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Genotype–phenotype studies of VCP-associated inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia

Authors


  • The authors have no personal financial or institutional interest or conflicts in any of the drugs, materials, or devices described in this article.

Corresponding Author

Virginia E. Kimonis, MD, MRCP,

Division of Genetics and Metabolism,

Department of Pediatrics,

University of California Irvine,

101 The City Drive South, ZC4482,

Orange CA 92868, USA.

Tel.: +1 714 456 5791; +1 714 456 2942;

fax: +1 714 456 5330

e-mail: vkimonis@uci.edu

Abstract

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.

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