title: Novel VCP mutations in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia.
abstract: 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.
authors.affiliation: Division of Genetics, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
authors.forename: G D J
authors.initials: GD
authors.lastname: Watts
authors.forename: D
authors.initials: D
authors.lastname: Thomasova
authors.forename: S K
authors.initials: SK
authors.lastname: Ramdeen
authors.forename: E C
authors.initials: EC
authors.lastname: Fulchiero
authors.forename: S G
authors.initials: SG
authors.lastname: Mehta
authors.forename: D A
authors.initials: DA
authors.lastname: Drachman
authors.forename: C C
authors.initials: CC
authors.lastname: Weihl
authors.forename: Z
authors.initials: Z
authors.lastname: Jamrozik
authors.forename: H
authors.initials: H
authors.lastname: Kwiecinski
authors.forename: A
authors.initials: A
authors.lastname: Kaminska
authors.forename: V E
authors.initials: VE
authors.lastname: Kimonis
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D018797:Cell Cycle Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D003704:Dementia / Q000150:complications* / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D018979:Myositis, Inclusion Body / Q000150:complications* / Q000235:genetics*; D010001:Osteitis Deformans / Q000150:complications* / Q000235:genetics*; D010375:Pedigree; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein