In-vivo evidence of synucleinopathy in parkinsonism due to VCP mutation

Multisystem proteinopathy 1 (MSP1) is a rare autosomal dominant disorder caused by mutations in the valosin-containing protein (VCP) gene typically presenting with inclusion body myopathy (IBM), Paget’s disease of bone (PDB), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Parkinsonism is a rare feature of MSP1, occurring in 3–4% of cases, with limited post-mortem evidence suggesting neuronal synucleinopathy. We report a case of VCP-related parkinsonism providing the first in vivo demonstration of phosphorylated alpha-synuclein deposition in skin biopsy, a highly sensitive and specific in vivo biomarker of synucleinopathy. A focused literature review on VCP-related parkinsonism is also presented to contextualize our findings. A 76-year-old man presented with akinetic-rigid parkinsonism, myopathy, pyramidal signs, and PDB. Genetic testing identified a pathogenic VCP mutation (c.277 C > T; p.R93C). Diagnostic workup included neuroimaging, electromyography, muscle biopsy, neuropsychological assessment, bone scintigraphy, and skin biopsy, which revealed abnormal intraneural phosphorylated α-synuclein deposits. Current evidence suggests that VCP mutations may promote alpha-synuclein aggregation in a subset of patients, leading to parkinsonism. This is the first in vivo demonstration of phosphorylated α-synuclein in a MSP1 patient, reinforcing the association between VCP mutations and synucleinopathy.