A missense mutation of causes 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) receptor subunits in HEK293T cells.

Results: We discovered a heterozygous missense mutation (c.859A>C [p.Thr287Pro]) in the -encoded β2 subunit of the GABA receptor in an infant with EME. No mutations were found in three other EME cases or in 166 patients with infantile spasms. GABA 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 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 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 receptors, including reduction of cell surface expression and attenuation of channel function, which would significantly perturb GABAergic inhibition in the brain.