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Parent-Reported Improvement in Seizure Control and Development After Phenylbutyrate Treatment in Children With STXBP1
Kristen Barbour1, Tommy Stӧdberg2, Anna Larsson3
1Scripps Research Translational Institute, Scripps Research, San Diego, California; Department of Pediatrics, University of California San Diego, San Diego, California; Division of Genetics, Rady Children's Hospital, San Diego, California.
Insights
Phenylbutyrate improved seizure control and development in children with STXBP1- and SLC6A1-encephalopathy. While generally well-tolerated, careful monitoring for toxicity is recommended.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Phenylbutyrate, approved for urea cycle disorders, shows promise for treating developmental and epileptic encephalopathies (DEEs).
- Its impact on development and potential toxicity risks, especially with comorbidities like hypotonia, require further investigation.
- This study offers real-world insights into phenylbutyrate use in children with DEEs outside formal clinical trials.
Purpose of the Study:
- To evaluate the efficacy and safety of phenylbutyrate in children with STXBP1- and SLC6A1-encephalopathy.
- To assess seizure control, developmental outcomes, and side effects associated with phenylbutyrate treatment.
- To provide early clinical experience data for phenylbutyrate in DEEs.
Main Methods:
- Semistructured phone interviews were conducted with parents of children diagnosed with STXBP1- or SLC6A1-encephalopathy.
- Seizure response was defined as a ≥50% reduction in seizure frequency.
- Outcomes, including seizure control, development, side effects, and toxicity, were evaluated.
Main Results:
- A 73% seizure response rate was observed in children with previously uncontrolled seizures (8/11 achieved ≥50% reduction).
- Nearly all participants (17/18) experienced developmental improvements.
- Mild, transient toxicities (sedation, appetite decrease, nausea) were common (14/18); one child experienced severe toxicity requiring hospitalization.
Conclusions:
- Phenylbutyrate demonstrated efficacy in improving seizure control and development for children with STXBP1- and SLC6A1-encephalopathy.
- The treatment was generally well-tolerated, with most side effects being mild and resolving quickly.
- These findings support phenylbutyrate as a treatment option for DEEs, underscoring the importance of safety monitoring.
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.
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