Phenotypic variability in three families with valosin-containing protein mutation
Article first published online: 20 AUG 2012
© 2012 The Author(s) European Journal of Neurology © 2012 EFNS
European Journal of Neurology
Volume 20, Issue 2, pages 251–258, February 2013
How to Cite
Spina, S., Van Laar, A. D., Murrell, J. R., Hamilton, R. L., Kofler, J. K., Epperson, F., Farlow, M. R., Lopez, O. L., Quinlan, J., DeKosky, S. T. and Ghetti, B. (2013), Phenotypic variability in three families with valosin-containing protein mutation. European Journal of Neurology, 20: 251–258. doi: 10.1111/j.1468-1331.2012.03831.x
- Issue published online: 12 JAN 2013
- Article first published online: 20 AUG 2012
- Manuscript Accepted: 29 JUN 2012
- Manuscript Received: 14 JAN 2012
- PHS. Grant Numbers: AG010133, AG005133
- frontotemporal dementia;
- genetic and inherited disorders;
- motor neuron disease;
- neurodegenerative disorders (other than dementia);
- Parkinson's disease
Background and purpose
The phenotype of IBMPFD [inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (FTD)] associated with valosin-containing protein (VCP) mutation is described in three families.
Probands were identified based on a pathological diagnosis of frontotemporal lobar degeneration with TDP-43-positive inclusions type IV. VCP sequencing was carried out. Clinical data on affected family members were reviewed.
Ohio family: four subjects presented muscle weakness and wasting. (One subject had both neuropathic and myopathic findings and another subject showed only evidence of myopathy. The etiology of weakness could not be ascertained in the remaining two subjects.) Two individuals also showed Parkinsonism (with associated FTD in one of the two). The proband's brain displayed FTLD-TDP type IV and Braak stage five Parkinson's disease (PD). A VCP R191Q mutation was found. Pennsylvania family: 11 subjects developed IBMPFD. Parkinsonism was noted in two mutation carriers, whilst another subject presented with primary progressive aphasia (PPA). A novel VCP T262A mutation was found. Indiana family: three subjects developed IBMPFD. FTD was diagnosed in two individuals and suspected in the third one who also displayed muscle weakness. A VCP R159C mutation was found.
We identified three families with IBMPFD associated with VCP mutations. Clinical and pathological PD was documented for the first time in members of two families. A novel T262A mutation was found. One individual had PPA: an uncommon presentation of IBMPFD.