Objective: We aimed to examine the role of VPS13C in the risk of iRBD and its association with α-synucleinopathy.

Background: While VPS13C is a recessively inherited Parkinson’s disease (PD) gene, its potential dominant effects in idiopathic Rapid-eye movement (REM) sleep behavior disorder (iRBD) remain unexplored. The relation between its monogenic form and the onset of PD suggested that subtype specificity may need to be considered.

Method: We examined the presence of likely pathogenic VPS13C variants in 150 iRBD and 180 α-synucleinopathy patients (iRBD-first and movement disorder-first). Clinical assessments, PSG and fMRI were combined to explore the characteristics of VPS13C variants in iRBD. Then, the Kaplan-Meier curve was performed to assess the disease conversion between iRBD and iRBD-first α-synucleinopathies.

Results: We included 150 iRBD patients. Analyses revealed that 63 individuals (42% of iRBD patients) carried likely pathogenic VPS13C variants. These VPS13C variants were significantly enriched in the RJ-iRBD cohort (OR=1.84, 95% CI: 1.43–2.36, P=3×10⁻⁶), and ten VPS13C variants associated with iRBD susceptibility were identified. Carriers of iRBD risk VPS13C variants exhibited a more severe RBD phenotype (P =0.022) and greater autonomic dysfunction (P =0.001), which was related to abnormalities in EEG function during REM sleep and brain autonomic function networks, respectively. Notably, enrichment was specific to the iRBD-first α-synucleinopathy subtype, and iRBD risk VPS13C variant carriers showed accelerated progression to overt α-synucleinopathy.

Conclusion: These results suggest that VPS13C not only contributes to iRBD susceptibility but also serves as a marker for the iRBD-first α-synucleinopathy and faster disease conversion.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-associations-of-vps13c-with-phenotype-and-conversion-of-idiopathic-rem-sleep-behavior-disorder/