for haploinsufficiency with or with

for haploinsufficiency with or without dominant negative suppression from the mutant allele as described in GABRG2 mutations10. We have previously characterized the functional consequences of both missense and nonsense SLC6A1 mutations associated with a wide spectrum of disease phenotypes. We identified the common mechanisms of the molecular pathophysiology underlying the heterogenous clinical phenotype. The molecular pathophysiological mechanisms include reduction or loss of GABA uptake, endoplasmic reticulum (ER) retention of the mutant GAT-1 protein, and reduced membrane and total GAT-1 protein expression due to impaired protein trafficking9,11-13. The mechanisms directly contributing to diminished GAT-1 function include decreased membrane protein trafficking due to protein misfolding and altered protein stability. This is a common phenomenon also observed in GABAA receptor subunit mutations in our previous studies14-16. Protein misfolding has been widely studied for later onset neurodegenerative diseases but much less in the early onset childhood neurodevelopmental disorders such as epilepsy or autism. Our studies in both GABAA receptors and more recently in GAT-1 indicate that ER retention of the mutant protein due to protein misfolding is common among pediatric neurological disorders. Thus leveraging the ER pathway and promoting membrane protein trafficking could be a novel treatment target for genetic epilepsy as well as other related disorders17. This could be disease modifying as leveraging the ER pathway via therapeutic intervention could correct the mutant protein upstream of signaling cascades of the complex disease mechanisms. 4-phenylbutyrate (PBA) or 4-phenylbutyric acid is a salt of an aromatic fatty acid. It is used to treat urea cycle disorders, because its metabolites offer an alternative pathway to the urea cycle allowing excretion of excess nitrogen18. PBA is a chaperone seen to reduce E