Phenylbutyrate for monogenetic epilepsy: Literature review.

Overview

Monogenetic epilepsies are seizure disorders with a single-gene etiology. More than 500 genes are linked to epilepsy. As many as 40 % of epilepsies are caused by variants in one of these genes. Single gene-linked epilepsies have a wide phenotypic spectrum and may be accompanied by comorbidities such as developmental and motor delays. Epilepsy is often pharmacoresistant and does not respond to existing drug therapies. Preclinical data suggests that 4-phenylbutyrate (PBA) may produce an anti-seizure effect in individuals with genetic epilepsies, including STXBP1, SLC6A1, SLC6A8, GABA(A) disorders, Dravet Syndrome (SCN1A), and LGI1 variants. Clinical data also suggests that PBA may have a therapeutic effect for SYNGAP1. This literature review describes the clinical profiles of several monogenetic epilepsies and the pathogenesis of seizure activity in these disorders. We focus on gene-linked epilepsy syndromes that may benefit from treatment with PBA according to several proposed theories of the drug's mechanism and functional impact.