15. Clinical Spectrum of VCP Myopathy, Paget Disease, and fronTotemporal Dementia: Experimental Models and Potential Treatments

  1. Valerie Askanas MD, PhD and
  2. W. King Engel MD
  1. Virginia E. Kimonis MD, MRCP1,
  2. Eric Dec2,
  3. Mallikarjun Badadani2,
  4. Angele Nalbandian2,
  5. Jouni Vesa2,
  6. Vincent Caiozzo3,
  7. Douglas Wallace2,4,
  8. Barbara Martin5,
  9. Charles Smith5 and
  10. Giles D. Watts6

Published Online: 19 DEC 2011

DOI: 10.1002/9781444398311.ch15

Muscle Aging, Inclusion-Body Myositis and Myopathies

Muscle Aging, Inclusion-Body Myositis and Myopathies

How to Cite

Kimonis, V. E., Dec, E., Badadani, M., Nalbandian, A., Vesa, J., Caiozzo, V., Wallace, D., Martin, B., Smith, C. and Watts, G. D. (2012) Clinical Spectrum of VCP Myopathy, Paget Disease, and fronTotemporal Dementia: Experimental Models and Potential Treatments, in Muscle Aging, Inclusion-Body Myositis and Myopathies (eds V. Askanas and W. K. Engel), Wiley-Blackwell, Oxford, UK. doi: 10.1002/9781444398311.ch15

Editor Information

  1. Departments of Neurology and Pathology, University of Southern California Neuromuscular Center, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA, USA

Author Information

  1. 1

    Department of Pediatrics, University of California Irvine School of Medicine, Orange, CA, USA

  2. 2

    Division of Genetics and Metabolism, Department of Pediatrics and Center for Molecular, and Mitochondrial Medicine and Genetics, University of California, Irvine, CA, USA

  3. 3

    Department of Orthopedic Surgery, University of California, Irvine, CA, USA

  4. 4

    Department of Biological Chemistry, Departments of Ecology and Evolutionary Biology, University of California, Irvine, CA, USA

  5. 5

    Department of Neurology, University of Kentucky Medical School, Lexington, KY, USA

  6. 6

    School of Medicine, Cell Biology and Biochemistry, Health Policy and Practice, University of East Anglia, Norwich, Norfolk, UK

Publication History

  1. Published Online: 19 DEC 2011
  2. Published Print: 27 JAN 2012

ISBN Information

Print ISBN: 9781405196468

Online ISBN: 9781444398311

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Keywords:

  • autophagy;
  • endoplasmic reticulum-associated degradation;
  • ERAD;
  • frontotemporal dementia;
  • inclusion-body myopathy;
  • Paget disease of bone;
  • TAR DNA-binding protein 43;
  • TDP-43;
  • ubiquitin-proteasome system;
  • valosin-containing protein

Summary

Hereditary inclusion-body myopathy (h-IBM) associated with Paget disease of bone (PDB) and frontotemporal dementia (FTD), or IBMPFD, was recognized as a distinct clinical syndrome by Kimonis et al. in 2000. IBMPFD is associated with mutations in the valosin-containing protein (VCP), the majority of which are located in the sequence encoding the ubiquitin-binding domain. Individuals have progressive muscle weakness and immunohistochemical examination of muscle biopsies reveals rimmed vacuoles and ubiquitin-/TAR DNA-binding protein 43 (TDP-43)-positive inclusions. PDB, seen in half of individuals and caused by overactive osteoclasts, is associated clinically with pain, elevated alkaline phosphatase, and X-ray findings of coarse trabecular pattern and sclerotic lesions. FTD is diagnosed at a mean age of 55 years in a third of individuals, and is characterized by comprehension deficits, dysnomia, dyscalculia, social unawareness, and ubiquitin-/TDP-43-positive inclusions in the brain. Cellular and animal models indicate pathogenetic disturbances in IBMPFD tissues including endoplasmic reticulum-associated degradation, autophagy, apoptosis, and mitochondrial dysfunction.