Stxbp1, also known as syntaxin-binding protein 1 or Munc18-1, is an essential protein for presynaptic vesicle release, involved in synaptic vesicle fusion and neurotransmitter release [1,5]. It functions in multiple pathways related to neuronal communication, and its proper function is crucial for normal brain development and neural activity [1,4,5]. Animal models, such as in vitro-and animal models used to study the pathophysiology of STXBP1-related disorders, are valuable for understanding its function [6].

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 and duplications, and whole-gene deletions [1]. Most patients with STXBP1-related disorders have neurodevelopmental abnormalities (95%) and seizures (89%), often with focal-onset seizures as the most common type (47%) [3]. Many patients have seizure onset in the first year of life, with neonatal seizure onset in 47% [3]. There is a lack of clear genotype-phenotype correlation [1,2,3]. Some genetic hotspots with recurrent variants have been identified, but they are not significantly associated with distinct electroclinical syndromes or phenotypic features [3]. The progression of neurologic symptoms in some older affected individuals shows extrapyramidal features, similar to early-onset parkinsonism [4]. The current understanding from animal models and basic research indicates that genetic knockout of Stxbp1 leads to widespread perinatal neurodegeneration, and it may be related to the self-replicating aggregation of α-synuclein, a protein involved in neurodegenerative diseases [4].

In conclusion, Stxbp1 is vital for presynaptic vesicle release and neuronal communication. Model-based research, especially through gene knockout studies, has revealed its crucial role in early epileptic encephalopathies and neurodevelopmental disorders. Understanding Stxbp1's function through these models provides insights into the pathophysiology of related diseases, which may help in the development of therapeutic strategies for these devastating disorders [1,3,4,6].

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. Lanoue, Vanessa, Chai, Ye Jin, Brouillet, Julie Z, Collins, Brett M, Meunier, Frederic A. 2019. STXBP1 encephalopathy: Connecting neurodevelopmental disorders with α-synucleinopathies? In Neurology, 93, 114-123. doi:10.1212/WNL.0000000000007786. https://pubmed.ncbi.nlm.nih.gov/31221716/

5. 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/

6. 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/