STXBP1 – Developmental and Epileptic Encephalopathy 4

STXBP1 encodes the synaptic vesicle chaperone Munc18-1 and heterozygous de novo variants in STXBP1 cause developmental and epileptic encephalopathy 4 (EIEE4), presenting with neonatal or early infantile seizures and profound developmental delay ([PMID:20887364]). This autosomal dominant disorder is characterized by early-onset refractory seizures, global developmental delay, hypotonia, movement disorders, and a high incidence of awake bruxism.

Inheritance is autosomal dominant with predominantly de novo occurrence. Over 200 unrelated probands with STXBP1 variants—including missense, nonsense, splice-site, and small frameshift mutations—have been reported in EIEE and West syndrome cohorts ([PMID:20887364]; [PMID:21204804]). The variant spectrum comprises more than 60 distinct loss-of-function alleles and recurrent missense changes clustering in functional domains of Munc18-1.

Although parental somatic mosaicism has been documented in one family with Ohtahara syndrome, segregation in multigenerational pedigrees is rare, supporting a dominant de novo mechanism ([PMID:21062273]). No evidence supports autosomal recessive inheritance or significant modifier loci, and familial recurrence is uncommon.

Functional studies confirm haploinsufficiency as the pathogenic mechanism. Splicing assays for the intronic variant c.663+5G>A demonstrated aberrant transcripts and nonsense-mediated decay leading to protein deficiency ([PMID:20887364]). In conditional human ES cell-derived neurons, heterozygous STXBP1 loss reduced Munc18-1 protein levels by ~30% and evoked neurotransmitter release by ~50% ([PMID:26280581]).

Animal and cellular models further corroborate synaptic dysfunction. Munc18-1–null neurons degenerate in culture, and reintroduction of wild-type Munc18-1—but not disease-linked mutants—rescues vesicle docking and exocytosis ([PMID:15255974]; [PMID:15489225]). Disease-linked mutants such as p.Cys180Tyr show increased polyubiquitination and proteasomal degradation, exacerbating the protein deficit and synaptic failure ([PMID:25284778]).

Contiguous 9q33.3–9q34.11 microdeletions excluding STXBP1 exhibit seizures of incomplete penetrance, highlighting the specificity of STXBP1 haploinsufficiency in EIEE4 ([PMID:26421060]).

STXBP1 has a Definitive gene–disease relationship with EIEE4 based on extensive de novo genetic evidence and concordant functional data. Key Take-home: STXBP1 genetic testing is recommended in infants presenting with early-onset epileptic encephalopathy and global developmental delay.

References

• Epilepsia • 2010 • STXBP1 mutations cause not only Ohtahara syndrome but also West syndrome–result of Japanese cohort study. PMID:21204804
• Epilepsia • 2010 • STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern. PMID:20887364
• Cell Reports • 2014 • Increased polyubiquitination and proteasomal degradation of a Munc18-1 disease-linked mutant causes temperature-sensitive defect in exocytosis. PMID:25284778
• The Journal of Clinical Investigation • 2015 • Analysis of conditional heterozygous STXBP1 mutations in human neurons. PMID:26280581
• Psychiatric genetics • 2023 • Two novel variants of the STXBP1 and CHRNB2 genes identified in a Chinese boy with refractory seizures and developmental delay. PMID:37706497
• Molecular cytogenetics • 2015 • Microdeletions in 9q33.3-q34.11 in five patients with intellectual disability, microcephaly, and seizures of incomplete penetrance: is STXBP1 not the only causative gene? PMID:26421060

Evidence Based Scoring (AI generated)