VPS13C heterozygous loss of function as a modifier for suboptimal response to levodopa in Parkinson's disease.

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).