Authors :
Presenting Author: Anna Prentice, MS, LCGC – CHOP
Jan Magielski, BA – CHOP
Johanna Mercurio, BS, BSFCS – CHOP
Sarah Tefft, MSN, RN, CRNP – Children's Hospital of Philadelphia
Michael Kaufman, MS – Children's Hospital of Philadelphia
Stacey Cohen, MS, LCGC – Penn Medicine
Sarah Ruggiero, MS, CGC – Children's Hospital of Philadelphia
Laura McGarry, MD, PhD – CHOP
Veronica Hood, PhD – Dravet Syndrome Foundation
Ethan Goldberg, MD, PhD – CHOP
Ingo Helbig, MD – Children's Hospital of Philadelphia
Rationale:
Pathogenic variants in SCN1A are the most common monogenic cause of epilepsy. Despite their prominence, gaps exist in understanding the natural history of SCN1A-related disorders (SCN1A-RD), an essential task to ensure a high standard of clinical care and optimize clinical trial readiness. Here, we describe the phenotypic characteristics of 100 individuals with SCN1A-RD across 681 patient-years.
Methods:
Seizure trajectories and non-epileptic phenotypes were abstracted from medical records and mapped to a standardized clinical dictionary: the Human Phenotype Ontology (HPO). HPO terms and seizure frequencies were assigned monthly. Clinical diagnoses were abstracted from medical records. Individuals were assigned to predicted loss-of-function (LoF) or gain-of-function (GoF) cohorts based on expert review.
Results:
90 individuals had phenotypes consistent with SCN1A LoF: 67 with Dravet syndrome (DS), 13 with borderline or atypical DS, and ten with genetic epilepsy with febrile seizures plus. Nine participants exhibited the early-onset developmental and epileptic encephalopathy consistent with SCN1A GoF. One participant displayed a non-DS, Lennox-Gastaut syndrome phenotype. 671 unique HPO terms were assigned 2,220 times across the cohort. Infancy was characterized by status epilepticus (SE; 96%), hemiclonic seizures (64%), and fever-induced seizures (81%). Bilateral tonic-clonic seizures (BTCS) (96%) and myoclonic seizures (42%) also onset in infancy but persisted into childhood. Later-onset semiologies included atonic (29%) and focal impaired awareness (47%) seizures. The frequency of fever-induced seizures was associated with the frequency of SE (p< 0.001). In contrast, myoclonic seizure frequency was not associated with SE. Seizures most often occurred monthly; only 45/100 individuals experienced at least weekly seizures for ≥ 6 months. Non-epileptic phenotypes included neurodevelopmental delay (82%), atypical behavior (56%), autistic features (28%), and motor coordination problems (54%) with characteristic age-related patterns. GoF variants caused distinct clinical features from LoF variants, including earlier onset of seizures (