Phenylbutyrate for syngap1-related Developmental and Epileptic Encephalopathy
Abstract number :
3.191
Submission category :
2. Translational Research / 2A. Human Studies
Year :
2024
Submission ID :
550
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Amelia Stone, BA – Weill Cornell Medicine
Scott Demarest, MD – Children's Hospital Colorado
Jennifer Cross, MD – Weill Cornell Medicine
Dara Jones, MD – Weill Cornell Medicine
Jaehyung Lim, MD – Colorado Children's
Natasha Basma, MPH – Weill Cornell Medicine
Andrea Miele, PhD – Children’s Hospital Colorado
Maria Abila, BS – Colorado Children's
Laurae Luevano, BS – Colorado Children's
Zachary Grinspan, MD, MS – Weill Cornell Medicine
Rationale: Children with monogenetic developmental and epileptic encephalopathies often have seizures that are refractory to antiseizure medications. Preclinical data and unpublished data suggest treatment with 4-phenylbutyrate may improve protein function in SLC6A1- and STXBP1- related disorders and reduce seizure burden. By conceptualizing SLC6A1- and STXBP1- related disorders as “synaptopathies”, we hypothesized that 4-phenylbutyrate would also improve clinical outcomes in children with mutations in SYNGAP1.
Methods: Children with refractory epilepsy due to mutations in SYNGAP1 were admitted for a 48-hour video EEG, accompanied by a developmental evaluation (the Bayley-IV and the Vineland Adaptive Behavior Scales). Each child received an initial dose of glycerol phenylbutyrate, then titrated up to the goal dose of 11.2 mL/m2/day. After 12-weekson glycerol phenylbutyrate, each child returned for a 24-hour video EEG and a repeat developmental evaluation. Seizure reduction was estimated by review of seizure diaries, clinical notes, and EEG reports. We defined response as 50% or more reduction in seizures.
Results: Eight children (four female, aged 2 to 7 years) were enrolled. Six were responders (Two with 90% or more reduction in seizures; four with 50-75% decrease in seizures). Seizure types included epileptic myoclonias and myoclonic-atonic seizures.Two participants had a transient response or no response. Side effects included metabolic acidosis, appetite suppression, sleepiness, and a honey-like body odor. There was one serious adverse event – a child developed pancytopenia that resolved after discontinuation of both glycerol phenylbutyrate and valproic acid.
Conclusions: Glycerol phenylbutyrate is a promising novel therapy for children with SYNGAP1. In ongoing work, we are (1) reviewing developmental assessment data and (2) enrolling additional children with SYNGAP1 and other monogenetic developmental and epileptic encephalopathies.
Funding: This study was funded by Orphan Disease Center University of Pennsylvania, Clara Inspired, SLC6A1-Connect, the STXBP1 Foundation, and Amgen Inc...
Translational Research