5 (45.4%) showed PVs in KCNQ2 (n=4) or KCNQ3 (n=1). Of these, 2 had the clinico-genetic profile of KCNQ2 Encephalopathy, and 3 had that of Self-limited Familial Neonatal Epilepsy (i.e., BFNE). There were 3 heterozygous variants of unknown significance in genes causing dominant early-infantile epilepsy (PNKP, PRRT2, SCN2A). For the 5 patients with KCNQ2/3 PVs, mean age at seizure onset, screening by the study, and genetic diagnosis were 2.2, 8.8, and 28.6 days old (Fig. 2). Delay between first seizure and screening, between study acceptance and blood collection, and the lab turnover time were the 3 largest contributors to age at diagnosis. Parental testing was offered for PVs and VUSs. Seven parental samples were tested; the mean proband age at second parental test report was 65 days (n=3). Chart review showed that 1 accepted patient with a negative genetic test had hypocalcemia. We have identified no other differences in application criteria between positive and negative test subgroups. Conclusions: Patients at high risk of neonatal-onset genetic epilepsy, most often but not always due to KCNQ2 variants, can be identified soon after birth using a brief checklist. The rate limiting steps to early confirmed diagnosis are early recognition, rapid trio sample collection, and a rapid genetics laboratory workflow. All are feasible. The approach outlined here can enable early recruitment to trials of candidate treatments for KCNQ2 encephalopathy and other neonatal-onset genetic epilepsies. Funding: Collaboratively funded by the Jack Pribaz Foundation, KCNQ2 Cure Alliance, and FamilieSCN2A Foundation.
Figure 1