Drosophila models show SYT1 variant D310N causes more severe Baker-Gordon syndrome phenotypes than D366E.

This research employed Drosophila models to investigate the clinical phenotype severity, locomotor impairment, seizure-like activity, and learning and memory deficits associated with newly described SYT1 variant D310N versus the previously reported D366E variant. The study population included a child with the newly described D310N variant and cases with the D366E variant, alongside Drosophila models used for mechanistic exploration. The sample size and specific setting were not reported in the available data.

Main results indicated that the D310N variant produced a consistently more severe clinical phenotype than the D366E variant. Heterozygous D310N flies displayed substantially greater locomotor impairment and higher incidences of seizure-like activity. Furthermore, learning and memory deficits were more pronounced in the D310N group. Both variants were found to disrupt synaptic vesicle recycling during repetitive stimulation. Notably, life-long locomotor abnormalities were induced during the mid-larval developmental window, even though the mutant SYT1 protein was no longer detectable in adult flies. Conversely, expression of mutant SYT1 in the adult stage did not have a detectable effect on climbing for over 10 days. Cholinergic interneurons were identified as major common drivers of the observed locomotor deficits, and expression of mutant SYT1 in cholinergic and GABAergic neurons induced seizure-like activity.

Safety and tolerability data were not reported, as adverse events, serious adverse events, discontinuations, and general tolerability metrics were not applicable or available. Key limitations include that pathogenic mechanisms are not well understood and no disease-modifying therapies currently exist. The study notes that BAGOS is likely caused by developmentally disrupted networks rather than synaptic transmission alone. Practice relevance highlights discrete developmental periods and neuronal subtypes as potential therapeutic targets.