Novel VCP mutations in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia
Authors
Watts, Giles D. J.Thomasova, Dana
Ramdeen, Sheena K.
Fulchiero, Erin C.
Mehta, Sarju G.
Drachman, David A.
Weihl, Conrad C.
Jamrozik, Zygmunt
Kwiecinski, Hubert
Kaminska, Anna
Kimonis, Virginia E.
UMass Chan Affiliations
Department of NeurologyDocument Type
Journal ArticlePublication Date
2007-10-16Keywords
Adenosine TriphosphatasesAdult
Cell Cycle Proteins
DNA Mutational Analysis
Dementia
Female
Humans
Male
Middle Aged
Models, Molecular
Mutation
Myositis, Inclusion Body
Osteitis Deformans
Pedigree
Neurology
Neuroscience and Neurobiology
Metadata
Show full item recordAbstract
Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD, OMIM 167320) has recently been attributed to eight missense mutations in valosin-containing protein (VCP). We report novel VCP mutations N387H and L198W in six individuals from two families who presented with proximal muscle weakness at a mean age of diagnosis of 40 years, most losing the ability to walk within a few years of onset. Electromyographic studies in four individuals were suggestive of 'myopathic' changes, and neuropathic pattern was identified in one individual in family 1. Muscle biopsy in four individuals showed myopathic changes characterized by variable fiber size, two individuals showing rimmed vacuoles and IBM-type cytoplasmic inclusions in muscle fibers, and electron microscopy in one individual revealing abundant intranuclear inclusions. Frontotemporal dementia associated with characteristic behavioral changes including short-term memory loss, language difficulty, and antisocial behavior was observed in three individuals at a mean age of 47 years. Detailed brain pathology in one individual showed cortical degenerative changes, most severe in the temporal lobe and hippocampus. Abundant ubiquitin-positive tau-, alpha-synuclein-, polyglutamine repeat-negative neuronal intranuclear inclusions and only rare intracytoplasmic VCP positive inclusions were seen. These new mutations may cause structural changes in VCP and provide some insight into the functional effects of pathogenic mutations.Source
Clin Genet. 2007 Nov;72(5):420-6. Link to article on publisher's siteDOI
10.1111/j.1399-0004.2007.00887.xPermanent Link to this Item
http://hdl.handle.net/20.500.14038/37682PubMed ID
17935506Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1111/j.1399-0004.2007.00887.x