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Published online before print June 21, 2006, doi:10.1212/01.wnl.0000225184.14578.d3)
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NEUROLOGY 2006;67:644-651
© 2006 American Academy of Neurology

Valosin-containing protein gene mutations

Clinical and neuropathologic features

L. Guyant-Maréchal, MD, A. Laquerrière, MD, PhD, C. Duyckaerts, MD, PhD, C. Dumanchin, PhD, J. Bou, RA, F. Dugny, MD, I. Le Ber, MD, T. Frébourg, MD, PhD, D. Hannequin, MD and D. Campion, MD, PhD

From the Departments of Neurology (L.G.-M., D.H.) and Neuropathology (A.L.), Rouen University Hospital; Neuropathology Laboratory (C. Duyckaerts), Salpêtrière Hospital, Paris; and INSERM U614 (C. Dumanchin, J.B., F.D., I.L.B., T.F., D.C.), IFRMP, Faculty of Medicine, Rouen, France.

Address correspondence and reprint requests to Dr. Dominique Campion, INSERM U 614, Faculty of Medicine, 22 Boulevard Gambetta, 76 183 Rouen Cedex 01, France; e-mail: dominique.campion{at}univ-rouen.fr

Background: Hereditary inclusion body myopathy (IBMPFD) with Paget disease of bone (PDB) and frontotemporal dementia (FTD) is a rare multisystem disorder with autosomal dominant inheritance. Recently, missense mutations in the gene encoding valosin-containing protein (VCP) have been found in individuals with IBMPFD. VCP/P97, which exerts a variety of cellular functions, plays a key role in the ubiquitin-proteasome dependent degradation of cytosolic proteins and in the retrotranslocation of misfolded proteins from the endoplasmic reticulum into the cytoplasm.

Methods: The authors describe the clinical features of two kindreds in which VCP R93C and R155C missense mutations segregate and perform a histopathologic examination of brain, muscle, bone, and liver of three subjects harboring the R155C mutation.

Results: Frontotemporal dementia was present in 100% of affected subjects in Family F1 and 70% in Family F2, as compared with an average of 30% in previously described IBMPFD families. In contrast, PDB was a more inconstant clinical feature. Biochemical and histopathologic data are consistent with the hypothesis that VCP R155C mutation disrupts normal VCP function, leading to diffuse accumulation of ubiquitinated proteins within the cells.

Conclusions: VCP mutations are present in two families in which FTD is the most prominent symptom. The histopathologic study performed in patients harboring the R155C mutation supports the hypothesis that this mutation disrupts normal VCP function, leading to diffuse accumulation of ubiquitinated proteins within the cells. IBMPFD belongs to a class of genetic diseases associated with an alteration of the ubiquitin-proteasome system.

Editorial, see page 560

This article was previously published in electronic format as an Expedited E-Pub on June 21, 2006, at www.neurology.org.

Disclosure: The authors report no conflicts of interest.

Received September 28, 2005. Accepted in final form April 21, 2006.




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