Valosin containing protein (VCP) disease associated with inclusion body myopathy, Paget disease of the bone and frontotemporal dementia is a progressive autosomal dominant disorder caused by mutations in Valosin containing protein gene. To establish genotype–phenotype correlations we analyzed clinical and biochemical markers from a database of 190 members in 27 families harboring 10 missense mutations. Individuals were grouped into three categories: symptomatic, presymptomatic carriers and noncarriers. The symptomatic families were further divided into ten groups based on their VCP mutations. There was marked intra and inter‐familial variation; and significant genotype–phenotype correlations were difficult to establish because of small numbers. Nevertheless when comparing the two most common mutations, R155C mutation was found to be more severe, with an earlier onset of myopathy and Paget (p = 0.03). Survival analysis of all subjects revealed an average life span after diagnosis of myopathy and Paget of 18 and 19 years respectively, and after dementia only 6 years. R155C had a reduced survival compared to the R155H mutation (p = 0.03).We identified amyotrophic lateral sclerosis (ALS) was diagnosed in 13 individuals (8.9%) and Parkinson's disease in five individuals (3%); however, there was no genotypic correlation. This study represents the largest dataset of patients with VCP disease and expands our understanding of the natural history and provides genotype–phenotype correlations in this unique disease.

Contrasts between two entities may be illuminating because of the emphasis on what each is not. Here we describe two proteinopathies producing brain neurodegeneration in mature adults, autosomal dominant valosin-containing protein (VCP) disease and Familial Alzheimer’s disease (FAD) caused by presenillin-1 (PSEN1) mutations, illustrating both contrasting patterns of clinical presentation and known neuropathologic and imaging features, and points of congruence. Mutations primarily in the ubiquitin binding domain of the VCP gene cause frontotemporal dementia as part of a rare but important disorder that also encompasses inclusion body myopathy, Paget disease of bone, and in some cases, motor neuron disease. The VCP dementia has onset in the 50s, characterized by abulia, expressive language loss, and executive dysfunction. The pattern of degeneration generally is anterior, in frontal and temporal lobes, involving neuronal nuclear inclusions of ubiquitin and TAR DNA binding protein 43 (TDP-43), but not amyloid or tau. The most common mutations causing FAD occur in the PSEN1 gene. The associated dementia has onset in the late 40s, characterized by early memory loss and diffuse amyloid vasculopathy, and posteriorly distributed neuritic amyloid plaque and neurofibrillary tau pathology in medial temporal and parietal lobes, but not ubiquitin or TDP-43. Nonetheless, both VCP and PSEN1 pathologies have extensively documented abnormalities in similar protein processing pathways.