Journal article
Muscle Biopsy Findings in Valosin-Containing Protein Multisystem Proteinopathy
Neurology Genetics, Vol.11(4), e200265
08/2025
DOI: 10.1212/NXG.0000000000200265
PMCID: PMC12270496
PMID: 40678441
Abstract
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 in biopsy findings among the 4 most common VCP gene variants, except for the absence of degeneration niches in muscle biopsies of 12 patients with c.277C>T (p.Arg93Cys). MRI data from 30 patients showed fat pockets corresponding to these niches and STIR hyperintensity correlated with inflammatory infiltrates in 42.9%. Concordance between clinical phenotype, biopsy, and neurophysiology was observed in only 49.4% of cases, indicating significant heterogeneity. Discussion 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. Some lack vacuoles, challenging diagnosis. Discrepancies between clinical, neurophysiology, and biopsy findings should prompt consideration of VCP-MSP to improve detection and management.
Details
- Title: Subtitle
- Muscle Biopsy Findings in Valosin-Containing Protein Multisystem Proteinopathy
- Creators
- Marianela Schiava - Newcastle UniversityYolande ParkhurstMatthew HendersonTuomo Polvikoski - Newcastle UniversityManouela V ValtchevaIchizo Nishino - National Center of Neurology and PsychiatryMichio Inoue - National Center of Neurology and PsychiatryYukako Nishimori - National Center of Neurology and PsychiatryYoshihiko Saito - National Center of Neurology and PsychiatryTanya Stojkovic - Sorbonne UniversitéRocío N Villar-quilesNorma Beatriz RomeroTeresinha Evangelista - Institut de MyologieEdoardo Malfatti - InsermSarah Souvannanorath - InsermElena Pegoraro - University of PaduaPietro Riguzzi - University of PaduaMauro Monforte - Agostino Gemelli University PolyclinicSara Bortolani - Agostino Gemelli University PolyclinicEleonora Torchia - Agostino Gemelli University PolyclinicMario Sabatelli - Agostino Gemelli University PolyclinicGiorgio Tasca - Newcastle UniversityVolker Straub - Newcastle UniversityChiara Marini-bettolo - Newcastle UniversityMichela Guglieri - Newcastle UniversityHakan Cetin - Medical University of ViennaEllen Gelpi - Medical University of ViennaSigrid Klotz - Medical University of ViennaJan L De BleeckerAlicia Alonso-jimenez - Antwerp University HospitalJonathan Baets - University of AntwerpWillem De Ridder - Antwerp University HospitalPeter De Jonghe - Antwerp University HospitalKristl G ClaeysDietmar Rudolf ThalJorge A BevilacquaSushan Luo - Huashan HospitalWenhua Zhu - Huashan HospitalJie Lin - Huashan HospitalGeorge Papadimas - Eginition HospitalConstantinos Papadopoulos - Eginition HospitalEleni Zamba-papanicolaou - Eginition HospitalSophia Xirou - National and Kapodistrian University of AthensEndre Pal - University of PecsCarmelo Rodolico - University of MessinaAnna Kostera-pruszczyk - Medical University of WarsawBiruta Kierdaszuk - Medical University of WarsawAnna Kaminska - Medical University of WarsawNuria Muelas - Hospital Universitari i Politècnic La FeJuan Jesus VilchezCristina Domínguez-gonzález - Centro de Investigación Biomédica en RedAurelio Hernandez-lain - Hospital Universitario del VinalopóJorge Alonso-perez - Hospital Universitario Nuestra Señora de CandelariaVelina Nedkova-hristova - Bellvitge University HospitalCarlos Aledo - Hospital Universitario del VinalopóAnders Oldfors - University of GothenburgUmesh A BadrisingHani Kushlaf - University of CincinnatiThomas E LloydChiseko Ikenaga - Johns Hopkins MedicineLindsay N AlfanoColin C QuinnDavid Walk - University of MinnesotaMatthias Vorgerd - BG University Hospital Bergmannsheil BochumConrad Weihl - Washington University in St. LouisMontse Olivé - Hospital de Sant PauJordi Diaz-manera - Newcastle UniversityAdolfo López De MunainAlba Ramos-fransiAleksandra Nadaj-paklezaAlicia Martinez-piñeiroAna TöpfAnna MayhewAnna RydeliusAnthony BehinAntonio ToscanoBeatrice LannesBeatriz VelezBenedikt SchoserBjarne UddBoel De PaepeBruno EymardCarla Marco CazcarraCarmen ParadasCarola Hedberg-oldforsChanna HewamaddumaCheryl LongmanChristopher NanceCorinne MetayDavid Hilton-jonesEdmar ZanotelliElizabeth A HarringtonEllen ElineEloy RivasFrancesc Miralles MorellGergious ManousakisGianni SorarùGiulia BisogniGiuseppe LucenteGuillaume BassezVCP International Study Group
- Resource Type
- Journal article
- Publication Details
- Neurology Genetics, Vol.11(4), e200265
- DOI
- 10.1212/NXG.0000000000200265
- PMID
- 40678441
- PMCID
- PMC12270496
- NLM abbreviation
- Neurol Genet
- ISSN
- 2376-7839
- eISSN
- 2376-7839
- Publisher
- Ovid Technologies (Wolters Kluwer Health); PHILADELPHIA
- Grant note
- National Institute for Health and Care Research (NIHR)NIHR Newcastle Biomedical Research Centre
The authors extend their gratitude to all the families; clinicians from the VCP International Multicenter Study Group; and the nurses, geneticists, pathologists, and physiotherapists who actively collaborated in the data collection process. The authors are especially grateful to Dr. Gianmarco Severa, MD (APHP Hopital Henri Mondor, France), for his contributions to the collection of muscle biopsy data. The NIHR Newcastle BRC is a partnership between Newcastle Hospitals NHS Foundation Trust, Newcastle University and Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust funded by the National Institute for Health and Care Research (NIHR). This work has been supported by the NIHR Newcastle Biomedical Research Centre, and the authors are grateful for that. The views expressed are those of the author(s) and not necessarily those of the NIHR or Department of Health and Social Care.
- Language
- English
- Electronic publication date
- 07/16/2025
- Date published
- 08/2025
- Academic Unit
- Neurology
- Record Identifier
- 9984961011702771
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