Authors :
Presenting Author: Kristen Barbour, MD – UC San Diego Rady Children's Health
Tommy Tommy Stӧdberg, PhD – Karolinska University Hospital
Anna Larsson, PhD Student – Karolinska University Hospital
Maria Dahlin, MD, PhD – Karolinska University Hospital
Zachary Grinspan, MD, MS – Cornell Weill Medicine
Rationale:
Data from preclinical models suggests that a repurposed therapeutic, phenylbutyrate, may treat seizures in genetic epileptic encephalopathies (Lewis Guiberson et al., 2018; Nat Commun; Nwosu et al., 2022; Brain Commun; Shen et al., 2024; Epilepsia). The first study in humans was recently published and demonstrated safety and improved seizure control in children with STXBP1 and SLC6A1 (Grinspan et al., Nov 8, 2024; medRxiv preprint). Clinicians have started prescribing phenylbutyrate off-label. The purpose of the current study is to understand real-world experiences using phenylbutyrate for genetic encephalopathies.Methods:
Children (age 0-17 years) treated with phenylbutyrate for STXBP1 or SLC6A1 were included. Parents participated in a phone interview describing their child’s clinical responses and adverse effects. Results:
Fifteen children (7 males) participated in the study with a median age when starting phenylbutyrate of 5.8 years (interquartile range = 3.7-7.4). Ten (67%) had STXBP1 and 5 (33%) had SLC6A1. All had developmental delays and 13 (87%) had epilepsy.
Of the 13 children with epilepsy, 8 (62%) had improved seizure control and 4 (31%) were able to stop or decrease at least one antiseizure medication. All families noticed improved development after starting phenylbutyrate, including improvements in social behaviors (13/15), gross motor (7/15), fine motor (6/15), expressive language (7/15), and receptive language (8/15). In addition, families noted improvements in attention/ engagement in therapies (12/15), sleep (6/15), and mood (6/15).
Adverse effects included odor (11/15), somnolence (8/15), decreased appetite (7/15), nausea (6/15), constipation (3/15), diarrhea (1/15), rash (1/15), ataxia (1/15), metabolic acidosis (1/15), and increased seizures (1/15). Phenylbutyrate was stopped for 3/15 children due to adverse effects - one because of hospitalization for metabolic acidosis, another due to increase in seizures, and a third due to constipation. Of the 12 who continued phenylbutyrate, nearly all (11/12) had resolution of adverse effects after an initial adjustment period around 2-10 days. One had constipation that persisted and was well controlled with a laxative.
Clinicians gradually uptitrated doses in 1 week or longer intervals to reach a maximum goal dose of 11.2 mL/m2/day. Some reached their goal dose in 1 month and others more gradually over several months. Many preferred 3 times a day dosing but this varied from 2-6 times per day.
Conclusions:
Early clinical experiences suggest improved seizure control and a well-tolerated side effect profile in children with STXBP1 and SLC6A1, consistent with data from a recent clinical trial (Grinspan et al., Nov 8, 2024; medRxiv preprint). Most families noticed improved seizure control, and a sizable minority were able to stop or decrease other antiseizure medications. All families noticed improved development; a promising result but it needs confirmation. Most adverse effects were mild and resolved after an initial adjustment period. Three stopped phenylbutyrate due to more serious adverse effects (metabolic acidosis, increased seizures, constipation).
Funding: None