VCP Multisystem Proteinopathy

Valosin-Containing Protein (VCP) myopathy, also known as Multisystem Proteinopathy (MSP1) or Inclusion Body Myopathy associated with Paget disease of bone and Frontotemporal Dementia (IBMPFD), is a complex, progressive, autosomal dominant adult-onset disorder caused by mutations in the VCP gene. The VCP protein, also called p97, is a highly conserved ATPase crucial for maintaining cellular protein homeostasis (proteostasis) through mechanisms like the ubiquitin-proteasome system (UPS) and autophagy, as well as other functions like membrane fusion and genomic integrity. Pathogenic mutations in VCP disrupt these processes, leading to the accumulation of ubiquitin-positive protein aggregates, a hallmark feature. The disease presents with significant clinical heterogeneity, even within families, commonly affecting muscle (Inclusion Body Myopathy), bone (Paget disease of bone), and brain (Frontotemporal Dementia), and can also be associated with amyotrophic lateral sclerosis (ALS) or other neurological phenotypes like peripheral neuropathy and parkinsonism. Muscle biopsies, a key diagnostic tool, consistently show features such as muscle fiber atrophy (87.5% of cases), rimmed vacuoles (72.3%), endomysial fibrosis (58.0%), and protein aggregates (51.8%), often staining positive for p62 and VCP. Notably, degenerative niches, focal areas of muscle degeneration with atrophic fibers embedded in fibrotic and fatty tissue, were observed in over 30% of biopsies and are proposed as starting points for disease progression. These histopathologic findings are generally consistent across different clinical phenotypes and VCP genetic variants, despite variations in VCP's ATPase activity, though some discrepancies between clinical, neurophysiological, and biopsy findings can occur. Currently, there is no cure, with treatment focusing on symptomatic management and supportive care. However, research is actively exploring targeted therapies, including VCP inhibitors like CB-5083, which show promise in preclinical studies by addressing the overactivity of mutant VCP.