In a girl with developmental and epileptic encephalopathy-13 (DEE13; 614558), Veeramah et al. (2012) identified a de novo heterozygous 5302A-G transition in the SCN8A gene, resulting in an asn1768-to-asp (N1768D) substitution in a highly conserved residue in the final transmembrane segment adjacent to the C-terminal cytoplasmic domain. The mutation was identified by whole-genome sequencing. Expression of the mutant protein in a neuronal cell line showed that it caused persistent sodium currents, incomplete channel inactivation, and a depolarizing shift in the voltage dependence of steady-state fast inactivation. Current-clamp analysis in rat hippocampal neurons transfected with the mutant protein showed increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency, consistent with a dominant gain-of-function phenotype. All of these studies were consistent with neuronal hyperexcitability. Whole-genome sequencing also identified putative recessive variants in the NRP2 (602070) and UNC13C (614568) genes in the proband, which may have contributed to the phenotype. The patient developed refractory generalized seizures at age 6 months. At age 4 years, the seizure phenotype changed to epileptic spasms, followed by regression of speech and language skills. She also had developmental delay, intellectual disability, autism, hypotonia, and difficulties with coordination and balance. Initial electroencephalogram (EEG) showed bifrontal spikes and brief bursts of generalized spike-wave activity. Later EEG showed diffuse slowing, multifocal spikes, and frontally predominant generalized spikes. Brain MRI was normal. The patient died suddenly at age 15 years. There was no family history of a similar disorder.
