Valosin-containing protein aggregation in inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia

Mutations of the valosin containing protein (VCP) on chromosome 9p13-p12 have recently been shown to cause autosomal dominant inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia (IBMPFD). Here, we report clinical and muscle pathology findings in a 54 year old German patient harbouring a 464 G>A nucleotide substitution (R155H) in exon 5 of the VCP gene. In addition to mild fronto-temporal cognitive dysfunction and Paget disease confined to her first lumbar vertebra whole body MRI demonstrated marked signal changes in her shoulder girdle, erector spinae, hamstring and calf muscles. Analysis of a diagnostic muscle biopsy showed mild myopathic features. Indirect immunofluorescence revealed multiple fibers containing small foci of cytoplasmic VCP- and ubiquitin- positive protein aggregates. Furthermore, VCP Western blot analysis confirmed an increase of VCP protein expression in diseased muscle. Our findings indicate that VCP-related IBMPFD is a new member of the family of aggresome-associated disorders characterized by abnormal protein aggregation.