- Mehta, Sarju G.;
- Khare, Manaswitha;
- Ramani, Rupal;
- Watts, Giles J.;
- Simon, Mariella;
- Osann, Kathryn E.;
- Donkervoort, Sandra;
- Dec, Eric;
- Nalbandian, Angele;
- Platt, Julia;
- Pasquali, Marzia;
- Wang, Annabel;
- Mozaffar, Tahseen;
- Smith, Charles D.;
- Kimonis, Virginia E.
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 ten missense mutations. Individuals were grouped into three categories: symptomatic, presymptomatic carriers and non-carriers. 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 because of small numbers. Nevertheless when comparing the two most common mutations, R155C mutation was found to be more severe, with 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) in thirteen 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 natural history and provides genotype-phenotype correlations in this unique disease.