Abstract
Mutations in valosin-containing protein (VCP), an ATPase involved in protein degradation and autophagy, cause VCP disease, a progressive autosomal dominant adult onset multisystem proteinopathy. The goal of this study is to examine if phenotypic differences in this disorder could be explained by the specific gene mutations. We therefore studied 231 individuals (118 males and 113 females) from 36 families carrying 15 different VCP mutations. We analyzed the correlation between the different mutations and prevalence, age of onset and severity of myopathy, Paget's disease of bone (PDB), and frontotemporal dementia (FTD), and other comorbidities. Myopathy, PDB and FTD was present in 90%, 42% and 30% of the patients, respectively, beginning at an average age of 43, 41, and 56 years, respectively. Approximately 9% of patients with VCP mutations had an amyotrophic lateral sclerosis (ALS) phenotype, 4% had been diagnosed with Parkinson's disease (PD), and 2% had been diagnosed with Alzheimer's disease (AD). Large interfamilial and intrafamilial variation made establishing correlations difficult. We did not find a correlation between the mutation type and the incidence of any of the clinical features associated with VCP disease, except for the absence of PDB with the R159C mutation in our cohort and R159C having a later age of onset of myopathy compared with other molecular subtypes.
Highlights
Inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) or multisystem proteinopathy is an adult-onset progressive, autosomal dominant lethal disease that involves degeneration of three main organ systems: muscle, bone, and brain
We have previously shown that the presence of one or two APOE4 alleles is associated with an increased risk of developing Frontotemporal dementia (FTD) in patients with valosin-containing protein (VCP) disease [13]
Among VCP patients who were diagnosed with myopathy, creatinine kinase (CK) was 187.4 U/L (SD = 161.75, SEM 17.03, Range 32-909)
Summary
Inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) or multisystem proteinopathy is an adult-onset progressive, autosomal dominant lethal disease that involves degeneration of three main organ systems: muscle, bone, and brain. Most cases are caused by heterozygous missense mutations in valosin-containing protein (VCP) [1], [2]. As awareness increases we are realizing that VCP disease is not as rare as previously considered since it is often misdiagnosed as related disorders. Pathology of IBMPFD Inclusion body myopathy (IBM) is characterized by progressive weakness and atrophy of skeletal muscles of pelvic and shoulder girdle muscles. IBM consists of cytoplasmic rimmed vacuoles containing the same proteins that aggregate in the brains of patients with neurodegenerative diseases: tau, amyloid, and TDP-43 (TAR DNA binding protein 43) [4]
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