Ade novomissense mutation ofGABRB2causes early myoclonic encephalopathy

Background Early myoclonic encephalopathy (EME), a disease with a devastating prognosis, is characterised by neonatal onset of seizures and massive myoclonus accompanied by a continuous suppression-burst EEG pattern. Three genes are associated with EMEs that have metabolic features. Here, we report a pathogenic mutation of an ion channel as a cause of EME for the first time. Methods Sequencing was performed for 214 patients with epileptic seizures using a gene panel with 109 genes that are known or suspected to cause epileptic seizures. Functional assessments were demonstrated by using electrophysiological experiments and immunostaining for mutant γ-aminobutyric acid-A (GABA A ) receptor subunits in HEK293T cells. Results We discovered a de novo heterozygous missense mutation (c.859A>C [p.Thr287Pro]) in the GABRB2 -encoded β2 subunit of the GABA A receptor in an infant with EME. No GABRB2 mutations were found in three other EME cases or in 166 patients with infantile spasms. GABA A receptors bearing the mutant β2 subunit were poorly trafficked to the cell membrane and prevented γ2 subunits from trafficking to the cell surface. The peak amplitudes of currents from GABA A receptors containing only mutant β2 subunits were smaller than that of those from receptors containing only wild-type β2 subunits. The decrease in peak current amplitude (96.4% reduction) associated with the mutant GABA A receptor was greater than expected, based on the degree to which cell surface expression was reduced (66% reduction). Conclusion This mutation has complex functional effects on GABA A receptors, including reduction of cell surface expression and attenuation of channel function, which would significantly perturb GABAergic inhibition in the brain.