Glycerol Phenylbutyrate Treatment in a Pediatric Cohort of SLC6A1-Related Neurodevelopmental Disorder

The SLC6A1 gene encodes the gamma-aminobutyric acid transporter 1 protein, which facilitates the reuptake of gamma-aminobutyric acid from the synaptic cleft in inhibitory synapses back into presynaptic neurons and glial cells. SLC6A1 haploinsufficiency leads to neurodevelopmental impairment including epilepsy, movement disorders, intellectual disability, and autism spectrum disorder. SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) is a rare condition with autosomal dominant inheritance for which there is no cure. Acting as a chemical chaperone, glycerol phenylbutyrate, used for urea cycle disorders, can cross the blood-brain barrier and increase GABA transporter 1 surface cell expression in animal and in vitro models. This research aimed to review the clinical characteristics of a cohort of pediatric patients with SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) in Spain and to assess the efficacy and safety of glycerol phenylbutyrate treatment.

We have conducted retrospective review of the clinical characteristics of SLC6A1-NDD pediatric patients from 13 hospitals in Spain and investigated the efficacy and safety of glycerol phenylbutyrate treatment.

Fourteen patients were included in the cohort, out of which eleven were treated with glycerol phenylbutyrate. A significant reduction in the number of epileptic seizures was observed in 80% of patients with uncontrolled seizures at baseline and 40% became seizure-free. A clear improvement in video-electroencephalogram abnormalities was evident in 64%, while 27.2% experienced cognitive improvement and 36.3% showed significantly improved psychiatric manifestations. Seven of the eleven treated patients experienced some side effects from which three has discontinued the treatment.

Glycerol phenylbutyrate treatment is relatively well tolerated, and although it is effective in reducing the frequency of seizures and improving video-electroencephalogram abnormalities, it is less effective in ameliorating cognitive and psychiatric manifestations.