A 2-year-old girl with febrile seizures and recent diagnosis of epilepsy treated with valproic acid and low dose LEV presented with status epilepticus and admitted to the PICU on midazolam. Continuous EEG monitoring revealed slowing but no seizures. LEV was maximized and the patient was transferred to the floor for further monitoring. After two days, she developed increased seizure frequency leading to refractory status epilepticus requiring midazolam and pentobarbital. Genetic testing revealed a de novo heterozygous variant in SV2A (NM_014849.5):c.1978G>A (p.Gly660Arg). The variant is rare (gnomAD allele frequency 3.979e-6), predicted damaging (CADD score 32), and is fully conserved. LEV was weaned, the ketogenic diet was initiated, and the patient was successfully discharged with alternative antiepileptics.

LEV is a commonly used antiepileptic medication and binds to the synaptic vesicle glycoprotein SV2A. Evidence from animal models and humans implicates biallelic SV2A variants in epilepsy. We provide evidence that a rare heterozygous de novo SV2A variant (p.Gly660Arg) predisposes to epilepsy and paradoxical worsening with LEV. Further research in larger cohorts as to whether rare heterozygous SV2A variants are risk factors for epilepsy and influence LEV responses is needed.