The phenotype of SCN8A-LOF epilepsy and related disorders

PURPOSE We aim to describe the phenotype ofSCN8A variants with loss-of-function (LOF) effect, to obtain data for early differential diagnosis and precision therapy management. METHOD From our database of 645 patients withSCN8A -disorders, we selected those carrying variants with confirmed LOF effect, including truncating variants and missense variants previously tested in vitro. We collected detailed demographic, genetic and electro-clinical data, including information about psychomotor development, epilepsy, and response to anti-seizures medications (ASMs). RESULTS Forty-four patients were included, with a median age of 8 years (range: 1 month-36 years). 32/44 had intellectual disability (ID), either severe/profound (16%), mild-moderate (43%), or global developmental delay (14%). Normal cognition was reported in 5 (11%) (data not available in 7). 20/44 (45%) had behavioral problems and/or autism. Epilepsy was reported in 28/44 (64%), with a median age at onset of 2 years, 2 months (range: 1 month– 14 years); 43% had genetic generalized epilepsy (GGE), 14% severe developmental and epileptic encephalopathy (DEE), 43% unclassified epilepsy. Seizure types included absences (50%), generalized tonic-clonic-seizure (TCS) (36%), clonic-myoclonic/hemiclonic (25%), focal (14%), tonic (11%), febrile seizures (7%), focal-to-bilateral TCS (4%). Two patients had seizures in cluster. EEG was normal in 4 (14%), and showed epileptiform discharges in 14 subjects, either generalized (50%), focal (29%), or multifocal (21%). 8/28 (29%) patients achieved seizure-freedom either in monotherapy with ETS (2), VPA (3) or in combination of TPM-LTG (1). Sodium Channel Blockers (SCB) induced seizure worsening in 7, and partial seizure control in 3 cases. Patients harbored 32 different variants (11 missense/ 21 truncating); only 17/32 (53%) occurredde novo. All patients with DEE had truncating variant. CONCLUSION We report detailed genotype-phenotype correlations in a large cohort of subject with LOF-SCN8A-diseases. Generalized epilepsy with absences, late epilepsy-onset, and poor response to SCBs seem to be the major features of LOF-SCN8A.