Muscle Biopsy Findings in Valosin-Containing Protein Multisystem Proteinopathy

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.

Figure 1. Frequency of Findings on Muscle Biopsies of Patients With VCP-MSP Disease

(A) Frequency of general patterns identified in muscle biopsies of the study. (B) Frequency of histologic abnormalities observed in the muscle biopsies included.

Figure 2. Examples of Histologic Findings Observed in Muscle Biopsies of Patients With VCP-MSP Disease

(A) Hematoxylin and eosin staining showing angulated atrophic fibers, rounded fibers, and prominent variability in fiber size. (B and C) Rimmed vacuoles identified on hematoxylin and eosin staining (B) and trichrome Gomori staining (C). (D) Hematoxylin and eosin staining showing a necrotic fiber undergoing phagocytosis. The necrotic fiber is in the center; it has lost its normal polygonal shape and appears eosinophilic (pink) because of protein denaturation. Individual nuclei are not identifiable because they may have disappeared or fragmented. Numerous macrophages, appearing as cells with foamy cytoplasm and dark nuclei, surround and invade the necrotic fiber. (E) Hematoxylin and eosin staining showing a muscle fiber with protein aggregates seen as eosinophilic inclusions in the sarcoplasm. These protein aggregates stained positive for the following proteins on immunohistochemistry: desmin (F), myotilin (G), VCP (H), and p62 (I). (J) TDP-43 aggregates in the sarcoplasm of a muscle fiber identified on immunohistochemistry. (K) Amyloid structures identified with Congo red staining. (L) Ubiquitin-positive inclusions and (M) AB-crystallin–positive protein aggregates identified on immunohistochemistry. Calibration bar: 20 × 50 μm for images A and B and 40 × 20 μm for the rest.

Figure 3. Examples of Degenerative Niches Identified in Muscle Biopsies of Patients With VCP-MSP Myopathy

(A, B, and C) Three examples of degenerative niches (arrows) characterized by areas of the muscle containing atrophic fibers embedded in fibrotic and fat tissue closely located to areas of the muscle with clearly lower involvement (asterisks). Calibration bar: 10 × 100 μm.

Figure 4. Natural History of Pathologic Progression in Muscle Biopsies of Patients With VCP-MSP Myopathy

(A) Example of a very mild case where only few atrophic scattered fibers (asterisk) were identified. VCP (A′) and p62 (A″) inclusions were identified in isolated fibers. (B) Mild case showing a group of small atrophic fibers (circle) with p62 inclusions (B′). (C) More advanced case displaying several groups of atrophic fibers closely located (arrow) and vacuolated fibers (asterisk). (D) Degenerative foci containing atrophic fibers staining positive for caveolin (D′) embedded in expanded fibrotic tissue surrounded by an area of normal muscle. (E) More advanced case with a large degenerative foci. (F) Hematoxylin and eosin staining at low resolution where 2 degenerative niches were identified (G and H) with several fibres containing p62-positive inclusions (G′ and H′) while the rest of muscle biopsy was almost nonaffected. (I) Severe case where the muscle biopsy was almost completely replaced by fat and fibrotic tissue (J), except an area (square) showing milder anomalies (K). (L) End-stage case where muscle architecture was lost, and extremely atrophic fibers were observed staining positive for embryonic myosin heavy chain (L′) embedded in expanded fibrotic tissue.

Figure 5. Correlations Between Muscle Findings, Phenotype, and EMG Changes

(A) Frequency of general muscle biopsy patterns in patients with VCP-MSP with 4 different phenotypes. (B) Level of agreement between the phenotypic description, EMG, and muscle biopsy results. MND = motor neuron disease; n = number of patients.