From synaptic dysfunction to targeted intervention: a comprehensive review of STXBP1 encephalopathy and precision therapeutic strategies.

Abstract

STXBP1- related disorders (STXBP1-RD), caused by pathogenic variants in STXBP1 encoding the presynaptic protein MUNC18-1, affects approximately 1 in 30,000-40,000 individuals and is among the most common monogenic developmental and epileptic encephalopathies (DEEs). It is characterized by universal neurodevelopmental impairment, early-onset epilepsy, movement disorders, and autism spectrum features, yet treatment remains largely empirical. We conducted a comprehensive narrative review of studies indexed in PubMed/MEDLINE, Embase, Cochrane Library, ClinicalTrials.gov, and American Epilepsy Society proceedings through January 2026, synthesizing molecularly confirmed cohorts, mechanistic studies, and therapeutic investigations. Over 300 pathogenic variants have been identified, predominantly de novo heterozygous, with haploinsufficiency as the principal mechanism. Seizure onset typically occurs within the first months of life, with the vast majority presenting in the first year. Two broad trajectories emerge across cohorts: spontaneous seizure remission in a substantial minority - most within the first year - and persistent drug-resistant epilepsy in the remainder, with a significant proportion experiencing frequent seizures at long-term follow-up. Severe to profound intellectual disability affects the great majority of individuals; independent ambulation and functional verbal communication are achieved by roughly half and less than one-third, respectively. Movement disorders and autism spectrum features are common, and mortality, while modest in absolute terms, includes a disproportionate contribution from SUDEP. Current management is empirical, with phenobarbital, clobazam, and ketogenic diet supported by the most consistent retrospective cohort evidence for seizure reduction. Emerging precision approaches include AAV-mediated gene replacement, antisense oligonucleotides, 4-phenylbutyrate, CRISPR-based transcriptional activation, microRNA inhibition, and serotonergic modulation. Advances in natural history studies and biomarker development are accelerating mechanism-based therapies, positioning STXBP1-RD as a leading test case for precision medicine in DEEs.