Veeramah et al. (2012) reported a girl with early-onset epileptic encephalopathy. She 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 ... Veeramah et al. (2012) reported a girl with early-onset epileptic encephalopathy. She 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, hypotonia, and difficulties with coordination and balance. The language and communication problems, in combination with regression in social interaction and the development of obsessive-compulsive and repetitive behaviors, led to the classification of autism at age 5 years. 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. Carvill et al. (2013) identified a heterozygous mutation in the SCN8A gene (L1290V; 600702.0003) in a boy with EIEE13. The mutation was inherited from his father, who was found to be somatic mosaic for the mutation. No further clinical information was provided. The patient was part of a cohort of 500 cases of epileptic encephalopathy who underwent sequencing of candidate genes; he was the only patient found to carry an SCN8A mutation.
In a girl with infantile epileptic encephalopathy-13, Veeramah et al. (2012) identified a de novo heterozygous mutation in the SCN8A gene (N1768D; 600702.0002). The mutation was identified by whole-genome sequencing. In vitro functional expression studies showed that the ... In a girl with infantile epileptic encephalopathy-13, Veeramah et al. (2012) identified a de novo heterozygous mutation in the SCN8A gene (N1768D; 600702.0002). The mutation was identified by whole-genome sequencing. In vitro functional expression studies showed that the mutation caused a dominant gain-of-function effect, with neuronal hyperexcitability, persistent sodium currents, incomplete channel inactivation, increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency. 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.