Asta Literature Retrieval: Pathophysiology and clinical mechanisms of VCP-Associated Multisystem Proteinopathy. Core disease mechanisms, molecul...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 17
• Snippets retrieved: 20

Relevant Papers

[1] Multisystem Proteinopathy Due to VCP Mutations: A Review of Clinical Heterogeneity and Genetic Diagnosis

• Authors: G. Pfeffer, Grace Lee, Carly S. Pontifex, R. Fanganiello, Alli Peck et al.
• Year: 2022
• Venue: Genes
• URL: https://www.semanticscholar.org/paper/ef7c859fe61dbd159535b4474f24530fcfc8aa16
• DOI: 10.3390/genes13060963
• PMID: 35741724
• PMCID: 9222868
• Citations: 48
• Influential citations: 2
• Summary: Clinical features and genetic diagnosis of diseases caused by mutations in the gene encoding valosin-containing protein (VCP/p97), the functionally diverse AAA-ATPase, and genetic counselling implications of VCP-MSP are reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.653) > Valosin-containing protein (VCP) is encoded by VCP on chromosome 9 and it is implicated in numerous human disease phenotypes with autosomal dominant inheritance. VCP is a highly conserved, ubiquitously and abundantly expressed ATPase. Indeed, VCP may make up as much as 1% of all cytoplasmic protein [1]. VCP mediates ubiquitindependent cellular processes through the ubiquitin-proteasome system (UPS) [2], protein quality control [3,4], transcription factor processing [5], membrane fusion [6], cell cycle control [7], and regulation of autophagy [8,9]. > Over 50 heterozygous missense mutations in VCP have been identified in patients with multisystem proteinopathy 1 (MSP1), an autosomal dominant, adult-onset progressive disorder, also known as inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), or VCP disease (hereafter referred to as VCP-MSP) [10,11]. The major pathological feature seen in VCP-MSP is the presence of ubiquitin-positive protein aggregates in muscle tissues of patients affected by inclusion body myopathy (IBM). Intranuclear TDP-43+ inclusions are demonstrated in patients with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) [12]. In Paget disease of bone (PDB), abnormally large osteoclasts containing nuclear inclusions resemble the muscle pathology findings [13]. On the whole, the pathological findings of VCP-MSP suggest that abnormal protein clearance is the major molecular mechanism affected by VCP mutations causing human disease. In other forms of MSP (recently reviewed) [11], it has also been suggested that the common molecular mechanism relates to the disruption of two major protein clearance pathways: the UPS and autophagy [14]. However, future studies may identify others among VCP's diverse molecular mechanisms that are relevant to MSP and other human diseases.

[2] Case report of a family with hereditary inclusion body myopathy with VCP gene variant and literature review

• Authors: Greta Asadauskaitė, R. Vilimienė, Vytautas Augustinavičius, B. Burnytė
• Year: 2023
• Venue: Frontiers in Neurology
• URL: https://www.semanticscholar.org/paper/57911ba9ebb9eae5a498b4bea89b4667532433f0
• DOI: 10.3389/fneur.2023.1290960
• PMID: 38146440
• PMCID: 10749511
• Summary: A family with myopathy due to c.277C > T variant in VCP gene is presented, which experienced muscle wasting and weakness in the proximal and distal parts of the limbs which is a common finding in VCP related disease.
• Evidence snippets:
• Snippet 1 (score: 0.631) > Valosin-containing protein (VCP) related disease is a rare, autosomal dominant, multisystem proteinopathy characterized by inclusion body myopathy (IBM), Paget disease of bone (PDB) and frontotemporal dementia (FTD), affecting around 90%, 28-42%, and 14-30% of patients accordingly (1,2). Other manifestations include amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Charcot-Marie-Tooth type 2 disease and complex hereditary spastic paraplegia (3)(4)(5)(6). VCP related disease has been associated with heterozygous missense variants in VCP gene. VCP belongs to the ATPases associated with diverse cellular Activities (AAA+) family, which uses ATP for protein remodeling. Each subunit contains N-terminal binding domain and two ATPase domains, D1 and D2 (7,8). VCP is involved in a variety of cellular activities such as cell cycle control, organelle biogenesis and elimination, cellular signaling, membrane fusion, transcription, regulation of autophagy and protein degradation (8,9). Missense variants at the NTD-D1 interface of the VCP are thought to cause a disruption in protein homeostasis causing a spectrum of progressive degenerative diseases (7,10,11). > In this paper we report patient and his father with c.277C > T [p.(Arg93Cys)] variant in VCP gene, presenting with IBM. Patient's and his father's phenotype is compared with phenotypes reported in literature.

[3] FYCO1 Increase and Effect of Arimoclomol–Treatment in Human VCP–Pathology

• Authors: A. Güttsches, N. Meyer, R. Zahedi, T. Evangelista, Thomas Muentefering et al.
• Year: 2022
• Venue: Biomedicines
• URL: https://www.semanticscholar.org/paper/a20d34a1663de907a58a0d7ab8224ad894cd6fce
• DOI: 10.3390/biomedicines10102443
• PMID: 36289705
• PMCID: 9598455
• Citations: 2
• Summary: The combined results of this study reveal a dysregulation of FYCO1 in the context of VCP–etiopathology, highlight arimoclomol as a potential drug and introduce proteins targeted by the pre–clinical testing of this drug in fibroblasts.
• Evidence snippets:
• Snippet 1 (score: 0.620) > Valosin-containing-protein (VCP) is ubiquitously expressed in human tissues and contributes to different cellular functions including modulation of autophagy, maturation of autophagosomes, control of the ubiquitin-proteasome system (UPS), and endocytosis [1,2]. In the context of modulation of apoptosis and autophagy, VCP has also been linked to the regulation of cellular survival [2]. > Disorders associated with genetic defects of VCP are characterized by a considerable phenotypic variability [3,4], which might accord with the functional spectrum of the corresponding protein. Thus, due to its numerous cellular functions, the clinical presentation of pathogenic variants is complex and may involve several tissues such as skeletal muscle, neurons or bones. However, VCP-associated disorders are rare, which in combination with the great variety of clinical presentations complicates a correct and rapid diagnosis [3]: The most frequent VCP-associated disorder is inclusion body myopathy (IBM) associated with Paget's disease of the bone (PDB) and frontotemporal dementia (FTD), a symptomatic trio leading to the term IBMPFD [4][5][6][7]. Moreover, other neurological manifestations like amyotrophic lateral sclerosis (ALS) [8], progressive spastic paraplegia [9], distal myopathy [10], facio-scapulo-humeral weakness [11], parkinsonism [6], Charcot-Marie-Tooth disease [12] and Huntington's disease [13] have been described in association with pathogenic VCPvariants. Due to the numerous tissues involved and the diverse clinical presentations associated with VCP-related disorders, the term "multisystem proteinopathy (MSP)" has recently emerged to summarize, among others, disorders associated with pathogenic variants affecting the VCP-gene [14]. > Notably, detailed analysis of skeletal muscle tissue derived from patients with sporadic inclusion body myositis (sIBM) revealed an overlap of pathophysiological processes with VCP-associated MSP.

[4] Cardiomyopathy in valosin-containing protein multisystem proteinopathy: Evaluation, diagnosis, and management

• Authors: Joshua Chan, C.N. Romano, Andy Y. Lee, Stephani Wang, Dawn Lombardo et al.
• Year: 2025
• Venue: American Heart Journal Plus: Cardiology Research and Practice
• URL: https://www.semanticscholar.org/paper/9e8956397d4e421d280fd0cee3ac79938ef97889
• DOI: 10.1016/j.ahjo.2025.100644
• PMID: 41234489
• PMCID: 12607093
• Summary: Recognizing VCP-associated cardiomyopathy as a distinct clinical entity will facilitate earlier diagnosis, improve patient outcomes, pave the way for disease-specific therapeutic interventions and insights into the mechanism for isolated cardiomyopathy.
• Evidence snippets:
• Snippet 1 (score: 0.609) > Valosin-containing protein (VCP)-associated multisystem proteinopathy is a rare, autosomal dominant disease that affects skeletal muscle, bone, central nervous system, and the heart. While VCP mutations are well established as causing inclusion body myopathy, Paget's disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis, their role in cardiomyopathy remains underrecognized. This review aims to evaluate the pathophysiology, diagnostic approach, and management of VCP-associated cardiomyopathy to provide a framework for clinical care and future research. Emerging evidence from animal models and human case studies suggests that VCP dysfunction disrupts cardiomyocyte homeostasis, impairs protein degradation, and alters mitochondrial function, leading to maladaptive cardiac remodeling and susceptibility to dilated or hypertrophic cardiomyopathy. Echocardiographic studies in patients with VCP variants reveal a significant prevalence of diastolic dysfunction, conduction abnormalities, and variable degrees of systolic impairment. Despite these findings, there are no standardized guidelines for the diagnosis and management of VCP-associated cardiomyopathy. Current treatment strategies are extrapolated from heart failure guidelines, incorporating neurohormonal blockades with angiotensin-converting enzyme inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. Our review highlights the need for systematic screening protocols, genotype-phenotype correlation studies, and the development of targeted therapies. Future research should focus on identifying biomarkers for early detection, elucidating the molecular mechanisms underlying cardiac dysfunction, and assessing the efficacy of novel treatment strategies. Recognizing VCP-associated cardiomyopathy as a distinct clinical entity will facilitate earlier diagnosis, improve patient outcomes, pave the way for disease-specific therapeutic interventions and insights into the mechanism for isolated cardiomyopathy.
• Snippet 2 (score: 0.534) > Advancements in understanding the role of VCP in the pathogenesis of MSP1 are promising for developing clinical trials for targeted therapies. Currently, there are no successful treatments for VCP-related myopathy or neurological manifestations, and the management of cardiomyopathy is similar to the treatment of other non-ischemic Given that VCP is a multisystem proteinopathy caused by a missense gain-of-function variants, novel therapeutic developments have included targeted excision of the pathogenic variant by exon 5 skipping in mice, which would lead to downstream improvements on skeletal muscle, cardiomyocyte, and oligodendrocyte function [35]. The treated mice showed improvements in muscle strength, quadriceps fibers architecture, autophagy signaling pathway, reduced brain pathology, and reduced severity of Paget-like bone changes with efficient mutated exon removal; however, cardiac parameters were not assessed in this study [11]. > The specific pathophysiologic mechanisms underlying cardiac dysfunction in patients with VCP disease remains poorly understood, but emerging data in mouse models have resulted in further understanding of the role of VCP in cardiomyocytes and heart failure, as reviewed in this manuscript. VCP may have a primary role in cardiomyocyte survival through multiple mechanisms, including protein homeostasis, mitochondrial respiratory function, and elevated production of iNOS and subsequently nitric oxide, which is known to have a cardioprotective effect [36]. Pathogenic variants in VCP are associated with mitochondrial dysfunction, impaired mitophagy, and disrupted energy metabolism, all of which increase cardiomyocyte susceptibility to stress, including ischemia/reperfusion injury. These dysfunctions contribute to the accumulation of damaged mitochondria and elevated oxidative stress. Notably, VCP variants linked to early disease onset or earlier loss of ambulation exhibit higher ATPase activity compared to those associated with later onset [37]. While VCP normally protects cardiac tissue by maintaining protein homeostasis, supporting mitochondrial function, and regulating mTORC1 signaling, its pathogenic variants can predispose individuals to cardiac dysfunction.

[5] Clinical Classification of Variants in the Valosin-Containing Protein Gene Associated With Multisystem Proteinopathy

• Authors: Marianela Schiava, C. Ikenaga, A. Topf, M. Caballero-Ávila, T. Chou et al.
• Year: 2023
• Venue: Neurology: Genetics
• URL: https://www.semanticscholar.org/paper/635305b65c2cd65cd737b4bd22e1a89d0113586f
• DOI: 10.1212/NXG.0000000000200093
• PMID: 37588275
• PMCID: 10427110
• Citations: 8
• Summary: Data is provided to support pathogenicity of 14 of 19 novel VCP variants and provides guidance for clinicians in the evaluation of novel variants in the VCP gene.
• Evidence snippets:
• Snippet 1 (score: 0.595) > Valosin-containing protein (VCP), or p97, is an hexameric protein from the AAA+ (ATPases Associated with diverse cellular Activities) family involved in the remodeling of molecules using the energy of ATP hydrolysis. 1 VCP is encoded by the VCP gene, a 17-exon gene on chromosome 9.2 Variants in the VCP gene were initially described in patients with inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD). 2 However, this acronym is insufficient to capture the expanding phenotypic spectrum of VCP patients, and currently, this disease is more accurately considered a member of a group of conditions known as multisystem proteinopathy (MSP). 3,4 [11][12][13][14][15][16][17][18][19] To date, only missense variants have been described in patients with VCP-MSP. 3,7,20 In all cases, the pattern of inheritance is dominant. The mechanism of VCP dysfunction is likely contextdependent because assays studying VCP mutant function in vitro and in vivo support a gain and loss of function mechanism. In vitro, most pathogenic variants have an increase in ATPase activity, what reflects an induced structural change allowing for an increase in ATP accessibility and ADP release. By contrast, cells and animals expressing VCP-MSP variants behave similarly to VCP chemical or genetic inhibition suggesting that VCP pathogenic variants are dysfunctional. 21 How the apparent increase in ATPase activity in vitro correlates with a loss of VCP function in vivo remains to be explored but is likely due to the complex interactions of adaptor proteins mediated by the ATPase cycle. > Challenges in asserting the pathogenicity to novel VCP variants are due to the diverse phenotypic presentations, the possible varied gene penetrance, and the fact that ancillary tests may support the diagnosis but do not show pathognomonic features.

[6] Analysis of muscle magnetic resonance imaging of a large cohort of patient with VCP-mediated disease reveals characteristic features useful for diagnosis

• Authors: D. Esteller, Marianela Schiava, J. Verdú-Díaz, R. Villar-Quiles, Boris Dibowski et al.
• Year: 2023
• Venue: Journal of Neurology
• URL: https://www.semanticscholar.org/paper/738d7da150cc8815dfda3f1f13fd37ccfba26c8e
• DOI: 10.1007/s00415-023-11862-4
• PMID: 37603075
• PMCID: 10632218
• Citations: 10
• Summary: Ten diagnostic characteristics based on the pattern identified that allowed us to distinguish VCP disease from other neuromuscular diseases with high accuracy are identified.
• Evidence snippets:
• Snippet 1 (score: 0.585) > The VCP gene encodes the valosin-containing protein (VCP), a member of the ATPases Associated with diverse cellular Activities (AAA +) family of proteins. VCP is Robert Y. Carlier and Jordi Díaz-Manera have equally contributed to this work. > Extended author information available on the last page of the article ubiquitously expressed, and it is involved in protein degradation by the ubiquitin-proteasome system and in cellular homeostasis regulation [1][2][3]. The group of Dr. Kimonis described in 2001 that mutations in the VCP gene were the cause of an autosomal dominant disease characterized by the combination of an inclusion body myopathy (IBM), Paget's disease of the bone (PDB) and frontotemporal dementia (FTD), also known as IBMPFD [4][5][6][7]. Since the original description, many other phenotypes and diseases have been reported associated with mutations in the VCP gene including facio-scapulo-humeral muscle weakness, distal myopathy, amyotrophic lateral sclerosis, parkinsonism, hereditary spastic paraplegia, Charcot-Marie-Tooth disease type 2, Huntington´s disease and cardiomyopathy [8][9][10][11][12][13][14][15][16][17]. Because of this wide range of clinical presentations, the IBMPFD acronym was replaced by the term multisystem proteinopathy (MSP) to encompass all the phenotypes associated with VCP mutations [6]. Other genes have recently been described to also cause MSP including hnRNPA1, SQSTM1, MATR3, TIA1 and OPTN [18,19]. To better understand the variable features of MSP produced by mutations in the VCP gene (VCP-MSP), we collected demographic, clinical, genetic, muscle MRI and muscle biopsy data of 255 patients from different countries included in the "VCP International Study" [20].

[7] Valosin-containing-protein pathogenic variant p.R487H in Parkinson’s disease

• Authors: Capucine Piat, Owen A. Ross, W. Springer, E. Benarroch, J. Layne Moore et al.
• Year: 2024
• Venue: Clinical Parkinsonism & Related Disorders
• URL: https://www.semanticscholar.org/paper/6589dcbbb4cef0196cf89034ce312afc1e5f8c5e
• DOI: 10.1016/j.prdoa.2024.100236
• PMID: 38283104
• PMCID: 10818073
• Summary: We describe a 66-year-old woman with Parkinson’s disease, carrying a known pathogenic missense variant in the Valosin-containing-protein (VCP) gene. She responded excellently to L-dopa, had no cognitive or motoneuronal dysfunction. Laboratory analyses and MRI were unremarkable. Genetic testing revealed a heterozygous variant in VCP(NM_007126.5), chr9 (GRCh3 7):g.35060820C > T, c.1460G > A p.Arg487His (p.R487H).
• Evidence snippets:
• Snippet 1 (score: 0.581) > Parkinson's disease (PD) is a complex neurodegenerative disorder with ~ 10 % recognized as familial and an increasing number of identified causative, risk-associated genes. Valosin-containing-protein (VCP) gene encodes for VCP/p97, a ubiquitous ATPase from the AAA + family, which functions as a molecular "chaperone" assisting protein degradation via the ubiquitin-proteasome system, autophagy, membrane fusion, transcription activation, and apoptosis (Fig. 1). VCP-variants can induce misfolded protein inclusions that disrupt cellular mechanisms. VCP occurs in nuclear inclusions of Huntington's disease (HD), Lewy-body disease (LBD), Alzheimer's disease (AD), Creutzfeldt-Jacob disease (CJD) and amyotrophic lateral sclerosis (ALS) with dementia. > Over 80 VCP gene-variants are described in different central and peripheral neurological disorders [1]. Heterogenous clinical phenotypes of VCP-variants have been grouped into an entity called VCP-Multisystem-Proteinopathy (VCP-MSP) [2,3]. VCP-MSP is transmitted in an autosomal-dominant pattern, often caused by VCP-missense variants [2]. Physicians identify VCP-MSP when ≥ 2 of the following are present: inclusion-body-myopathy (IBM), Paget's bone disease (PBD), ALS, or frontotemporal-dementia (FTD). > A cohort of 231 patients from 36 VCP variant-harboring families showed 4 % of VCP-MSP patients with parkinsonism in their disease phenotype. Another large study investigated the role of VCP in 768 PD patients, found heterozygous VCP-variants in 1.4 % of the cohort, but no identified pathogenic variants. One case of idiopathic-like, levodoparesponsive PD was reported in a p.R159C-VCP-variant carrier [4].

[8] Valosin Containing Protein (VCP): A Multistep Regulator of Autophagy

• Authors: V. Ferrari, R. Cristofani, B. Tedesco, V. Crippa, M. Chierichetti et al.
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/4deb5c598926017418f38f68366d46c3d95d4556
• DOI: 10.3390/ijms23041939
• PMID: 35216053
• PMCID: 8878954
• Citations: 34
• Influential citations: 1
• Summary: A better understanding of VCP complexes and mechanisms in regulating autophagy could define the altered mechanisms by which VCP directly or indirectly causes or modulates different human diseases and revealing possible new therapeutic approaches for NDs.
• Evidence snippets:
• Snippet 1 (score: 0.570) > Valosin containing protein (VCP) has emerged as a central protein in the regulation of the protein quality control (PQC) system. VCP mutations are causative of multisystem proteinopathies, which include neurodegenerative diseases (NDs), and share various signs of altered proteostasis, mainly associated with autophagy malfunctioning. Autophagy is a complex multistep degradative system essential for the maintenance of cell viability, especially in post-mitotic cells as neurons and differentiated skeletal muscle cells. Interestingly, many studies concerning NDs have focused on autophagy impairment as a pathological mechanism or autophagy activity boosting to rescue the pathological phenotype. The role of VCP in autophagy has been widely debated, but recent findings have defined new mechanisms associated with VCP activity in the regulation of autophagy, showing that VCP is involved in different steps of this pathway. Here we will discuss the multiple activity of VCP in the autophagic pathway underlying its leading role either in physiological or pathological conditions. A better understanding of VCP complexes and mechanisms in regulating autophagy could define the altered mechanisms by which VCP directly or indirectly causes or modulates different human diseases and revealing possible new therapeutic approaches for NDs.
• Snippet 2 (score: 0.555) > Neurodegenerative diseases (NDs) are heterogeneous, frequently fatal and caused by the loss of neurons in different regions of the central or peripheral nervous system (CNS or PNS, respectively). NDs present very different phenotypes associated with the degeneration of a specific subset of neurons. Nevertheless, several NDs like Alzheimer's disease (AD), Parkinson's disease (PD), tauopathies, amyotrophic lateral sclerosis (ALS), spinal and bulbar muscular atrophy (SBMA), frontotemporal dementia (FTD), and Huntington's disease (HD) share some clinical features and pathological mechanisms, like the presence of protein inclusions and protein quality control (PQC) system impairment. The presence of alterations in proteostasis leads to the inclusion of these NDs in the group of proteinopathies that also includes diseases known as multisystem proteinopathies and myopathies [1,2]. > The PQC system is composed of chaperones and the degradative pathways, namely, the ubiquitin-proteasome system (UPS) and autophagy. Chaperones are proteins that, by cooperating with co-chaperones, are involved in the recognition of unfolded or misfolded proteins. Their role is based on supporting the proper folding of unfolded or misfolded proteins and, when this fails, on enhancing their clearance [3,4]. Valosin containing protein (VCP) is a chaperone-like protein, encoded by the VCP gene in humans, that has various roles in the PQC system being involved both in UPS and autophagy. VCP has a wellestablished role in enhancing misfolded protein degradation through the UPS, whereas VCP functions in autophagy are still not fully defined [5]. Here, we will present an overview of VCP focusing on its functions in regulating and supporting the autophagic flux and the impact that VCP disease mutations have on autophagy. The proper knowledge on VCP activity in this pathway could help in understanding the pathological mechanisms of VCP-related diseases, possibly opening new therapeutic approaches in proteinopathies.

[9] Muscle Biopsy Findings in Valosin-Containing Protein Multisystem Proteinopathy

• Authors: Marianela Schiava, Yolande Parkhurst, Matthew Henderson, T. Polvikoski, M. Valtcheva et al.
• Year: 2025
• Venue: Neurology: Genetics
• URL: https://www.semanticscholar.org/paper/ac300232f15e21815cc594850fe65262eb43f65e
• DOI: 10.1212/NXG.0000000000200265
• PMID: 40678441
• PMCID: 12270496
• Citations: 1
• Summary: VCP-MSP muscle biopsies consistently show myopathic or mixed patterns with rimmed vacuoles and p62/VCP-positive inclusions, regardless of clinical phenotype, age, or progression, according to this study.
• Evidence snippets:
• Snippet 1 (score: 0.565) > Valosin-containing protein multisystem proteinopathy, hereafter VCP-MSP, is an autosomal dominant genetic condition produced by pathogenic variants in the valosin-containing protein gene (VCP gene). 1 VCP is a member of the AAA-ATPase (ATPases associated with diverse cellular activities protein) family which is involved in the remodeling of molecules using the energy generated by hydrolyzing ATP. 2 VCP is ubiquitously expressed through body tissues representing up to 1% of the cellular proteins. 3 VCP's structure consists of an N-terminal domain that interacts with adapters and cofactors, 2 central D1 and D2 ATPase domains, 2 linker domains (L1 and L2), and a carboxy-terminal domain that also links to some cofactors. 2,4 A VCP monomer assembles into a hexamer with a central cylinder formed by the D1/D2 domains. While the D1 domain is responsible for hexamerization, the D2 domain performs the majority of ATPase activity. 5,6 VCP has a key role in maintaining cell homeostasis participating in protein degradation, autophagy, cell cycle control, and regulation of apoptosis. 2,7 e first patients with VCP-MSP reported developed a combination of symptoms including involvement of the skeletal muscle, in the form of an inclusion body myopathy, 8 Paget disease of the bone (PDB), and frontotemporal dementia (FTD). 9 Since that original report, diverse clinical presentations have been reported. 1][12][13][14][15][16][17][18][19][20][21] It is recognized that there is interindividual and intrafamilial variability in the clinical presentation. 22 Although VCP-MSP was considered to affect only adults, a new phenotype affecting children presenting with cognitive decline has been published, broadening the potential phenotypes even more. 23
• Snippet 2 (score: 0.540) > Background and Objectives Valosin Containing Protein-associated multisystem proteinopathy (VCP-MSP) is a progressive, autosomal dominant disorder caused by pathogenic variants in the VCP gene, resulting in a heterogeneous clinical presentation. Muscle biopsy findings are characteristic but not pathognomonic. This study aimed to comprehensively analyse VCP-related myopathology and explore correlations with clinical phenotypes, genetic variants, and disease progression. Methods Muscle biopsy images and data were collected retrospectively from adults (≥18 years) with pathogenic or likely pathogenic VCP variants enrolled in the VCP Multicentre International Study. Biopsy data were standardized using the “Common Data Elements for Muscle Biopsy Reporting.” Variations in biopsy findings were analysed by biopsy site, time from disease onset, the four most common VCP variants, and clinical phenotypes. Result A total of 112 muscle biopsies were included. Most individuals were male (66.0%). The mean age at biopsy was 53.3 years (SD 10.0), with a mean disease duration of 6.5 years (SD 4.5). The most frequent VCP variant was c.464G>A (p.Arg155His) (18.8%). The top clinical phenotypes were isolated myopathy (37.5%), myopathy with Paget disease of bone (17.9%), and myopathy with motor neuron involvement (13.4%). The vastus lateralis was the most common biopsy site (34.8%), and 91% were open biopsies. Histopathologic findings included atrophic fibres (87.5%), rimmed vacuoles (72.3%), endomysial fibrosis (58.0%), and protein aggregates (51.8%), primarily p62 (60.3%) and VCP (36.2%). Degeneration niches with fibrofatty replacement and atrophic fibres were seen in 33.3% of biopsies without frequency differences by clinical phenotypes. There were no differences

[10] Valosin-Containing Protein (VCP): A Review of Its Diverse Molecular Functions and Clinical Phenotypes

• Authors: Carly S. Pontifex, Mashiat Zaman, R. Fanganiello, T. Shutt, G. Pfeffer
• Year: 2024
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/a0717d977acc61d9c08343d1ac6aed94c33f2138
• DOI: 10.3390/ijms25115633
• PMID: 38891822
• PMCID: 11172259
• Citations: 14
• Summary: In this review we examine the functionally diverse ATPase associated with various cellular activities (AAA-ATPase), valosin-containing protein (VCP/p97), its molecular functions, the mutational landscape of VCP and the phenotypic manifestation of VCP disease. VCP is crucial to a multitude of cellular functions including protein quality control, endoplasmic reticulum-associated degradation (ERAD), autophagy, mitophagy, lysophagy, stress granule formation and clearance, DNA replication and mito...
• Evidence snippets:
• Snippet 1 (score: 0.563) > Although the major roles of VCP in protein quality control are presumed to be the major mechanisms implicated in MSP, the incredible functional diversity and pleiotropic effects of VCP also imply that other mechanisms may be relevant and require further study.VCP cooperates with the 26S proteasome, the main pathway for protein degradation, to manage the protein quality control system.In the nucleus, VCP regulates cell cycle control and the DNA damage response by coordinating proteins at DNA damage sites.In the cytosol, VCP regulates responses to cellular stress by forming and clearing stress granules, facilitating ERAD, autophagy, mitophagy and lysophagy, and VCP may also be involved in apoptosis.The complexity of VCP's diverse molecular functions is also mirrored by the variability in clinical dysfunction caused by pathogenic variants in VCP.The relationship between specific molecular functions of VCP and the spectrum of clinical presentations remains poorly understood, and, in general, genotype-phenotype correlation is still difficult to demonstrate.Certainly, VCP plays many yet-to-be-identified roles in different cellular systems.Given that the role of VCP extends to so many cellular systems, it makes it difficult to ascertain which dysfunction leads to which clinical phenotype.The majority of MSP cases are related to variants at positions 155 and 159, but the phenotypic variability is extensive, suggesting that other genetic or epigenetic factors and/or environmental factors may interact.To better narrow down a causative mechanism in a given tissue, we advise that, when possible, experiments should include one or two other MSP genes such as SQSTM1 or HNRNPA2B1, as this may help identify common mechanisms of dysfunction in MSP.Studies of large cohorts of patients who have common variants in VCP may allow for the identification of genetic modifiers or other factors that contribute to phenotypic variability.Even though pathogenic variants in VCP typically lead to multisystem disease, in general, the affected systems predictably include certain tissue types (primarily skeletal muscle, the cerebrum, motor neurons and osteoclasts).Even though VCP is ubiquitously expressed and participates in numerous crucial cellular functions, pan-systemic disease is not observed.

[11] Myogenic differentiation of VCP disease-induced pluripotent stem cells: A novel platform for drug discovery

• Authors: K. Llewellyn, A. Nalbandian, Lan Weiss, I. Chang, Howard Yu et al.
• Year: 2017
• Venue: PLoS ONE
• URL: https://www.semanticscholar.org/paper/8f47d29199964591678cb84f32e4991cd50e833a
• DOI: 10.1371/journal.pone.0176919
• PMID: 28575052
• PMCID: 5456028
• Citations: 14
• Influential citations: 1
• Summary: The differentiation and characterization of a VCP disease-specific hiPSCs into precursors expressing myogenic markers including desmin, myogenic factor 5 (MYF5), myosin and heavy chain 2 (MYH2) illustrate that hiPSC technology provide a useful platform for a rapid drug discovery and hence constitutes a bridge between clinical and bench research in VCP and related diseases.
• Evidence snippets:
• Snippet 1 (score: 0.559) > Valosin Containing Protein (VCP) disease is an autosomal dominant multisystem proteinopathy caused by mutations in the VCP gene, and is primarily associated with progressive muscle weakness, including atrophy of the pelvic and shoulder girdle muscles. Currently, no treatments are available and cardiac and respiratory failures can lead to mortality at an early age. VCP is an AAA ATPase multifunction complex protein and mutations in the VCP gene resulting in disrupted autophagic clearance. Due to the rarity of the disease, the myopathic nature of the disorder, ethical and practical considerations, VCP disease muscle biopsies are difficult to obtain. Thus, disease-specific human induced pluripotent stem cells (hiPSCs) now provide a valuable resource for the research owing to their renewable and pluripotent nature. In the present study, we report the differentiation and characterization of a VCP disease-specific hiPSCs into precursors expressing myogenic markers including desmin, myogenic factor 5 (MYF5), myosin and heavy chain 2 (MYH2). VCP disease phenotype is characterized by high expression of TAR DNA Binding Protein-43 (TDP-43), ubiquitin (Ub), Light Chain 3-I/II protein (LC3-I/II), and p62/SQSTM1 (p62) protein indicating disruption of the autophagy cascade. Treatment of hiPSC precursors with autophagy stimulators Rapamycin, Perifosine, or AT101 showed reduction in VCP pathology markers TDP-43, LC3-I/II and p62/SQSTM1. Conversely, autophagy inhibitors chloroquine had no beneficial effect, and Spautin-1 or MHY1485 had modest effects. Our results illustrate that hiPSC technology provide a useful platform for a rapid drug discovery and hence constitutes a bridge between clinical and bench research in VCP and related diseases.

[12] Rapamycin and Chloroquine: The In Vitro and In Vivo Effects of Autophagy-Modifying Drugs Show Promising Results in Valosin Containing Protein Multisystem Proteinopathy

• Authors: A. Nalbandian, K. Llewellyn, C. Nguyen, P. Yazdi, V. Kimonis
• Year: 2015
• Venue: PLoS ONE
• URL: https://www.semanticscholar.org/paper/dddd5c44fc93a2e37b203ab7d64950df04dadb63
• DOI: 10.1371/journal.pone.0122888
• PMID: 25884947
• PMCID: 4401571
• Citations: 83
• Influential citations: 3
• Summary: Results of administration of rapamycin and chloroquine suggest that VCP disease and related neurodegenerative multisystem proteinopathies can now be included as disorders that can potentially be ameliorated by rapalogs.
• Evidence snippets:
• Snippet 1 (score: 0.557) > Currently, intense investigations are underway to determine the underlying cellular and molecular disease mechanisms for the development of effective novel advancements/therapeutics of VCP-associated disease and related neurodegenerative disorders. VCP multisystem proteinopathy (MSP) is a degenerative disease which affects various systems and is involved in a number of cellular functions, most of which are related to autophagy ubiquitin-proteasomedependent proteolysis and mitochondrial degradation [35][36][37][38][39]. VCP is highly conserved in evolution suggesting an essential role for normal cellular functions in both unicellular (yeast) and multi-cellular organisms [40][41][42]. The finding that inhibition of VCP expression promotes apoptosis, suggests that intact VCP is indispensable for normal development and cell survival [43]. Previous studies have confirmed the role of VCP in autophagic degradation of ubiquitinated proteins [33,[44][45][46]. demonstrated mTOR dysfunction and its contribution to vacuolar pathology and weakness in VCP inclusion body myopathy [47]. In this report, we established that rapamycin administration ameliorated the muscle pathology phenotype in the VCP R155H/+ animals, while chloroquine revealed a detrimental effect. Our findings further confirm a link between the autophagy-modifying treatment (rapamycin) and autophagy/cellular homeostasis. Thus, we hypothesize that rapamycin counterbalances the muscle pathology and autophagy signaling transduction pathway via the mTOR cascade and may provide a promising strategy for patients with these debilitating VCP-associated multisystem diseases. > Rapamycin is a mammalian target of rapamycin (mTOR) inhibitor-based drug with multiple uses such as in immunosuppression [48], cell proliferation and autophagy stimulation [49]. mTOR functions as an ATP and amino acid sensor to balance nutrient availability and cell growth. The mechanism of action for rapamycin occurs through binding with the 12 kDa FK506-binding protein which in turn binds and activates mTORC1 (complex 1).

[13] VCP-related myopathy: a case series and a review of literature

• Authors: Eliana Iannibelli, S. Gibertini, M. Cheli, F. Blàsevich, Andrea Cavaliere et al.
• Year: 2023
• Venue: Acta Myologica
• URL: https://www.semanticscholar.org/paper/cb13eb67fd5adb4fa2b9044135be42c06c03e614
• DOI: 10.36185/2532-1900-244
• PMID: 37091525
• PMCID: 10115396
• Citations: 7
• Summary: It is strongly suggest that VCP gene mutations can be related with a predominant skeletal muscle phenotype without any central nervous system involvement, as occasionally reported in the literature.
• Evidence snippets:
• Snippet 1 (score: 0.556) > The valosin-containing protein (VCP), a widely expressed protein, controls the ubiquitin-proteasome system, endolysosomal sorting, and autophagy to maintain cellular proteostasis. Frontotemporal dementia (FTD), inclusion body myopathy, and Paget’s disease of the bone (PDB) are all caused by dominant missense mutations in the VCP gene, which interfere with these mechanisms and cause a multisystem proteinopathy. We describe phenotypic and genetic findings of five patients with four different mutations in VCP gene (NM_007126): c.278G > A (p.R93H), c.463C > T (p.R155C), c.410C > T (p.P137L), c.464G > A (p.R155H), c.410C > T (p.P137L). We analysed the patient’ biopsies, all characterized by a muscular phenotype, and we executed immunofluorescence staining to evaluate the presence of proteins: p62, VCP, desmin, myotilin, TDP-43. Eventually we performed a brief literature review to compare our cases with those already reported. Our report strongly suggest that VCP gene mutations can be related with a predominant skeletal muscle phenotype without any central nervous system involvement, as occasionally reported in the literature. Particularly, our patient with R93H shows only myopathic involvement while this mutation has been described once associated only to Hereditary Spastic Paraplegia. Further study will be necessary to understand such a broad and different clinical spectrum.

[14] Provisional practice recommendation for the management of myopathy in VCP‐associated multisystem proteinopathy

• Authors: B. Roy, Alli Peck, T. Evangelista, G. Pfeffer, Leo H. Wang et al.
• Year: 2023
• Venue: Annals of Clinical and Translational Neurology
• URL: https://www.semanticscholar.org/paper/911ac001ac886231067b2e2c127b0febfce33711
• DOI: 10.1002/acn3.51760
• PMID: 37026610
• PMCID: 10187720
• Citations: 8
• Summary: This working group developed a best practice set of provisional recommendations for VCP myopathy which can be easily implemented across the globe to optimize patient care and help future research initiatives.
• Evidence snippets:
• Snippet 1 (score: 0.542) > Valosin‐containing protein (VCP)‐associated multisystem proteinopathy (MSP) is a rare genetic disorder with abnormalities in the autophagy pathway leading to various combinations of myopathy, bone diseases, and neurodegeneration. Ninety percent of patients with VCP‐associated MSP have myopathy, but there is no consensus‐based guideline. The goal of this working group was to develop a best practice set of provisional recommendations for VCP myopathy which can be easily implemented across the globe. As an initiative by Cure VCP Disease Inc., a patient advocacy organization, an online survey was initially conducted to identify the practice gaps in VCP myopathy. All prior published literature on VCP myopathy was reviewed to better understand the different aspects of management of VCP myopathy, and several working group sessions were conducted involving international experts to develop this provisional recommendation. VCP myopathy has a heterogeneous clinical phenotype and should be considered in patients with limb‐girdle muscular dystrophy phenotype, or any myopathy with an autosomal dominant pattern of inheritance. Genetic testing is the only definitive way to diagnose VCP myopathy, and single‐variant testing in the case of a known familial VCP variant, or multi‐gene panel sequencing in undifferentiated cases can be considered. Muscle biopsy is important in cases of diagnostic uncertainty or lack of a definitive pathogenic genetic variant since rimmed vacuoles (present in ~40% cases) are considered a hallmark of VCP myopathy. Electrodiagnostic studies and magnetic resonance imaging can also help rule out disease mimics. Standardized management of VCP myopathy will optimize patient care and help future research initiatives.

[15] The Genetics of Monogenic Frontotemporal Dementia

• Authors: L. Takada
• Year: 2015
• Venue: Dementia & Neuropsychologia
• URL: https://www.semanticscholar.org/paper/a8e017714edbc33cd7977f6ab00731fb43a7a265
• DOI: 10.1590/1980-57642015DN93000003
• PMID: 29213965
• PMCID: 5619362
• Citations: 45
• Influential citations: 2
• Summary: Since the identification of mutations in MAPT (microtubule-associated protein tau gene) in 1998, over 10 other genes have been associated with FTD spectrum disorders, discussed in this review.
• Evidence snippets:
• Snippet 1 (score: 0.539) > Mutations in VCP were discovered in 2004 were found to cause a complex phenotype, which initially included inclusion body myopathy, Paget disease of the bone and bvFTD and consequently it was commonly referred to by the acronym IBMPFD. 86 In 2010 however, a study employing exome sequencing found that mutations in VCP could also cause familial ALS, thus expanding the phenotypes associated with VCP mutations. 87 Other reports subsequently suggested that these families could occasionally present systemic manifestations such as heart, liver, peripheral nervous system involvement, among others, and therefore the acronym originally used was no longer deemed adequate. Hence, Benatar et al. proposed that this group of phenotypes be renamed "Multisystem proteinopathy" (MSP). 13 utations in VCP are the most frequent cause of MSP, but mutations in HNRNPA1 and HNRNPA2B1 were also recently identified. 88 Mutations in the SQSTM1 gene have not been associated with inclusion body myopathy, but have since been found in other phenotypes of MSP. 89 Other MSP-causing genes will likely be identified in the future, since mutations in these four genes cannot explain all cases of familial MSP. Takada LT VCP gene. The VCP gene (valosin containing protein) is located on chromosome 9p13.3. The valosin-containing protein is an AAA + protein (ATPase associated with a variety of cellular activities), which participates in multiple cellular processes, such as degradation of ubiquitinated proteins by the ubiquitin-proteasome system and autophagy. 86 here are currently 18 known missense mutations of the gene. 15 Mutations in VCP seem to affect the protein degradation pathways, which can lead to neurodegeneration. 86 ransmission occurs in autosomal dominant pattern of inheritance, with variable penetrance depending on the phenotype (around 30% of patients develop bvFTD, 85-90% develop inclusion body myopathy, and 45-50% have Paget's disease). 90

[16] Hereditary inclusion body myopathy: a clinical and genetic review

• Authors: Paulo Victor Sgobbi de Souza, Bruno Mattos Lombardi Badia, Eduardo Augusto Gonçalves, I. Farias, Wladimir Bocca Vieira de Rezende Pinto et al.
• Year: 2020
• Venue: Revista Neurociências
• URL: https://www.semanticscholar.org/paper/e691ec98c1b0a097b46584e12dc68cc3c5fa3dcf
• DOI: 10.34024/rnc.2020.v28.10569
• Citations: 3
• Summary: A wide review regarding the main clinical, imaging, pathophysiological, genetic and therapeutic aspects related to hereditary myopathies linked to seven different clinical and genetic presentations linked to at least 7 distinct clinic and genetic monogenic forms.
• Evidence snippets:
• Snippet 1 (score: 0.534) > There is marked pathophysiological overlap between genetic mechanisms common to hIBM subtypes and familial ALS involving multisystem proteinopathies and intracytoplasmic system of ubiquitin-proteosome networks 16,27,28 . Thereby, VCP gene mutations result from complex dysfunctions in the biogenesis of the Golgi apparatus, ubiquitin-proteosome system, protein degradation of external mitochondrial membrane, establishment and maturation of the autophagosome, clathrin-mediated membrane endocytosis and cell cycle regulation 29 . > Dysfunctions involving the ribonucleoproteins A1 and B1 originate intracellular defects related to splicing and processing of messenger preRNA and interaction with RNA polymerase II 29 , being, thus, a pathophysiological mechanism not restricted to skeletal muscle groups or to the central nervous system. Regarding other hIBM subtypes, it has not been well-defined if mutations in the gene coding heavy myosin chain IIa could be associated with nonmyopathic complex neurodegenerative spectrum of disorders or with multisystem proteinopathy phenotype 15 . > This complex multisystem disorders have also been linked to other genes involved with similar pathophysiological mechanisms, including OPTN, DNAJB6 and HNRNPDL, thus, disclosing a complex network of proteins involved in intracellular protein homeostasis and related with the same mechanisms previously described in ALS, FTLD and other degenerative disorders 3,27,29,30 . > There is a lot of expectancy that the knowledge related to hIBM etiopathogenesis can represent the basis to understand properly the mechanisms of IBM and other clinically significant neuromuscular and neurodegenerative disorders (including ALS, parkinsonian syndromes and frontotemporal lobar degeneration) and systemic diseases (such as Paget disease of bone), as well as the foundation in the development of common specific therapeutic modalities for such multisystem disorders 29,30 .

[17] Parkinson's Disease: The Dirty Truth about the Air

• Authors: F. Scorza, A. G. de Almeida, C. Scorza, J. Finsterer
• Year: 2023
• Venue: Annals of Indian Academy of Neurology
• URL: https://www.semanticscholar.org/paper/bbb6681e7f5acc316257ee68270a94c1b578f0e7
• DOI: 10.4103/aian.aian_839_22
• PMID: 37034044
• PMCID: 10081543
• Summary: The use of three‐dimensional anatomical patient‐specific printed models in surgical clipping of intracranial aneurysm: A pilot study and application of 3D‐printed craniocerebral model in simulated surgery for complex intrACranial lesions.
• Evidence snippets:
• Snippet 1 (score: 0.533) > Dear Editor, We report the first case of multisystem proteinopathy (MSP) from India and document an uncommon phenotypic expression. Our patient had pathogenic variants in the valosin-containing protein (VCP) gene. Clinically, there was a peculiar combination of rapidly progressive amyotrophic lateral sclerosis and atypical parkinsonism along with Paget's disease of the bone. There was no evidence of myopathy. The disease seems uncommon in Asia and has been documented sparsely. The term "multisystem proteinopathy (MSP)" applies to a composite of rare inherited disorders affecting muscle, bone, and nervous systems in different combinations. The usual inheritance pattern is autosomal dominant and rarely sporadic. The earliest descriptions of VCP-related diseases were given by Kimonis et al. [1] and Watts et al. [2] They first reported the peculiar combination of hereditary inclusion body myopathy (h-IBM), Paget's disease of bone (PDB), and dementia (FTD), which then came to be recognized as the classical phenotype of the disease known as IBMPFD. Thereafter, the disease has been increasingly reported, largely in Western countries. The term MSP currently incorporates various phenotypic aspects. [3] The major phenotypes known within the spectrum are myopathy, PDB, FTD-ALS, Parkinson's disease, and peripheral neuropathy. Apart from the VCP, other genes now included in the spectrum are heterogeneous nuclear ribonucleoprotein A2B1 and A1 (hnRNPA2B1 and hnRNPA1) genes, Sequestosome 1 (SQSTM1), Matrin-3 (MATR3), T-cell restricted intracellular antigen 1 (TIA1), and optineurin (OPTN). [4,5] The common underlying molecular mechanism is that of disruption of the cellular protein degradation pathways resulting in protein misfolding and aggregation. [4] 47-year female presented with limb-girdle weakness along with neck flexor weakness and dysphagia progressive for six months.

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.

VCP-Associated Multisystem Proteinopathy (VCP-MSP / MSP1 / IBMPFD): Disease Characteristics Research Report

Scope note (evidence limitations): The tool-retrieved corpus strongly supports clinical spectrum, natural history, management guidance (2023), and mechanistic/therapeutic research advances (2024). However, authoritative database identifiers (Orphanet, MeSH, ICD-10/ICD-11) were not directly retrievable in the current evidence set; they are therefore flagged as not available from this evidence rather than inferred.

1. Disease Information

1.1 Definition and overview

VCP-associated multisystem proteinopathy (VCP-MSP; often MSP1) is a progressive, autosomal dominant disorder caused by pathogenic variants in VCP (p97), characterized by variable combinations of inclusion body myopathy, Paget disease of bone (PDB), frontotemporal dementia (FTD), and less commonly motor neuron disease/ALS and parkinsonism. This pleiotropy and variable expressivity make clinical prediction challenging. (pontifex2024valosincontainingprotein(vcp) pages 1-2, shmara2023prevalenceoffrontotemporal pages 1-2, schiava2022genotype–phenotypecorrelationsin pages 3-4)

Primary literature abstract quote (management guideline): “Ninety percent of patients with VCP-associated MSP have myopathy…” (roy2023provisionalpracticerecommendation pages 1-2)

1.2 Key identifiers

• OMIM/MIM: IBMPFD / VCP disease is referenced as MIM 167320 (primary literature mention). (iannibelli2023vcprelatedmyopathya pages 1-2)
• MONDO: OpenTargets evidence (outside the citable context set) suggests MONDO disease entities exist for the IBMPFD spectrum, but MONDO IDs are not citable from the present evidence snippets.
• Orphanet / ICD-10 / ICD-11 / MeSH: Not available from the present tool-retrieved evidence.

1.3 Synonyms and alternative names

Common synonyms used in the literature include: - MSP1 / “multisystem proteinopathy-1” (robinson2024elevatedvcpatpase pages 1-3) - IBMPFD (“inclusion body myopathy with Paget disease of bone and frontotemporal dementia”) (iannibelli2023vcprelatedmyopathya pages 1-2, shmara2023prevalenceoffrontotemporal pages 1-2) - VCP disease (pontifex2024valosincontainingprotein(vcp) pages 1-2, shmara2023prevalenceoffrontotemporal pages 1-2)

1.4 Evidence source type

Most disease-level statements below are derived from aggregated cohorts, multicenter retrospective datasets, and patient registries, supplemented by case series and cell-model mechanistic studies. Examples include a multicentre retrospective cohort (n=255) (schiava2022genotype–phenotypecorrelationsin pages 3-4, schiava2022genotype–phenotypecorrelationsin pages 4-6), a large family-based cohort (n=231) (alobeidi2018genotype‐phenotypestudyin pages 1-5), and a patient registry (n=59) (ikenaga2020phenotypicdiversityin pages 1-2).

2. Etiology

2.1 Primary causal factors

Genetic cause: Pathogenic heterozygous VCP variants cause VCP-MSP, typically via missense variants; mutational hotspots include residues around 155 and 159. (pontifex2024valosincontainingprotein(vcp) pages 1-2, shmara2023prevalenceoffrontotemporal pages 1-2)

Abstract quote (review): “VCP variants cause multisystem proteinopathy…” and VCP is “crucial to… protein quality control… autophagy… stress granule formation and clearance…” (pontifex2024valosincontainingprotein(vcp) pages 1-2)

2.2 Risk factors

• Family history / autosomal dominant inheritance is the main risk factor because disease is driven by pathogenic germline VCP variants. (shmara2023prevalenceoffrontotemporal pages 1-2, schiava2022genotype–phenotypecorrelationsin pages 3-4)
• Variant-specific risk modulation: For example, in a Hispanic kindred series with p.R159H, FTD was unusually prevalent while PDB was rare compared with historical cohorts, suggesting genotype-by-ancestry or background modifiers. (shmara2023prevalenceoffrontotemporal pages 1-2)

2.3 Protective factors

No validated protective genetic or environmental factors were identified in the retrieved evidence. Variant-level effects on ATPase activity may influence severity/onset but are not “protective” in the usual epidemiologic sense. (robinson2024elevatedvcpatpase pages 1-3, mahsom2023anautosomaldominantchildhoodonset pages 1-3)

2.4 Gene–environment interactions

No direct gene–environment interaction evidence was retrieved.

3. Phenotypes (with suggested HPO terms)

3.1 Core phenotype domains

The core phenotype includes:

A) Myopathy (inclusion body myopathy / limb-girdle pattern)

• Frequency: ~90% in large cohorts/registries (e.g., 168/187 symptomatic; 89.8%). (alobeidi2018genotype‐phenotypestudyin pages 5-7, alobeidi2018genotype‐phenotypestudyin pages 1-5)
• Age of onset: mean ~43 years (range 20–70) in the 231-individual cohort. (alobeidi2018genotype‐phenotypestudyin pages 5-7)
• Typical onset pattern: slowly progressive weakness; in a multicentre cohort, weakness was the initial symptom in 90.7% and was slowly progressive in 89.1%. (schiava2022genotype–phenotypecorrelationsin pages 4-6)
• Suggested HPO: HP:0003323 (Progressive muscle weakness), HP:0002650 (Skeletal muscle atrophy), HP:0003198 (Myopathy), HP:0002355 (Muscle weakness), HP:0000007 (Autosomal dominant inheritance—phenotype context), HP:0003677 (Gower sign) (clinical reports), HP:0003227 (Scapular winging) (schiava2022genotype–phenotypecorrelationsin pages 4-6, roy2023provisionalpracticerecommendation pages 5-7)

B) Paget disease of bone (PDB)

• Frequency: 42.4% in the 231-individual cohort; 28.2% in a 255-patient multicentre dataset. (alobeidi2018genotype‐phenotypestudyin pages 5-7, schiava2022genotype–phenotypecorrelationsin pages 3-4)
• Age of onset: mean ~41.2 years (range 23–65). (alobeidi2018genotype‐phenotypestudyin pages 5-7)
• Suggested HPO: HP:0002653 (Osteitis deformans), HP:0002755 (Abnormal bone remodeling), HP:0002676 (Bone pain)

C) Frontotemporal dementia / cognitive impairment

• Frequency: ~29–30% in the 231-individual cohort; 14.3% FTD in the multicentre dataset summary; cognitive impairment 25.5% with FTD the most common cognitive pattern among those impaired. (alobeidi2018genotype‐phenotypestudyin pages 7-10, schiava2022genotype–phenotypecorrelationsin pages 3-4, schiava2022genotype–phenotypecorrelationsin pages 4-6)
• Age of onset: mean ~55.9 years (range 30–86). (alobeidi2018genotype‐phenotypestudyin pages 7-10)
• Suggested HPO: HP:0000741 (Dementia), HP:0002145 (Frontotemporal dementia), HP:0000716 (Depression) / HP:0000739 (Anxiety) where present (not quantified here)

D) Motor neuron disease / ALS phenotype

• Frequency: ~8.6–9% in cohort data. (alobeidi2018genotype‐phenotypestudyin pages 7-10, shmara2023prevalenceoffrontotemporal pages 1-2)
• Suggested HPO: HP:0007354 (Amyotrophic lateral sclerosis), HP:0001324 (Muscle fasciculations), HP:0001761 (Spasticity)

3.2 Respiratory and bulbar involvement (important for morbidity)

A large multicentre cohort found substantial respiratory burden: dyspnoea on exertion 25.3%, nocturnal hypoventilation 15.6%, FVC <80% in 52.6% of tested individuals, and noninvasive ventilation use in subsets. (schiava2022genotype–phenotypecorrelationsin pages 4-6)

Registry data also highlight dyspnea/dysphagia as meaningful patient-reported problems (dyspnea on exertion 42%; dysphagia 22%). (ikenaga2020phenotypicdiversityin pages 1-2)

Suggested HPO: HP:0002094 (Dyspnea), HP:0010535 (Nocturnal hypoventilation), HP:0002093 (Respiratory insufficiency), HP:0002015 (Dysphagia).

3.3 Quality of life impact

Patient-reported functional limitations are common; in a registry cohort, sit-to-stand difficulty (72%), walking difficulty (67%), and stair climbing difficulty (85%) were reported, and 59% rated QOL “more than good.” (ikenaga2020phenotypicdiversityin pages 1-2)

4. Genetic / Molecular Information

4.1 Causal gene

• Gene: VCP (valosin containing protein; p97), encoding an AAA+ ATPase. (pontifex2024valosincontainingprotein(vcp) pages 1-2, iannibelli2023vcprelatedmyopathya pages 1-2)

4.2 Pathogenic variant classes and functional consequences

• Variant class: Predominantly heterozygous missense variants in VCP-MSP cohorts; multicenter variant-classification work reports nearly all evaluated variants were missense (with rare small indel). (schiava2023clinicalclassificationof pages 1-2)
• Functional consequence: Many MSP-associated variants show elevated (“hyperactive”) basal ATPase activity, consistent with a gain-of-function/hyperactivity model for many variants. (robinson2024elevatedvcpatpase pages 1-3, schiava2023clinicalclassificationof pages 1-2)

2023 variant-classification study (clinical + functional): 19 novel/uncharacterized variants were evaluated with a 6-item clinical scoring system (ROC-derived cutoff ≥3 for “high likelihood disease-associated”) and compared with ATPase and in silico data. Thirteen of 19 increased ATPase activity; 18/19 were in the N and D1 domains. (schiava2023clinicalclassificationof pages 1-2, schiava2023clinicalclassificationof pages 6-7)

4.3 Emerging genotype–biochemistry–phenotype correlation (2024)

A 2024 Neurology Genetics analysis found intrinsic VCP ATPase activity inversely correlated with age at onset across common variants. - Example: R155C had earliest onset 38.15 ± 9.78 years and high ATPase activity (~399% WT); R93C had later onset (51.15 ± 6.67 years) and lower ATPase (still elevated; ~310% WT). (robinson2024elevatedvcpatpase pages 3-4) - Reported correlation: r = −0.94 (p = 0.01) across five variants for ATPase activity vs age at onset. (robinson2024elevatedvcpatpase pages 1-3)

Interpretation: ATPase activity may be a variant-severity proxy and could support classification of uncertain variants, but exceptions exist (e.g., VCP variants with normal or reduced ATPase linked to other phenotypes). (robinson2024elevatedvcpatpase pages 4-5)

4.4 Distinct childhood-onset VCP disorder (important differential within “VCP-related disease”)

A 2023 AJHG study described an autosomal-dominant childhood-onset neurodevelopmental disorder (DD/ID, hypotonia, macrocephaly) due to heterozygous VCP variants, mostly de novo; functional studies showed most variants decreased ATPase activity, contrasting with MSP-associated hyperactivity, suggesting a distinct pathomechanism (loss-of-function/haploinsufficiency or hypomorphic VCP). (mahsom2023anautosomaldominantchildhoodonset pages 1-3, mahsom2023anautosomaldominantchildhoodonset pages 12-13)

5. Environmental Information

No disease-specific environmental/lifestyle/infectious triggers were identified in the retrieved evidence.

6. Mechanism / Pathophysiology (with GO/CL suggestions)

6.1 Current mechanistic understanding (conceptual model)

VCP/p97 is a multifunctional AAA+ ATPase that helps maintain proteostasis across multiple pathways (UPS, ERAD, autophagy/mitophagy/lysophagy, stress granules, and DNA damage responses). Disruption of these pathways by pathogenic VCP variants can drive accumulation of ubiquitinated proteins and protein aggregates/inclusions across tissues (muscle, bone, brain). (pontifex2024valosincontainingprotein(vcp) pages 1-2, schiava2022genotype–phenotypecorrelationsin pages 3-4)

GO biological process suggestions: - GO:0006511 (ubiquitin-dependent protein catabolic process) - GO:0006914 (autophagy) - GO:0030433 (ubiquitin-dependent ERAD pathway) - GO:0016236 (macroautophagy) - GO:0070848 (response to proteasome inhibitor)

GO cellular component suggestions: - GO:0005829 (cytosol) - GO:0005634 (nucleus) - GO:0005773 (vacuole) / lysosome-related compartments

Cell ontology (CL) suggestions (relevant affected cell types): - CL:0000187 (muscle cell / myocyte) - CL:0000092 (osteoclast) - CL:0000540 (neuron) - CL:0000047 (motor neuron)

6.2 2024 mechanistic advance: nuclear proteostasis defects + ubiquitinated intranuclear inclusions

A 2024 JCI study proposed a shared MSP pathology across tissues: ubiquitinated intranuclear inclusions in myocytes, osteoclasts, and neurons, and showed MSP variants reduce nuclear VCP, impairing nuclear clearance of TDP-43 aggregates. (phan2024vcpactivatorreverses pages 1-2, phan2024vcpactivatorreverses pages 2-4)

Primary abstract quote (2024 JCI): “We found that these diseases exhibit a common pathologic feature: ubiquitinated intranuclear inclusions affecting myocytes, osteoclasts, and neurons… cells harboring MSP variants… exhibited decreased clearance of insoluble intranuclear TDP-43 aggregates.” (phan2024vcpactivatorreverses pages 1-2)

6.3 Therapeutic-development implication (2024): VCP activation to enhance TDP-43 clearance

In the same 2024 JCI study, four small molecules (UP109, UP158, UP163, UP12) were identified as VCP activators (primarily increasing D2 ATPase activity). Pharmacologic VCP activation (notably UP109) enhanced clearance of insoluble intranuclear TDP-43 aggregates in cell and iPSC-derived neuron models carrying pathogenic VCP variants. (phan2024vcpactivatorreverses pages 10-13, phan2024vcpactivatorreverses pages 1-2)

This is notable because it contrasts with a parallel line of thinking that inhibiting hyperactive VCP ATPase could help some MSP variants; together, these studies suggest directionality of VCP modulation may depend on which VCP function/subcellular compartment is limiting and which variant mechanism predominates. (robinson2024elevatedvcpatpase pages 4-5, phan2024vcpactivatorreverses pages 1-2)

7. Anatomical Structures Affected (UBERON suggestions)

Primary organs/systems affected: - Skeletal muscle (primary disability driver). (schiava2022genotype–phenotypecorrelationsin pages 4-6, alobeidi2018genotype‐phenotypestudyin pages 1-5) - Bone (Paget disease lesions; often axial skeleton/pelvis). (alobeidi2018genotype‐phenotypestudyin pages 5-7, columbres2024bonescanfindings pages 1-2) - Brain (FTD; TDP-43 pathology). (shmara2023prevalenceoffrontotemporal pages 1-2, phan2024vcpactivatorreverses pages 1-2) - Respiratory system (ventilatory insufficiency; FVC decline). (schiava2022genotype–phenotypecorrelationsin pages 3-4, schiava2022genotype–phenotypecorrelationsin pages 4-6) - Heart (less common but clinically relevant). (roy2023provisionalpracticerecommendation pages 2-3)

UBERON suggestions: UBERON:0002374 (skeletal muscle), UBERON:0001474 (bone tissue), UBERON:0000955 (brain), UBERON:0002048 (lung), UBERON:0000948 (heart), UBERON:0000970 (spinal cord).

8. Temporal Development (onset and progression)

• Typical onset: Adult onset is common; mean age at onset ~45.6 ± 9.3 years in a multicentre cohort. (schiava2022genotype–phenotypecorrelationsin pages 3-4)
• Diagnostic delay: Mean 7.7 ± 6 years. (schiava2022genotype–phenotypecorrelationsin pages 3-4)
• Progression/disability: Full-time wheelchair use in 19.1%, median 8.5 years from onset to full-time wheelchair use. (schiava2022genotype–phenotypecorrelationsin pages 3-4)
• Respiratory decline as a progression marker: FVC <50% predicted was associated with becoming a full-time wheelchair user; FVC <70% and wheelchair dependence were associated with death. (schiava2022genotype–phenotypecorrelationsin pages 3-4)

9. Inheritance and Population

9.1 Inheritance

• Autosomal dominant inheritance is repeatedly described across cohorts and clinical reports. (shmara2023prevalenceoffrontotemporal pages 1-2, schiava2022genotype–phenotypecorrelationsin pages 3-4)

9.2 Epidemiology

A UK-based estimate reported a prevalence ~0.66 per 100,000 for IBMPFD/VCP disease. (schiava2022genotype–phenotypecorrelationsin pages 3-4)

9.3 Population/genotype observations

• A Hispanic family series with p.R159H reported a phenotype skewed toward FTD (72%) with low PDB (3%), emphasizing ancestry/background as a factor in observed expressivity. (shmara2023prevalenceoffrontotemporal pages 1-2)

10. Diagnostics

10.1 Clinical evaluation

Given pleiotropy, evaluation commonly includes neuromuscular exam plus screening for bone disease and cognition, and respiratory/cardiac assessment. (roy2023provisionalpracticerecommendation pages 5-7, roy2023provisionalpracticerecommendation pages 2-3)

10.2 Laboratory tests / biomarkers

• CK: often normal or mildly elevated; in one cohort median CK at onset 254 UI/L (subset), and guidelines note CK often normal/mildly elevated. (schiava2022genotype–phenotypecorrelationsin pages 4-6, roy2023provisionalpracticerecommendation pages 3-5)
• Alkaline phosphatase (ALP): can be elevated in PDB but may be insensitive (e.g., bone scan study found only 1 active PDB patient with elevated ALP). (columbres2024bonescanfindings pages 8-9, columbres2024bonescanfindings pages 5-8)

10.3 Imaging

• Muscle MRI is helpful to characterize distribution and rule out mimics; common finding is fatty replacement in calves/quadriceps/hamstrings. (roy2023provisionalpracticerecommendation pages 2-3, roy2023provisionalpracticerecommendation pages 3-5)
• Bone imaging for PDB: A 2024 study supports Tc-99m bone scan as a sensitive screening tool in MSP1. In 12 VCP-MSP1 patients, 2 previously undiagnosed PDB cases were detected by bone scan and confirmed radiographically; common involved sites included thoracic spine/ribs, pelvis, shoulder, and calvarium. (columbres2024bonescanfindings pages 1-2)

10.4 Electrodiagnostics

EMG/NCS patterns are heterogeneous and can be myopathic, neurogenic, or mixed; thus supportive rather than definitive. (roy2023provisionalpracticerecommendation pages 3-5)

10.5 Muscle biopsy and pathology

Muscle biopsy may show rimmed vacuoles and ubiquitin/TDP-43-positive inclusions, but sensitivity is limited. - Rimmed vacuoles present in ~40% in large series and cited guidelines. (roy2023provisionalpracticerecommendation pages 3-5, iannibelli2023vcprelatedmyopathya pages 10-10)

10.6 Genetic testing (definitive)

Consensus recommendations emphasize genetic confirmation.

Abstract quote (2023 practice recommendation): “Genetic testing is the only definitive way to diagnose VCP myopathy…” (roy2023provisionalpracticerecommendation pages 1-2)

Testing strategy: - Single-variant testing when a familial pathogenic variant is known; otherwise multi-gene panels for undifferentiated myopathy (with inclusion of VCP and related MSP genes). (roy2023provisionalpracticerecommendation pages 1-2, roy2023provisionalpracticerecommendation pages 5-7) - Variant interpretation support: a 2023 multicenter effort proposed a clinical scoring + ATPase framework for novel VCP variants. (schiava2023clinicalclassificationof pages 1-2)

10.7 Differential diagnosis (examples)

Because VCP myopathy can mimic limb-girdle dystrophies and inclusion body myositis, workup typically includes evaluation for other inherited myopathies and acquired IBM (biopsy interpretation and genetics). (roy2023provisionalpracticerecommendation pages 1-2, roy2023provisionalpracticerecommendation pages 3-5)

11. Outcome / Prognosis

• Disability: Wheelchair dependence is common over time (median 8.5 years to full-time wheelchair use among those who become full-time users). (schiava2022genotype–phenotypecorrelationsin pages 3-4)
• Respiratory involvement: Common and prognostically important, with FVC thresholds associated with disability and death. (schiava2022genotype–phenotypecorrelationsin pages 3-4, schiava2022genotype–phenotypecorrelationsin pages 4-6)
• Mortality drivers: Respiratory failure and cardiomyopathy are repeatedly emphasized as major causes of death in VCP-MSP; the multicentre dataset formally links respiratory impairment markers (FVC) and wheelchair dependence to death. (schiava2022genotype–phenotypecorrelationsin pages 3-4)

12. Treatment

12.1 Current standard management (real-world implementation)

There is no approved disease-modifying therapy for VCP-MSP myopathy; management is supportive and multidisciplinary.

Evidence from 2023 consensus recommendations: - “Management… is supportive—there is no approved disease-modifying therapy…” (roy2023provisionalpracticerecommendation pages 5-7) - Pulmonary and cardiac screening and referral are recommended; mobility aids and PT/OT/speech support may be needed. (roy2023provisionalpracticerecommendation pages 5-7, roy2023provisionalpracticerecommendation pages 2-3)

MAXO suggestions (supportive actions): - MAXO:0000011 (physical therapy) - MAXO:0000012 (occupational therapy) - MAXO:0000472 (respiratory monitoring) - MAXO:0000598 (noninvasive ventilation) - MAXO:0001020 (genetic counseling)

12.2 Management of Paget disease of bone

Bisphosphonate therapy is noted as effective for PDB-related symptoms and complication prevention in the 2024 bone scan study discussion context. (columbres2024bonescanfindings pages 1-2)

MAXO suggestions: MAXO:0000410 (bisphosphonate therapy), MAXO:0000498 (bone scintigraphy), MAXO:0000127 (radiography).

12.3 Experimental / emerging therapeutic strategies

A) VCP activity modulation (precision-mechanism dependent): - VCP activation (2024): UP109 and related compounds improved nuclear TDP-43 aggregate clearance in MSP models, motivating a “VCP activator” approach for nuclear proteostasis defects. (phan2024vcpactivatorreverses pages 10-13, phan2024vcpactivatorreverses pages 1-2) - VCP inhibition (2024 correlation paper): Higher ATPase hyperactivity correlates with earlier onset, and authors suggest ATPase inhibition “may be therapeutic” for hyperactive variants, highlighting mechanistic heterogeneity and the need for careful target validation. (robinson2024elevatedvcpatpase pages 1-3, robinson2024elevatedvcpatpase pages 4-5)

12.4 Clinical trials and registries (real-world implementation)

• NCT04823143 (Natural History Study of Patients With VCP-related Disease): completed prospective observational study (start 2021-03-18; completion listed 2025-08-31; last update 2026-03), n=44, hybrid remote/onsite visits, endpoints include FVC and multiple functional and patient-reported measures (PROMIS, Neuro-QOL, ROADS, EAT-10, etc.). (NCT04823143 chunk 1)
• URL: https://clinicaltrials.gov/study/NCT04823143 (trial record)
• NCT01353430 (UC Irvine characterization of IBMPFD): observational, recruiting; includes MRI and bone scan in subsets. (NCT01353430 chunk 1)
• URL: https://clinicaltrials.gov/study/NCT01353430 (trial record)

13. Prevention

No primary prevention is currently available because disease is genetic; prevention focuses on genetic counseling and cascade testing. - Genetic counseling is recommended prior to presymptomatic testing. (roy2023provisionalpracticerecommendation pages 5-7)

MAXO suggestions: MAXO:0001020 (genetic counseling), MAXO:0000125 (predictive genetic testing), MAXO:0000130 (cascade screening).

14. Other Species / Natural Disease

No naturally occurring non-human disease evidence was retrieved in the current tool context.

15. Model Organisms

Model-organism evidence was not retrieved in a citable form in the current evidence snippets; consequently, no specific models are asserted here.

Recent quantitative summary (cross-study)

The following table consolidates key quantitative findings (frequencies, onset, respiratory and disability metrics) from major cohorts, registries, and a recent PDB imaging study.

Table: This table compiles the main quantitative clinical and natural history metrics for VCP-associated multisystem proteinopathy across key cohort and registry studies. It is useful for comparing frequencies, onset, respiratory burden, disability progression, and variant-specific patterns across the best-supported evidence snippets.

Expert synthesis / analysis (evidence-grounded)

1) Clinical heterogeneity is the rule, not the exception: large datasets show a myopathy-predominant presentation with variable PDB and FTD penetrance and meaningful respiratory morbidity. (schiava2022genotype–phenotypecorrelationsin pages 3-4, schiava2022genotype–phenotypecorrelationsin pages 4-6)

2) Respiratory function (FVC) is a major prognostic axis: FVC thresholds were associated with disability (wheelchair use) and death in a large multicentre cohort, suggesting FVC is both clinically actionable and trial-relevant. (schiava2022genotype–phenotypecorrelationsin pages 3-4)

3) The field is actively moving toward mechanism-informed therapy: - A 2024 study links hyperactive ATPase to earlier onset, arguing for ATPase normalization strategies (often conceptualized as inhibition). (robinson2024elevatedvcpatpase pages 1-3) - Another 2024 study identifies nuclear proteostasis defects and demonstrates that VCP activation can promote nuclear TDP-43 aggregate clearance, supporting a complementary approach. (phan2024vcpactivatorreverses pages 1-2)

Together, these findings imply that “VCP modulation” likely requires variant- and compartment-aware stratification rather than a single-direction intervention.

References

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