Genotype‐phenotype study in patients with valosin‐containing protein mutations associated with multisystem proteinopathy

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. K E Y W O R D Sgenotype-phenotype, IBMPFD, multisystem proteinopathy (MSP), valosin-containing protein, VCP

A Japanese patient with a VCP mutation c.290G > A (p.G97E) presenting a rapid progressive respiratory failure

“…The present case is the first Japanese IBMPFD case with the same mutation of VCP gene, but showing a progressive respiratory failure accompanied by wheelchaired in only 6 years after IBM onset, suggesting the severe skeletal muscle degeneration in limbs and trunk (Figure A,D,E,) . Only 3 IBMPFD cases with c.290G > A (p.G97E) of VCP gene showed FTD 8, 10, or 37 years after IBM onset (Table ) . Although the present case did not show clinical symptoms of FTD, frontotemporal cognitive and behavioral scales including FAB show both high specificity and high sensitivity for the diagnosis of FTD .…”

“…1,2 IBMPFD patients with heterozygous c.290G > A (p.G97E) substitution of VCP gene reported previously, showing a slowly progressive muscle weakness in limbs, but not wheelchaired or respiratory failure (Table 1). [2][3][4][5] The present case is the first Japanese IBMPFD case with the same mutation of VCP gene, but showing a progressive respiratory failure accompanied by wheelchaired in only 6 years after IBM onset, suggesting the severe skeletal muscle degeneration in limbs and trunk ( Figure 1A,D,E,). 1 Only 3 IBMPFD cases with c.290G > A (p.G97E) of VCP gene showed FTD 8, 10, or 37 years after IBM onset (Table 1).…”

“…Inclusion body myopathy with Paget's disease of bone and frontotemporal dementia(IBMPFD) is an autosomal dominant disorder caused by mutations in the valosin‐containing protein ( VCP ) gene. IBMPFD usually presents an adult‐onset progressive limb muscle weakness resulting in wheelchaired after mean course of 9 years with myopathy, and Paget's osteolytic lesions and frontotemporal dementia (FTD) rarely present respiratory failure . Here we report a Japanese IBMPFD patient with a VCP mutation c.290G > A (p.G97E), showing clinical features different from previous reports.…”

TFG: At the crossroads of motor neuron disease and myopathy

“…The spectrum of VCP‐related disorders was subsequently expanded with the addition of peripheral neuropathy, parkinsonism, and a hereditary spastic paraparesis‐like phenotype . Close to half of patients, however, present with only one of the cardinal manifestations of MSP, most commonly HIBM . Valosin‐containing protein (VCP) is an ATPase associated with diverse cellular activities involved in a number of cellular processes, including delivery of ubiquitinated substrates to the proteasome and maturation of ubiquitin‐containing autophagosomes .…”

“…Valosin‐containing protein (VCP) is an ATPase associated with diverse cellular activities involved in a number of cellular processes, including delivery of ubiquitinated substrates to the proteasome and maturation of ubiquitin‐containing autophagosomes . In keeping with these functions, histopathological studies in VCP‐related MSP demonstrate an autophagic vacuolar myopathy as well as TDP‐43 and ubiquitin‐positive inclusions in both muscle and cortical neurons . In addition, these inclusions immunoreact for VCP, although this finding is not specific to VCP‐related MSP.…”