This case shows that POLG mutations can initially manifest phenotypically with polyneuropathy and SLE, which occurs before the onset of seizures, status epilepticus due to POLG variants may require thiopental anesthesia and that levetiracetam, lacosamide, and perampanel may have a favorable long-term effect on seizure activity in carriers of POLG mutations. Here, POLG is linked to systemic lupus erythematosus.