Expanding the phenotype of SCN8A-LOF epilepsy and related disorders

OBJECTIVES Our aim is to describe the phenotype of patients carrying SCN8A variants with loss-of-function (LOF) effect, through the description of a large cohort, expanding the clinical phenotype and obtaining data for early differential diagnosis and precision therapy management. METHODS From our database of 692 individuals with SCN8A-disorders, we selected those carrying variants with confirmed LOF effect (truncating variants or previously tested with functional studies). Detailed demographic, genetic and electro-clinical data were collected, including information about psychomotor development, neurological examination, epilepsy, and response to anti-seizures medications (ASMs). RESULTS Sixty patients were included, with a median age of 12 years (range: 18 months-42 years). Epilepsy was reported in 33/60 (55%), with a median age at onset of 2 years, 9 months (range: 1 month-14 years); 30% had generalized epilepsy (GE), 16.7% severe developmental and epileptic encephalopathy (DEE), 5% myoclonic epilepsy, unclassified in 3.3%. Seizure types included absences (44.5%), generalized tonic-clonic-seizure (TCS) (42.4%), clonic-myoclonic/hemiclonic (36.4%), atonic (6.1%), tonic (9.1%). Three patients presented status epilepticus. Among epileptic patients EEG was normal in 2 (6.5%), and showed epileptiform discharges in 25 subjects, either generalized (55%), focal (36%), or multifocal (29%). Seizure-freedom was achieved in 13/33 (39.4%) patients either in monotherapy with ETS (2), LEV (2), VPA (4) or in combination of TPM-LTG (1), VPA-LTG (2) or LEV-TPM (1). One is no longer taking ASMs. Sodium Channel Blockers (SCB) induced seizure worsening in 2, partial seizure control in 7 cases and complete seizure control in 2 patients in add-on with other ASMs. Forty-nine/60 had intellectual disability (ID), either severe/profound (15%), mild-moderate (52%), or global developmental delay (15%). Normal cognition was reported in 10 (17%). Behavioral problems and/or autism were reported in 47% of patients. Patients harbored 46 different variants (16 missense, 30 truncating/frameshift); 26/60 (43%) occurred de novo. CONCLUSION We report detailed genotype-phenotype correlations in a large cohort of subject with LOF-SCN8A-diseases. Four main phenotypes have emerged, namely generalized epilepsy, myoclonic epilepsy (never described before), DEE and neurodevelopmental disorders without epilepsy.