Objective: To describe a retrospective clinical study of four cases carrying heterozygous pathogenic variants in the VPS13C gene with a clinical diagnosis of Early-Onset Parkinson’s Disease (EOPD).

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. Variants in VPS13C have been associated with early-onset PARK23 and Dementia with Lewy Bodies, highlighting its role in lysosomal and mitochondrial homeostasis [1]. Additionally, VPS13C-related lysosomal dysfunction increases cGAS–STING pathway activation, leading to prolonged neuroinflammation [2].

Method: Patients were identified through the Mayo Clinic Data Explorer. We included all cases with a clinical diagnosis of EOPD who tested positive for a heterozygous loss-of-function VPS13C variant classified as pathogenic according to ACMG guidelines [Table 1]. The genetic test analyzed a panel of 94 parkinsonism-related genes.

Results: Four patients met the inclusion criteria, and three of them had DaT-SCAN imaging consistent with PD. Non-motor symptoms and cognitive impairment were prominent phenotypical characteristics: all patients presented insomnia, anxiety, depression, severe fatigue, and short-term memory loss [Table 2]. The response to oral levodopa treatment was suboptimal, showing initial benefit followed by a rapid decreased responsiveness. Additionally, two patients developed wearing-off episodes, and one exhibited treatment-induced dyskinesias.

Conclusion: Heterozygous pathogenic VPS13C variants may increase the risk of EOPD in a multigenic inheritance pattern. Moreover, this gene may function as a phenotype modifier, contributing to significant non-motor symptoms development and suboptimal levodopa response. Specifically, the diminished treatment response may be linked to reduced levels of the dopamine transporter LAT1, potentially associated with an increased cGAS–STING pathway activity [Figure 1].

Table 1

Table 2

Figure 1

References: [1] Smolders S, Philtjens S, Crosiers D, Sieben A, Hens E, Heeman B, Van Mossevelde S, Pals P, Asselbergh B, Dos Santos Dias R, Vermeiren Y, Vandenberghe R, Engelborghs S, De Deyn PP, Martin JJ, Cras P, Annaert W, Van Broeckhoven C; BELNEU consortium. Contribution of rare homozygous and compound heterozygous VPS13C missense mutations to dementia with Lewy bodies and Parkinson’s disease. Acta Neuropathol Commun. 2021 Feb 12; 9(1): 25.
[2] Hancock-Cerutti W, Wu Z, Xu P, Yadavalli N, Leonzino M, Tharkeshwar AK, Ferguson SM, Shadel GS, De Camilli P. ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling. J Cell Biol. 2022 Jul 4; 221(7): e202106046.

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/vps13c-a-modifier-gene-causing-suboptimal-response-to-levodopa-in-early-onset-parkinsons-disease/