A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-62 (DEE62) is caused by heterozygous mutation in the SCN3A gene (182391) on chromosome 2q24.

Heterozygous mutation in the SCN3A gene can also cause the less severe disorder familial focal epilepsy with variable foci-4 (FFEVF4; 617935).

Developmental and epileptic encephalopathy-62 (DEE62) is a severe neurologic disorder characterized by the onset of various types of refractory seizures in the first weeks or months of life. Affected individuals have severe to profound developmental delay with hypotonia and impaired motor and cognitive development. Additional features may include spasticity, microcephaly, and brain imaging abnormalities (summary by Zaman et al., 2018).

For a discussion of genetic heterogeneity of DEE, see 308350.

Zaman et al. (2018) reported 4 unrelated children with refractory epilepsy beginning in the first weeks or months of life resulting in severe to profound intellectual disability and global neurologic impairment. The patients had multiple seizure types, including tonic, clonic, and myoclonic, and EEG showed multifocal sharp waves and spikes, intermittent slowing, and hypsarrhythmia. Brain imaging showed polymicrogyria in 2 patients, thin corpus callosum in 2, and white matter abnormalities in 2. Additional more variable features included microcephaly, hypotonia, spastic tetraparesis, and cortical blindness. The oldest patient was a 13-year-old boy who was nonverbal and nonambulatory with poor growth and dysphagia necessitating a feeding tube.

The heterozygous mutations in the SCN3A gene that were identified in patients with DEE62 by Zaman et al. (2018) occurred de novo.

In 4 unrelated patients with DEE62, Zaman et al. (2018) identified identified 3 different de novo heterozygous missense mutations in the SCN3A gene (182391.0005-182391.0007). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Whole-cell voltage clamp electrophysiologic recordings showed that the mutant channels had an increase of a slowly inactivating/noninactivating persistent current compared to controls, consistent with a gain-of-function effect. In addition, 2 variants (I875T, 182391.0005 and P1333L, 182391.0006) caused a leftward shift in the voltage dependence of activation to a hyperpolarized potential. Both mechanisms were predicted to increase neuronal excitability. Both patients with the I875T variant had polymicrogyria. In vitro studies showed that the antiseizure medications lacosamide and phenytoin selectively blocked the abnormal currents. Zaman et al. (2018) noted that SCN3A is highly expressed in embryonic brain, with low or undetectable postnatal expression in rodents, which may explain why this encephalopathy presents in the early infantile period.