Unraveling 4-Phenylbutyrate's Therapeutic Role in SLC6A1 Disorders: Pharmacochaperoning Over HDAC Inhibition.

Notably, PBA administration produced a robust and highly significant reduction in seizure events in Slc6a1 +/A288V mice (** p < 0.0001) (Figure 8G ), mirroring the therapeutic efficacy observed in the Slc6a1 +/S295L model. 4 Discussion 4.1 SLC6A1 Variants Cause Loss of Function via ER Retention and Protein Trafficking Deficits SLC6A1 variants lead to profound GABA transporter dysfunction, disrupting inhibitory neurotransmission through a combination of impaired trafficking, altered protein folding, and reduced transporter activity.

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In Slc6a1 +/A288V mice, butyrate treatment did not significantly alter seizure frequency, although a mild trend toward reduction was observed ( p = 0.1046) (Figure 8F ).

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Only one variant, G232V, failed to reach statistical significance.

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