Epileptic Encephalopathy, Early Infantile, 13

A number sign (#) is used with this entry because infantile epileptic encephalopathy-13 (EIEE13) is caused by heterozygous mutation in the SCN8A gene (600702) on chromosome 12q13.

For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).

Clinical Features

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.

Ohba et al. (2014) reported 7 unrelated children with EIEE13 ranging between 1 and 13 years of age. Five patients were Japanese and 2 were Israeli. Two patients had onset of intractable seizures in the first days of life, and 5 had onset between 3 and 7 months of age. Seizure type was variable and included tonic-clonic, absence, and atonic. All patients had developed delayed psychomotor development with severe to profound intellectual disability; 3 were bedridden at the time of the report. Brain imaging showed mild cerebral atrophy in all but 1 patient. Initial EEG was normal in 4 patients, but most eventually showed some abnormalities. Over time, 1 patient became seizure-free with medication and 3 were controlled with medication.

De Kovel et al. (2014) reported a 3-year-old girl with EIEE13 who had onset of intractable seizures at age 6 months. She had slightly delayed development in early infancy, but showed development regression, progressive microcephaly, and severe psychomotor retardation after seizure onset. EEG showed hypsarrhythmia, and seizures continued despite multiple medications. Brain imaging was initially normal but showed diffuse brain atrophy, mild cerebellar atrophy, and interrupted myelination at age 9 months. At age 3 years, she was unable to sit without support and had no speech.

Molecular Genetics

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.

In 7 unrelated patients with early-onset epileptic encephalopathy, Ohba et al. (2014) identified 7 different de novo heterozygous missense mutations in the SCN8A gene (see, e.g., 600702.0004-600702.0006). Whole-exome or targeted capture sequencing detected mutations in 6 (10%) of 60 patients with EIEE and in 1 (16.7%) of 6 patients diagnosed clinically with malignant migrating partial seizures of infancy (MMPSI). Functional studies of the variants were not performed, but all occurred at highly conserved residues scattered throughout the gene with variable predicted effects. There were no apparent genotype-phenotype correlations.

In a 3-year-old girl with EIEE13, de Kovel et al. (2014) identified a de novo heterozygous missense mutation in the SCN8A gene (R223G; 600702.0007). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro cellular functional expression studies showed that the mutant protein had significantly reduced stability (about 20% of wildtype) and that the mutant channel had reduced peak current amplitude (20% of wildtype) at 37 degrees C. There was a 3-fold increase in the ramp current at 30 degrees C, but this was still a significant reduction in terms of absolute current levels. The findings were consistent with a loss-of-function effect. De Kovel et al. (2014) noted that SCN8A is expressed in inhibitory neurons, where a loss of function may yield an epileptic phenotype.

Genotype/Phenotype Correlations

In 2 unrelated patients with EIEE13, Blanchard et al. (2015) identified 2 different de novo heterozygous missense mutations in the SCN8A gene (N984K, 600702.0008 and G1451S, 600702.0009). The patients were ascertained from a cohort of 500 patients with intellectual disability and 100 patients with a movement disorder who underwent exome sequencing. In vitro functional expression studies showed that the N984K mutation resulted in increased channel opening and increased neuronal excitability, consistent with a gain of function, whereas the G1451S mutation resulted in decreased current density, consistent with a loss of function. The patient with the N984K mutation had onset of intractable seizures at age 6 weeks and severe developmental delay with no speech and inability to sit independently at age 7 years; the patient with the G1451S mutation had a slightly less severe phenotype, with onset of seizures at age 18 months, moderate to severe developmental delay, spastic tetraplegia, ataxia, and nystagmus with cerebellar atrophy at age 33 years. Blanchard et al. (2015) concluded that SCN8A mutations resulting in a gain of function may result in a more severe phenotype, but noted that the G1451S mutation may also have some gain-of-function effects that were not detected in the cellular assay.