Abstracts

Rationale: SCN1A is the most established epilepsy gene and is associated with a phenotypic spectrum ranging from the mild disorder of Genetic Epilepsy with Febrile Seizures Plus to the severe phenotype of Dravet Syndrome. We describe a far more severe, novel SCN1A phenotype of early onset epileptic encephalopathy with profound impairment and movement disorder, associated with a hotspot recurrent mutation. Methods: 7 children were identified as having an SCN1A mutation with a profound phenotype. Seizure and medical history, neurological examination, MRI, and video-EEG monitoring data were obtained. Results: We identified 7 unrelated males (6 - 12 years) who presented at 8-12 weeks of age with hemiclonic seizures in 5 and generalized tonic clonic seizures (GTCS) in 2. All developed GTCS by 18 months and became intractable with convulsive status (6/7), myoclonic seizures (5/7), tonic seizures (4/7) or spasms (3/7). Triggers included fever (4), auditory stimuli (2), excitement (2), feeding (2) and bowel opening (1). Development was initially normal but became delayed at 8-16 weeks. Six children had periods of regression or plateauing of development. They all had profound intellectual disability with no ambulation or speech and a gastrostomy tube. All children developed a severe hyperkinetic movement disorder (onset 9 weeks-20 months) with choreoathetosis, dystonia and mini-myoclonus particularly in the orofacial area. All had axial hypotonia. EEGs, initially normal, developed background slowing and frequent multifocal discharges. Neuroimaging was normal. 6 children shared a recurrent missense mutation p.Thr226Met, which was proven de novo in 5. The seventh child had a de novo p.Pro1345Ser missense mutation. Conclusions: We have identified a novel SCN1A phenotype with a profound early-onset epileptic encephalopathy associated with a prominent choreoathetoid, dystonic movement disorder. This new SCN1A phenotype can be distinguished from Dravet syndrome by earlier age of onset, profound developmental impairment and movement disorder. Phenotype-genotype correlation has been elusive for SCN1A diseases, but we found striking genetic homogeneity with 6/7 cases sharing the same hotspot mutation. Funding: This project was supported by Cure Kids (New Zealand) and the Health Research Council of New Zealand.