Epileptic Encephalopathy, Early Infantile, 45

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-45 (EIEE45) is caused by heterozygous mutation in the GABRB1 gene (137190) on chromosome 4p13.

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

Clinical Features

The Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) reported a 4.5-year-old boy with early infantile epileptic encephalopathy. The patient had onset of seizures at age 12 months and showed developmental regression at age 35 months. EEG showed hypsarrhythmia. He had global developmental delay, hypotonia, ataxia, cortical visual impairment, and thin corpus callosum.

Lien et al. (2016) reported a 32-month-old boy with severe developmental delay and hypotonia who developed refractory epilepsy at age 3 months. Brain imaging was normal.

Molecular Genetics

In a boy with EIEE45, the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) identified a de novo heterozygous missense mutation in the GABRB1 gene (F246S; 137190.0001). The patient was part of a cohort of 264 probands with epileptic encephalopathy who underwent exome sequencing. Functional studies of the variant were not performed. Janve et al. (2016) noted that the F246S mutation occurs at a highly conserved residue in transmembrane domain 1. In vitro functional studies in HEK293 cells showed that the mutation altered the kinetic properties of the channel, resulting in the net loss of GABAergic inhibition.

In a boy with EIEE45, Lien et al. (2016) identified a de novo heterozygous missense mutation in the GABRB1 gene (T287I; 137190.0002). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed.