Epileptic Encephalopathy, Early Infantile, 57

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-57 (EIEE57) is caused by heterozygous mutation in the KCNT2 gene (610044) on chromosome 1q31. One such patient has been reported.

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

Clinical Features

Gururaj et al. (2017) reported a 4-year-old boy with neonatal hypotonia, poor feeding, and developmental delay. At 3 months of age, he developed intractable seizures associated with developmental regression. Seizure type was mainly prolonged tonic, but he also had myoclonic jerks and atypical absence. EEG showed disorganized background activity, multifocal epileptogenic activity, and hypsarrhythmia. Brain imaging showed a reduction in white matter and thin corpus callosum. He had no dysmorphic features or congenital abnormalities.

Molecular Genetics

In a 4-year-old boy with EIEE57, Gururaj et al. (2017) identified a de novo heterozygous missense mutation in the KCNT2 gene (F240L; 610044.0001). The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed decreased expression of the mutant protein as well as significantly altered ion selectively, with decreased sensitivity to chloride and increased sodium current conductance compared to wildtype. Expression of the mutation in primary rat dorsal root ganglion neurons induced membrane hyperexcitability and neuronal toxicity. The findings indicated that the P240L mutation altered a K+ channel upregulated by Cl- into a Na+ channel downregulated by Cl-.