Parent-Reported Improvement in Seizure Control and Development After Phenylbutyrate Treatment in Children With STXBP1 and SLC6A1

BACKGROUND: Preclinical studies and early clinical trials suggest phenylbutyrate (an FDA and European Medicines Agency-approved medication for urea cycle disorders) may improve seizure control in certain developmental and epileptic encephalopathies (DEEs). Its effect on development is unknown, and comorbidities like hypotonia may raise toxicity risks. This study examines early clinical experiences with phenylbutyrate in children with DEEs, outside the context of a clinical trial. METHODS: We conducted semistructured phone interviews with parents of children with STXBP1- and SLC6A1-encephalopathy treated with phenylbutyrate. We evaluated seizure and developmental outcomes, side effects, and toxicity. Among children with uncontrolled seizures before treatment, we defined seizure response as having a ≥50% reduction in seizures. We assessed the proportion of children experiencing clinical changes and provided narrative descriptions of these changes. RESULTS: Eighteen children (median age 6 years) were included, with a median treatment duration of 6 months. Among 11 children with uncontrolled seizures, 8 showed improvement (all with ≥50% seizure reduction), resulting in a 73% seizure response rate. Nearly all families (17/18) reported improvements in development. Mild toxicity (sedation, decreased appetite, and/or nausea) was common (14/18) at the start of phenylbutyrate treatment but typically resolved within 2-10 days. One child (1/18) had severe toxicity, with metabolic acidosis and aspiration pneumonia requiring intubation. CONCLUSIONS: Phenylbutyrate was generally well tolerated with improved seizure control and development in children with STXBP1- and SLC6A1-encephalopathy, although we observed 1 intensive care unit-level hospitalization from dose-related toxicity. These results support the use of phenylbutyrate treatment for DEEs and highlight safety considerations.