Journal of Child Neurology· 2026Q2
Phenylbutyrate-Responsive SLC6A1 -Related Neurodevelopmental Disorder Associated With a Familial Variant
- 0citations
- Q2SCImago
- 2026year
Short summary
Glycerol phenylbutyrate (GPB) achieved complete seizure freedom and reduced epileptiform discharges in a proband with SLC6A1-related neurodevelopmental disorder, a synaptopathy caused by impaired GABA transporter-1 (GAT-1) function.
AI-generated from the title and abstract; the full text is not read.
Key points
- SLC6A1 variants impair GABA transporter-1 (GAT-1) folding and trafficking, leading to reduced inhibitory neurotransmission and hyperexcitability.
- A proband with drug-resistant epilepsy and developmental delay carried a heterozygous SLC6A1 variant that segregated with the phenotype in a 3-generation family.
- Treatment with glycerol phenylbutyrate (GPB) resulted in complete seizure freedom and reduced epileptiform discharges on EEG.
- The findings suggest that GPB can restore GAT-1 function and offer a genotype-informed precision therapy for SLC6A1-related disorders.
AI-generated from the title and abstract; the full text is not read.
Abstract
SLC6A1 -related neurodevelopmental disorder is a synaptopathy characterized by developmental delay, epilepsy, and neurobehavioral manifestations with marked phenotypic variability. Variants impair γ-aminobutyric acid (GABA) transporter-1 (GAT-1) folding and trafficking, reducing inhibitory neurotransmission and promoting hyperexcitability. Pharmacologic chaperones such as 4-phenylbutyrate (4-PBA) may restore GAT-1 function. We report a 3-generation family harboring a heterozygous SLC6A1 variant with segregating neurodevelopmental and epileptic phenotypes. The proband presented with drug-resistant developmental and epileptic encephalopathy, multiple seizure types, diffuse epileptiform abnormalities, and global developmental delay. Segregation analysis demonstrated co-segregation of the variant with epilepsy and neurodevelopmental features across affected relatives. Because of persistent seizures despite antiseizure medications, glycerol phenylbutyrate (GPB), a prodrug of 4-PBA, was initiated, resulting in complete seizure freedom and reduction of epileptiform discharges on follow-up electroencephalography. These findings highlight the potential role of genotype-informed precision therapy in SLC6A1 -related disorders and underscore the importance of careful variant interpretation in familial cases.
The authors' abstract, as published at the source. Journal of Child Neurology, 2026 · DOI ↗
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Field: Biochemistry (Biochemistry, Genetics and Molecular Biology)
BiochemistryBiochemistry, Genetics and Molecular Biology