The Multiple Faces of Valosin-Containing Protein-Associated Diseases: Inclusion Body Myopathy with Paget’s Disease of Bone, Frontotemporal Dementia, and Amyotrophic Lateral Sclerosis

  • Angèle Nalbandian
  • Sandra Donkervoort
  • Eric Dec
  • Mallikarjun Badadani
  • Veeral Katheria
  • Prachi Rana
  • Christopher Nguyen
  • Jogeshwar Mukherjee
  • Vincent Caiozzo
  • Barbara Martin
  • Giles D. Watts
  • Jouni Vesa
  • Charles Smith
  • Virginia E. Kimonis


Inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) is a progressive, fatal genetic disorder with variable penetrance, predominantly affecting three main tissue types: muscle (IBM), bone (PDB), and brain (FTD). IBMPFD is caused by mutations in the ubiquitously expressed valosin-containing protein (VCP) gene, a member of the AAA-ATPase superfamily. The majority of individuals who develop IBM have progressive proximal muscle weakness. Muscle biopsies reveal rimmed vacuoles and inclusions that are ubiquitin- and TAR DNA binding protein-43 (TDP-43)-positive using immunohistochemistry. PDB, seen in half the individuals, is caused by overactive osteoclasts and is associated clinically with pain, elevated serum alkaline phosphatase, and X-ray findings of coarse trabeculation and sclerotic lesions. FTD diagnosed at a mean age of 55 years in a third of individuals is characterized clinically by comprehension deficits, dysnomia, dyscalculia, and social unawareness. Ubiquitin- and TDP-43-positive neuronal inclusions are also found in the brain. Genotype–phenotype correlations are difficult with marked intra-familial and inter-familial variations being seen. Varied phenotypes within families include frontotemporal dementia, amyotrophic lateral sclerosis, Parkinsonism, myotonia, cataracts, and anal incompetence, among others. Cellular and animal models indicate pathogenetic disturbances in IBMPFD tissues including altered protein degradation, autophagy pathway alterations, apoptosis, and mitochondrial dysfunction. Currently, mouse and drosophila models carrying VCP mutations provide insights into the human IBMPFD pathology and are useful as tools for preclinical studies and testing of therapeutic strategies. In this review, we will explore the pathogenesis and clinical phenotype of IBMPFD caused by VCP mutations.


Valosin containing protein Amyotrophic lateral sclerosis Inclusion body myopathy Paget’s disease of bone Frontotemporal dementia Autophagy NFKB Ubiquitin TAR DNA Binding Protein-43 Endoplasmic reticulum associated degradation 


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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Angèle Nalbandian
    • 1
  • Sandra Donkervoort
    • 1
  • Eric Dec
    • 1
  • Mallikarjun Badadani
    • 1
  • Veeral Katheria
    • 1
  • Prachi Rana
    • 1
  • Christopher Nguyen
    • 1
  • Jogeshwar Mukherjee
    • 2
  • Vincent Caiozzo
    • 3
  • Barbara Martin
    • 4
  • Giles D. Watts
    • 5
  • Jouni Vesa
    • 1
  • Charles Smith
    • 4
  • Virginia E. Kimonis
    • 1
  1. 1.Department of Pediatrics, Division of Genetics and Metabolism, 2501 Hewitt HallUniversity of California–IrvineIrvineUSA
  2. 2.Preclinical Imaging Center, Department of Psychiatry & Human Behavior, 162 Irvine HallUniversity of California–IrvineIrvineUSA
  3. 3.Department of Physiology and Biophysics, and Department of Orthopedics, College of Health SciencesUniversity of CaliforniaIrvineUSA
  4. 4.Sanders-Brown Center on AgingUniversity of KentuckyLexingtonUSA
  5. 5.Cell Biology and Biochemistry, School of Medicine, Health Policy and Practice, Biomedical Research CentreUniversity of East AngliaNorwichUK

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