Stxbp1, also known as syntaxin-binding protein 1 or Munc18-1, is an essential protein for presynaptic vesicle release. It is involved in synaptic vesicle fusion and neurotransmitter release, playing a crucial role in neuronal communication [4]. Genetic models, such as animal and cellular models, are valuable for studying its function [4].

Mutations in Stxbp1 are linked to various severe early epileptic encephalopathies and neurodevelopmental disorders [1]. Heterozygous mutations include missense, nonsense, frameshift, splice-site mutations, intragenic deletions/duplications, and whole-gene deletions [1]. Most patients have severe to profound intellectual disability, with 95% having epilepsy, often starting in the first year of life [2]. Focal-onset seizures are common, and there is no clear genotype-phenotype correlation [3]. Some patients present with Ohtahara or West syndrome, while the majority have non-syndromic early-onset epilepsy and encephalopathy [2]. Neurologic comorbidities like autistic features and movement disorders are frequent [2]. Protein-truncating variants and deletions in Stxbp1 may be associated with a higher likelihood of West syndrome [3]. There are also genetic hotspots with recurrent variants, but these are not significantly associated with distinct electroclinical syndromes or single phenotypic features [3]. Anti-seizure medications show a dynamic pattern of seizure control, with some like adrenocorticotropic hormone and phenobarbital being more effective initially in certain seizure types, and the ketogenic diet being better for maintaining seizure freedom [3].

In conclusion, Stxbp1 is vital for presynaptic function and neurotransmitter release. Studies on Stxbp1-related disorders, often using animal models, have revealed its significance in epileptic encephalopathies and neurodevelopmental disorders. Understanding Stxbp1 function from these models is crucial for developing therapies for these devastating diseases [1,5].

References:

1. Abramov, Debra, Guiberson, Noah Guy Lewis, Burré, Jacqueline. 2020. STXBP1 encephalopathies: Clinical spectrum, disease mechanisms, and therapeutic strategies. In Journal of neurochemistry, 157, 165-178. doi:10.1111/jnc.15120. https://pubmed.ncbi.nlm.nih.gov/32643187/

2. Stamberger, Hannah, Nikanorova, Marina, Willemsen, Marjolein H, Møller, Rikke S, Weckhuysen, Sarah. 2016. STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy. In Neurology, 86, 954-62. doi:10.1212/WNL.0000000000002457. https://pubmed.ncbi.nlm.nih.gov/26865513/

3. Xian, Julie, Parthasarathy, Shridhar, Ruggiero, Sarah M, Striano, Pasquale, Helbig, Ingo. . Assessing the landscape of STXBP1-related disorders in 534 individuals. In Brain : a journal of neurology, 145, 1668-1683. doi:10.1093/brain/awab327. https://pubmed.ncbi.nlm.nih.gov/35190816/

4. Goss, James R, Prosser, Benjamin, Helbig, Ingo, Son Rigby, Charlene. 2024. STXBP1: fast-forward to a brighter future - a patient organization perspective. In Therapeutic advances in rare disease, 5, 26330040241257221. doi:10.1177/26330040241257221. https://pubmed.ncbi.nlm.nih.gov/38898886/

5. Stamberger, Hannah, Weckhuysen, Sarah, De Jonghe, Peter. 2017. STXBP1 as a therapeutic target for epileptic encephalopathy. In Expert opinion on therapeutic targets, 21, 1027-1036. doi:10.1080/14728222.2017.1386175. https://pubmed.ncbi.nlm.nih.gov/28971703/