VCP disease associated with myopathy, Paget disease of bone and frontotemporal dementia: review of a unique disorder

Biochim Biophys Acta. 2008 Dec;1782(12):744-8. doi: 10.1016/j.bbadis.2008.09.003. Epub 2008 Sep 18.


Inclusion body myopathy (IBM) associated with Paget disease of the bone (PDB) and frontotemporal dementia (FTD) (now called IBMPFD), is a progressive autosomal dominant disorder that was recently identified as being caused by mutations in the VCP (p97 or CDC48) gene which plays a key role in the ubiquitin-proteasome dependent degradation of cytosolic proteins and in the retro translocation of misfolded proteins from the endoplasmic reticulum into the cytoplasm. Approximately 90% of the affected persons in the study have myopathy or muscle weakness particularly of the shoulder and hip girdles, which can lead to loss of walking ability and even death by complications of respiratory and cardiac failure. About half of affected study participants have Paget disease of bone characterized by abnormal rates of bone growth that can result in bone pain, enlargement and fractures. Findings of premature FTD affecting behavior and personality are seen in a third of affected individuals. Within 20 IBMPFD families whose data was analyzed for this study, ten missense mutations have been identified, the majority of which are located in the N-terminal ubiquitin binding domain. Inclusions seen in the muscle, brain and heart in VCP disease contain ubiquitin, beta amyloid and TDP-43, also seen in other neurodegenerative disorders thus implicating common pathways in their pathogenesis.

Publication types

  • Review

MeSH terms

  • Adenosine Triphosphatases / genetics*
  • Cell Cycle Proteins / genetics*
  • Dementia / genetics*
  • Dementia / pathology
  • Frontal Lobe / physiopathology*
  • Genetic Predisposition to Disease
  • Humans
  • Muscular Diseases / genetics*
  • Muscular Diseases / pathology
  • Mutation / genetics*
  • Osteitis Deformans / genetics*
  • Osteitis Deformans / pathology
  • Valosin Containing Protein


  • Cell Cycle Proteins
  • Adenosine Triphosphatases
  • VCP protein, human
  • Valosin Containing Protein