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NEUROLOGY 2009;73:626-632
© 2009 American Academy of Neurology

Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His

J. van der Zee, PhD, D. Pirici, MD, T. Van Langenhove, MD, S. Engelborghs, MD, PhD, R. Vandenberghe, MD, PhD, M. Hoffmann, MD, G. Pusswald, PhD, M. Van den Broeck, BSc, K. Peeters, BSc, M. Mattheijssens, BSc, J. -J. Martin, MD, PhD, P. P. De Deyn, MD, PhD, M. Cruts, PhD, D. Haubenberger, MD, S. Kumar-Singh, MD, PhD, A. Zimprich, MD and C. Van Broeckhoven, PhD, DSc

From the Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB (J.v.d.Z., D.P., T.V.L., M.V.d.B., K.P., M.M., M.C., S.K.-S., C.V.B.), Laboratory of Neurogenetics, Institute Born-Bunge (J.v.d.Z., D.P., T.V.L., M.V.d.B., K.P., M.M., M.C., S.K.-S., C.V.B.), Laboratory of Neurochemistry and Behavior (S.E., P.P.D.D.) and Laboratory of Neuropathology (J.-J.M.), Institute Born-Bunge, University of Antwerp (J.v.d.Z., D.P., T.V.L., S.E., M.V.d.B., K.P., M.M., P.P.D.D., M.C., S.K.-S., C.V.B.), Memory Clinic and Division of Neurology, ZNA Middelheim (S.E., P.P.D.D.), Antwerp, Belgium; Department of Neurology, University Hospitals Leuven, Belgium (R.V.); and Department of Nuclear Medicine (M.H.) and Department of Neurology (G.P., D.H., A.Z.), Medical University of Vienna, Austria.

Address correspondence and reprint requests to Dr. Christine Van Broeckhoven, Department of Molecular Genetics, VIB, Neurodegenerative Brain Diseases Group, University of Antwerp–CDE, Universiteitsplein 1, B-2610 Antwerpen, Belgium christine.vanbroeckhoven{at}molgen.vib-ua.be

Background: Families associated with missense mutations in the valosin-containing protein (VCP) present with a rare autosomal dominant multisystem disorder of frontotemporal lobar degeneration (FTLD), inclusion body myopathy (IBM), and Paget disease of bone (PDB), referred to as IBMPFD.

Methods: We used exon-based genomic DNA sequencing to test for VCP mutations in 123 unrelated Belgian patients with FTLD and their relatives, and the absence of such mutations in 157 control individuals. We analyzed haplotype sharing among mutation carriers by genotyping 8 microsatellite markers in the VCP locus. We obtained family history and clinical and pathologic data using established diagnostic instruments.

Results: Mutation analysis of VCP identified 2 Belgian patients with FTLD carrying the p.Arg159His mutation, which segregated in their families. In one family, patients presented with FTLD only, whereas in the other family, patients developed FTLD, PDB, or both without signs of IBM for any of the mutation carriers. We had previously identified p.Arg159His in an Austrian family with patients exhibiting both IBM and PDB. Haplotype sharing analysis indicated that the 3 p.Arg159His families are unrelated. Clinical follow-up of the Austrian family identified dementia symptoms in 1 patient. Autopsy data of 3 patients of the 2 Belgian families revealed FTLD pathology with numerous ubiquitin-immunoreactive, intranuclear inclusions and dystrophic neurites staining positive for TDP-43 protein.

Conclusions: In 3 unrelated families with IBMPFD segregating VCP p.Arg159His, we observed a high degree of clinical heterogeneity and variable penetrance of the 3 cardinal clinical phenotypes: inclusion body myopathy, Paget disease of bone, and frontotemporal lobar degeneration. In contrast, the neuropathologic phenotype was consistent with FTLD-TDP type 4.

Abbreviations: FCx = frontal cortex; FDG = fluorodeoxyglucose; FTLD = frontotemporal lobar degeneration; FTLD-TDP = frontotemporal lobar degeneration with TDP-43 positive inclusions; FWO-V = Fund for Scientific Research–Flanders; IBM = inclusion body myopathy; IBMPFD = inclusion body myopathy with Paget disease of bone and frontotemporal dementia; IWT-V = Institute for the Promotion of Innovation through Science and Technology in Flanders; MAPT = microtubule-associated protein tau; MMSE = Mini-Mental State Examination; PDB = Paget disease of bone; PGRN = progranulin; TCx = temporal cortex; VCP = valosin-containing protein.

Supplemental data at www.neurology.org

The research described by the authors was in part funded by the InterUniversity Attraction Poles program P6/43 of the Belgian Federal Science Policy office, the Foundation for Alzheimer Research, the Fund for Scientific Research–Flanders (FWO-V), the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-V), and the Special Research Fund of the University of Antwerp; Belgium. T.V.L. is holder of a PhD fellowship of the IWT-V. The FWO-V provided a postdoctoral fellowship to J.v.d.Z.

Disclosure: Author disclosures are provided at the end of the article.

Received February 12, 2009. Accepted in final form May 19, 2009.






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