Abstracts

Rationale: SCN2A mutations were first identified in benign familial neonatal-infantile seizures (BFNIS). Recently, SCN2A mutations were reported in infants with severe epilepsies. Clinical features that suggest SCN2A encephalopathy are poorly defined. Methods: Eleven patients with an epileptic encephalopathy due to a SCN2A mutation were recruited. Mutations were de novo in 6; parental testing is pending in 5. Their clinical, EEG and imaging features were reviewed. Results: The 11 patients were aged 1-22 years; 3 patients are deceased. Seizure onset ranged from day 1 to 16 years (median day 3). Seizures commenced on day 1-4 in 7, week 2-6 in 2 and after the first year in 2. For those with onset after the first week of life, development was normal prior to seizure onset in 3 cases and abnormal in 1. Three clinical phenotypes were identified: 1. Severe neonatal-infantile phenotype (7 patients) with migrating focal seizures of infancy (MFSI) (6) or Ohtahara syndrome (1). They had ongoing seizures and severe to profound intellectual disability. 2. Intermediate neonatal-infantile phenotype (2 patients) presenting with an MFSI-like phenotype but persistently normal EEG background, seizure offset at 3-6 months with or without recurrence >2 years, with normal or borderline development. 3. Childhood phenotype (2 patients) presenting with explosive onset of refractory focal seizures after one year of age, severe developmental regression and severe ID. Common clinical features across phenotypes included clusters of brief focal seizures, multiple hourly (9 patients) or multiple daily (2 patients) seizures, peaking at the maximal seizure frequency within 3 months of onset, multifocal interictal epileptiform discharges on EEG, improved seizure control with sodium channel blockers including a marked response to supratherapeutic or high therapeutic phenytoin levels in 4, movement disorders including dystonia, chorea, dyskinesias and stereotypies, axial hypotonia with intermittent or persistent appendicular hypertonia, early handedness and severe gastrointestinal symptoms. Clinical features associated with the severe neonatal-infantile onset group included visual inattention, extreme irritability, autonomic features such as episodes of hyperventilation and requirement for supplemental feeding. Conclusions: SCN2A mutations cause, in addition to BFNIS, encephalopathy with a broad phenotypic spectrum. We found three phenotypic groups with the encephalopathies: the severe and intermediate outcome neonatal-infantile onset groups and a childhood onset group. Distinguishing features across groups included clusters of brief focal seizures, multiple daily seizure frequency, response to sodium channel blockers, movement disorders and severe gastrointestinal symptoms. The response to phenytoin was striking, suggesting it should be considered early in this disorder.