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

Area of Science:

• Neurology
• Genetics
• Pathology

Background:

• Multisystem proteinopathy 1 (MSP1) is a rare genetic disorder linked to valosin-containing protein (VCP) gene mutations.
• MSP1 typically manifests as inclusion body myopathy, Paget's disease of bone, frontotemporal dementia, and ALS.
• Parkinsonism is an infrequent symptom of MSP1, with prior evidence suggesting neuronal synucleinopathy.

Purpose of the Study:

• To report a case of VCP-related parkinsonism.
• To provide the first in vivo demonstration of phosphorylated alpha-synuclein in a skin biopsy of an MSP1 patient.
• To review VCP-related parkinsonism literature.

Main Methods:

• Case report of a 76-year-old man with parkinsonism, myopathy, and Paget's disease of bone.
• 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.

Main Results:

• Skin biopsy revealed abnormal intraneural phosphorylated alpha-synuclein deposits.
• This finding represents the first in vivo detection of synucleinopathy in a patient with MSP1.
• The patient presented with akinetic-rigid parkinsonism, myopathy, pyramidal signs, and Paget's disease of bone.

Conclusions:

• VCP mutations may contribute to alpha-synuclein aggregation and parkinsonism in some individuals.
• This case highlights the diagnostic utility of skin biopsy for detecting synucleinopathy in vivo.
• The findings reinforce the association between VCP mutations and synucleinopathy.