Parkinsonism Relat Disord. 2025 Sep 23:108061. doi: 10.1016/j.parkreldis.2025.108061. Online ahead of print.
ABSTRACT
OBJECTIVE: To report a clinical series of four patients diagnosed with early-onset Parkinson’s disease (EOPD) who exhibit heterozygous pathogenic variants in the VPS13C gene.
BACKGROUND: VPS13C encodes vacuolar protein sorting 13C, a lipid transport protein that localizes between the endoplasmic reticulum and endosomes-lysosomes, functioning as a bridge to allow phospholipids to traverse the cytosol. Mutations in this gene have been associated with early-onset PARK23 and dementia with Lewy bodies (DLB), highlighting its importance in mitochondrial and lysosomal homeostasis.
METHODS: Cases were identified through the Mayo Clinic Data Explorer. We included all subjects with a clinical diagnosis of PD who tested positive for a heterozygous VPS13C variant defined as pathogenic by the ACMG guidelines.
RESULTS: DaT-SCAN imaging was consistent with PD diagnosis in three patients. Non-motor symptoms and cognitive impairment were prominent phenotypical characteristics in all cases: all the patients presented with insomnia, anxiety, depression, severe fatigue, and short-memory loss. The response to oral levodopa treatment was suboptimal, with an initial benefit followed by rapid decreased responsiveness. Additionally, two patients developed wearing-off episodes and one of them also exhibited treatment-induced dyskinesias.
CONCLUSION: We hypothesize that VPS13C may confer an increased risk of EOPD in carriers of pathogenic variants, and may function as a phenotype modifier gene, contributing to significant non-motor symptoms development and suboptimal levodopa response. Specifically, we propose that the suboptimal treatment response is associated with a decrease level of dopamine L-type amino acid transporter 1 (LAT1).
PMID:41006073 | DOI:10.1016/j.parkreldis.2025.108061
Recent Comments