De novo pathogenic variants in STXBP1 encoding syntaxin1-binding
protein (STXBP1, also known as Munc18-1) lead to a range of early-onset neurocognitive conditions, most commonly
early infantile epileptic encephalopathy type 4 (EIEE4, also called STXBP1
encephalopathy), a severe form of
epilepsy associated with developmental delay/
intellectual disability. Other neurologic features include
autism spectrum disorder and
movement disorders. The progression of
neurologic symptoms has been reported in a few older affected individuals, with the appearance of extrapyramidal features, reminiscent of early onset
parkinsonism. Understanding the pathologic process is critical to improving
therapies, as currently available
antiepileptic drugs have shown limited success in controlling
seizures in EIEE4 and there is no precision medication approach for the other neurologic features of the disorder. Basic research shows that genetic knockout of STXBP1 or other presynaptic
proteins of the exocytic machinery leads to widespread perinatal neurodegeneration. The mechanism that regulates this effect is under scrutiny but shares intriguing hallmarks with classical
neurodegenerative diseases, albeit appearing early during brain development. Most critically, recent evidence has revealed that STXBP1 controls the self-replicating aggregation of α-
synuclein, a presynaptic
protein involved in various
neurodegenerative diseases that are collectively known as
synucleinopathies, including
Parkinson disease. In this review, we examine the tantalizing link among STXBP1 function, EIEE, and the neurodegenerative
synucleinopathies, and suggest that neural development in EIEE could be further affected by concurrent synucleinopathic mechanisms.