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Review
. 2025 Jul 1:217:107621.
doi: 10.1016/j.eplepsyres.2025.107621. Online ahead of print.

Phenylbutyrate for monogenetic epilepsy: Literature review

Amelia Stone  1 , Jacqueline Burré  2 , Natalie Wayland  3 , Zachary M Grinspan  3
Affiliations
Review

Phenylbutyrate for monogenetic epilepsy: Literature review

Amelia Stone et al. Epilepsy Res. .

Abstract

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.

Keywords: Chemical chaperone; Drug repurposing; Monogenetic epilepsy; Phenylbutyrate.

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Conflict of interest statement

Declaration of Competing Interest Z.G currently receives research funding from Weill Cornell Medicine, NIH/NINDS (R01NS130113), Amgen, Harmony Biosciences, SLC6A1 Connect, STXBP1 Foundation, the Morris and Alma Schapiro Fund, the Jain Foundation, and the D′Addario Foundation. Z.G has conducted paid consulting work for UCB, Jazz Pharmaceuticals, Capsida Therapeutics, Mahzi Therapeutics, Encoded Therapeutics, and Neurvati Neurosciences. J.B receives research funding from NIH/NINDS (R01NS113960, R01NS121077, R01AG083949, RF1NS126342, R01NS113960). The remaining authors have no conflicts of interest to report.

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