E S van Walree, D Z Dekker, J J Sprengers, I Boussaad, M M van Muilekom, M J Smits, M A Alders, M M van Haelst, A Altinbas, W B Gunning, C A Haaxma, J P M van der Vegt, J S Verhoeven, Z M Grinspan, J H Schieving, A R Müller, C D van Karnebeek
Glycerol phenylbutyrate was associated with improvements in individualized outcomes in children with SLC6A1-NDD. However, personalized goal attainment measures are susceptible to expectation and observer bias in open-label study designs. Controlled studies are needed to determine efficacy and guide patient selection.
BACKGROUND: SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) is characterized by intellectual disability, epilepsy, and behavioral difficulties. It is caused by pathogenic variants in SLC6A1, encoding the GABA transporter protein 1 (GAT1). Glycerol phenylbutyrate increases GAT1 expression in preclinical models and has shown promising effects on seizure control in a clinical study.
METHODS: We conducted a prospective open-label observational study of glycerol phenylbutyrate (target dose 11.2 ml/m2/day) in pediatric patients with NDD and/or epilepsy and rare SLC6A1 variants (including (likely) pathogenic variants and variants of uncertain significance (VUS)). Primary outcomes were personalized goals. Secondary outcomes included seizure burden, development, irritability, quality of life, and tolerability.
RESULTS: We initiated treatment in six children; one was excluded due to lack of consent, leaving five for analysis. Three had (likely) pathogenic SLC6A1 variants and constituted the main case series; two had a VUS and were analyzed separately. Mean treatment duration was 33.7 months (range 16-46). Side effects included mild gastrointestinal complaints (n = 2) and a honey-like body odor (n = 3). All three molecularly confirmed SLC6A1-NDD patients achieved or exceeded predefined personalized goals at 12 months, with improvements in goals associated with amelioration in behavior and development, even though standardized developmental assessments show a more nuanced picture. In a single patient with absence-like episodes without clear EEG correlate at baseline, a reduction in these events and in epileptiform activity on EEG was observed following treatment. Positive signals in quality of life (n = 1) and irritability (n = 2) questionnaires were observed.
CONCLUSION: Glycerol phenylbutyrate was associated with improvements in individualized outcomes in children with SLC6A1-NDD. However, personalized goal attainment measures are susceptible to expectation and observer bias in open-label study designs. Controlled studies are needed to determine efficacy and guide patient selection.