Authors :
Presenting Author: Sachi Lele, – Children's Hospital of Philadelphia
Jan Magielski, BA – CHOP
Sarah Ruggiero, MS, CGC – Children's Hospital of Philadelphia
Anna Prentice, MS, LCGC – CHOP
Alicia Harrison, MS, LCGC – CHOP
Nasha Fitter, MBA – Citizen Health
Elise Brimble, MSc, MS, CGC – Citizen Health
Ingo Helbig, MD – Children's Hospital of Philadelphia
Jillian McKee, MD, PhD – Children's Hospital of Philadelphia & University of Pennsylvania
Rationale:
KCNT1 encodes a sodium-activated potassium channel, and rare variants in this gene are an established cause of epilepsy, contributing to a broad phenotypic spectrum that includes developmental and epileptic encephalopathy as well as seizure clusters. While many studies have identified the clinical features of KCNT1-related epilepsies, the longitudinal trajectories of these symptoms remain unclear.Methods:
We performed a phenotypic reconstruction of the clinical histories of individuals living with causative KCNT1 variants, drawn from a local cohort and Citizen Health. This involved extracting seizure types and frequencies, general neurological features, medication prescriptions, and developmental milestones from each individual’s electronic medical records (EMRs) on a monthly basis.
Results:
We identified 58 individuals, with a total of 339 patient-years and 706 unique phenotypic terms. The most prevalent phenotypes included seizures (n=55/58) and digestive system abnormalities (n=50/58). Three recurrent variants showed distinct genotype-phenotype correlations. Individuals with p.Arg474His/Ser (n=12) commonly exhibited abnormalities in oral and eye physiology, p.Ala934Thr/Ser (n=7) were associated with apnea and impaired coordination, and p.Gly288Ser (n=7) with ankle clonus and gastrointestinal abnormalities. 85% (n=47/55) of individuals experienced seizures within the first year of life, including all individuals with the p.Gly288Ser variant (n=7/7). Seizure frequency was tracked longitudinally, with 50 individuals experiencing ≥5 seizures per day. In the first month, 50% (n=8/16) had ≥5 daily seizures, and this high frequency persisted across all 12 months of the first year of life. Developmental impairment was observed across multiple domains; only a small proportion of the cohort was able to attain crucial milestones, such as walking (n=11/41), verbal communication (n=8/35), rolling (n=12/41), and head control (n=15/41), with some individuals (n=7/58) unable to reach any of the milestones evaluated. Treatment responses were also assessed, with no single anti-seizure medication universally effective. However, levetiracetam (P = 0.0369, OR 1.31, CI 1.01-1.68), clonazepam (P < 0.001, OR 1.68, CI 1.29-2.18), and lacosamide (P < 0.001, OR 2.67, CI 1.97-3.60) were each associated with either seizure severity improvement or seizure freedom maintenance.