SLC6A1-Related Neurodevelopmental Disorder: A Scoping Review of Clinical Features and Emerging Therapeutic Strategies

Solute carrier family 6 member 1 (SLC6A1) gene encodes gamma-aminobutyric acid transporter 1 (GAT-1), the principal synaptic gamma-aminobutyric acid (GABA) transporter. Pathogenic heterozygous loss-of-function variants of SLC6A1 cause a developmental and epileptic encephalopathy characterized by early-onset epilepsy, intellectual disability, and autistic features. Despite a rapidly expanding translational pipeline, clinical evidence remains fragmented. This scoping review systematically maps the published evidence on the phenotypic spectrum and therapeutic landscape of SLC6A1-related neurodevelopmental disorder.

A systematic search of PubMed, Embase, OVID/MEDLINE, Web of Science, and ClinicalTrials.gov was conducted through March 2026, supplemented by hand-searching reference lists and American Epilepsy Society conference abstracts (2019-2025). The review was conducted per the Arksey and O'Malley framework and reported following Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews guidelines.

Epilepsy affects approximately 90% of clinically identified individuals, with seizure onset typically between 14 months and 5 years; predominant types include absence (60-72%), myoclonic-atonic (24-35%), and atonic seizures. Intellectual disability or developmental delay is present in 82-100% of patients, with cognitive impairment antedating seizure onset in over 60% of cases. Autistic features occur in 22-65% and hypotonia in 60-71%. Clinical severity correlates with degree of residual GAT-1 activity as follows: variants with near-total loss of GABA uptake (<10% residual function) are 4.6-fold enriched in severe phenotypes. Valproate remains the most consistently effective antiseizure medication, followed by lamotrigine, clobazam, and ethosuximide. Although levetiracetam is commonly used, behavioral adverse effects should be monitored. The ketogenic diet and acetazolamide represent evidence-supported adjunctive options. Among disease-modifying strategies, 4-phenylbutyrate restores GAT-1 trafficking in endoplasmic reticulum -retained variants and has demonstrated seizure reduction in 80% and seizure freedom in 40% of treated patients in the largest clinical cohort. Adeno-associated virus serotype 9-mediated gene replacement normalized electroencephalography abnormalities in preclinical models, with the first Phase I/II human trial (NCT07173153) dosing its initial patient in December 2025.

As a severe developmental and epileptic encephalopathy, SLC6A1-related neurodevelopmental disorder is defined by a specific functional loss of GABA transport. This clear mechanistic substrate has allowed for the development of a highly focused translational pipeline, ranging from gene therapies to pharmacological chaperones. Critical gaps include the absence of prospective natural history data with standardized outcomes, lack of randomized controlled trials, and incomplete characterization of the adult phenotype. Prioritizing multinational registry-based cohort studies and validated disease-specific outcome measures is essential to support rigorous evaluation of transformative emerging therapies.