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


The VCP gene, on chromosome 9p13-p12, encodes for the valosin-containg protein (VCP/p97), a ubiquitously expressed protein belonging to the AAA+ (ATPases associated with various activities) protein family 1. This protein is involved in several cellular functions as cell cycle regulation, DNA damage response and homotypic membrane assembly. Furthermore, VCP has a crucial role in cellular proteostasis being directly involved in endoplasmatic reticulum-associated degradation of protein (ERAD) 2 and Ubiquitin-proteasome system (UPS) processes 3. Loss of VCP activity leads to the accumulation of ubiquitinated proteins and impaired ERAD 4,5.

Mutations in VCP gene, inherited in an autosomal dominant manner, may result in a multisystem degenerative disorder, affecting muscle, bone and brain as Inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) (MIM 167320) that show variable penetrance of its 3 main entities: the inclusion body myopathy, the Paget’s disease of the bone (PDB) and the fronto-temporal dementia (FTD). Moreover, VCP mutations have also been associated to amyotrophic lateral sclerosis (ALS), distal myopathy, autosomal dominant Charcot-Marie-Tooth disease type 2Y and behavioural impairment and progressive non-fluent aphasia 6. VCP- and TDP-43 positive aggregates have been documented in the cytoplasmic compartment of IBMPFD skeletal muscles, although not specific since they have also been observed in a wide variety of neurodegenerative disorders including Parkinson’s disease, Lewy body disease, Huntington’s disease, amyotrophic lateral sclerosis and spinocerebellar ataxia type III 7.

Patients with VCP mutations, usually present in mid-adulthood with muscle weakness, sometimes associated with respiratory and cardiac muscle impairment, leading to life-threatening breathing difficulties and heart failure 8,6. We here describe clinical, histological and molecular features of a small cohort of Italian patients with VCP mutations and a revision of the available literature.

Materials and methods

This is a retrospective study on 5 VCP-mutated patients (4 males, 1 female) and their follow-up at Fondazione IRCCS Istituto Neurologico Carlo Besta. All patients signed informed consent for publication.

Molecular analysis

Genomic DNA was extracted from the peripheral blood on Freedom Evo 100 (Tecan, Männedorf, Switzerland) by NucleoSpin blood Kit following the manufacturer’s instructions (Macherey–Nagel, Düren, Germany). DNA quality and quantity were analysed by NanoDrop (Thermo Fisher, Foster City, CA, USA), gel electrophoresis, and fluorescence absorbance (Qubit® 2.0 Fluorometer; Thermo Fisher).

We performed a custom target gene panel testing for vacuolar, distal and myofibrillar myopathies by Next Generation Sequencing (NGS) approach, designed with Agilent’s HaloPlex technology (Agilent Technologies Santa Clara, California) loaded on Illumina MiSeq sequencer.

Sanger sequencing using the BigDye Terminator Cycle Sequencing Kit (Applied Biosystems) on an ABI Prism 3100 Genetic Analyzer (Applied Biosystems), was performed to verify and validate the variants.

Muscle biopsy

Skeletal muscle biopsies were available for all patients except patient 3 and were obtained at the Fondazione IRCCS Istituto Neurologico Carlo Besta. Muscle tissues were frozen in liquid nitrogen-cooled isopentane and histological staining was performed on 8μm-thick cryosections.


Immunohistochemical staining on 4% paraformaldehyde fixed sections was carried out using the following antibodies: anti-desmin (1:100 M0760, clone D33 mouse monoclonal DAKO), anti-TDP43 (1:200 10784-2-AP rabbit monoclonal Proteintech), anti-myotilin (1:100 mouse monoclonal Novacastra Leica), anti-p62 (1:100 gp62-c guinea-pig polyclonal; Progen), anti-VCP (1:100 MA3-004 mouse; ThermoScientific). Specific secondary Alexa 488/546/555 antibodies (1: 1500; Invitrogen Life Technology) were used and visualized under a fluorescence microscope (Carl Zeiss AG, Oberkochen, Germany).


Clinical, neurophysiological, histological, imaging and molecular features of included patients are summarized in Table I.

Genetic findings

Among the variants identified by NGS, only those in VCP were already reported in the literature as pathogenic and were correlating with the phenotypes in our patients. No other potential causative variants were found by NGS analysis. No other affected family members were available for segregation while the variants were absent in the healthy relatives tested.

Clinical features

The mean age of disease onset was 46 ± 5.8 years (range 40-54), with 4 patients presenting with lower limb muscle weakness, notably distal for patients 1, 3 and 5 and proximal in patients 2, while patient 4 presented with proximal upper limb muscle weakness. No familiarity for myopathy was reported in patient 2, 4 and 5, while patient 1’s father had a myopathy with rimmed and patient 3 a sister with similar muscular symptoms.

At the last examination at a mean age of 51.6 ± 6.8 (range 59-43) years, the predominant pattern of muscle weakness included distal lower limb muscles in 3/5 patients, and scapular and pelvic muscles in remaining 2 cases. No cranial nerve involvement was observed, except for patient 4 showing mild tongue and orbicularis oculi muscle weakness. Notably, patients 2 and 4 showed Beevor’s sign. Severity of motor dysfunction according to Walton and Gardner & Medwin scale (WGM) 9 was 4 in all patients, except for patient 2 that was unable to walk unassisted (WGM = 8).

Three out of 5 patients (60%) showed increased level of CK (within x 5 upper normal limit).

Heart involvement was reported only in 2/5 (40%) patients, with patient 1 presenting at the age of 61 years with mild atrial dilatation and diastolic dysfunction and patient 3 with hypertensive cardiopathy. Moreover, respiratory involvement requiring non-invasive ventilation (NIV) during night was reported only in patient 2 (20%) since the age of 54 years due to concomitant restrictive and obstructive pulmonary syndrome.

Different types of cancer were present in 3/5 (60%) patients.

Furthermore, patient 1 had also a mild lower limb sensory axonopathy.

No patients showed evidence of FTD or central nervous system involvement and only patient 2 had PDB. Furthermore, no positive family history for FTD or PDB was reported, except for patient 3 whose father was affected by PDB.

All patients underwent electromyography showing always spontaneous activity with fibrillation and/or complex repetitive discharges; a myopathic pattern was found in 4 out of 5 patients, combined to neurogenic finding in 2 cases. An exclusively neurogenic pattern with myopathic signs was observed in patient 5.


The muscle biopsies were performed at a mean age of 49.2 ± 6.38 (42-58) and were undertaken in our centre for all patients but patient 3. Histological analysis showed mild to moderate myopathic changes with fibre degeneration/regeneration and rimmed vacuoles in all patients analysed, without rimmed vacuoles (Fig. 1 a-b).

Immunofluorescence staining with the selected antibodies showed comparable signals for TDP-43 (Fig. 1 c-d) and VCP (Fig. 1 g-h) between patients and control and no desmin and myotilin positive aggregates (Fig.1 c-d/e-f). However, positivity for p62 (Fig. 1 e-f) was present in two muscle biopsies (patient 1 and 2) as also described in the literature (Tab. II).

Muscle imaging

The muscle imaging was performed through CT or MRI scans at calf and thigh levels at a mean age of 49.6 ± 9.4 (43-54) years, revealing fatty replacement, predominantly affecting adductor magnus and vastus intermedius and medialis in the thighs (Fig. 2) and tibialis anterior and medial gastrocnemius in the legs.

Discussion and conclusions

We here present 5 Italian patients affected by VCP-related myopathies. Our patients were characterized by distal lower or upper limb weakness at onset in 3 out of 5 cases, whereas remaining 2 subjects presented with predominant proximal upper or lower limb muscle weakness. Interestingly, the predominant pattern of weakness at onset was further maintained during the follow-up over the years. Two patients showed asymmetric weakness, that is present in VCP-related myopathies 10. We also reported Beevor’s sign in 2 patients, suggestive of selective lower abdominal muscles, never reported before in VCP-related myopathies; Beevor’s sign is usually observed in late-onset Pompe disease and in facio-scapulo-humeral dystrophy 11,12. So far, a genotype-phenotype correlation has only been reported in axonal Charcot-Marie-Tooth disease that has only been associated to the amino acid changes E185H, S171R and G87E mutations as well as spastic paraplegia that has been solely related to R93H and R159C mutations 13. The most common mutations in the VCP gene are found within the N-terminal domain (exons 1-5), as showed in Figure 3. This domain is involved in the binding of the ubiquitin and other co-factors, such as UFD1 (ubiquitin recognition factor in ER associated degradation 1) and NPL4 (ubiquitin recognition factor), which are essential for UPS function. There are two other important domains that bind and hydrolase the ATP, the D1 and D2 domains. These domains are organized as two stacked rings with a central channel, whereas its regulatory N-domain is situated at the periphery of the D1 ring 14. The complexity of VCP’s diverse molecular functions is also expressed by the broad clinical variability caused by pathogenic variants in VCP as shown in Table II revising the literature. The P137L variant described by Palmio et al. 15 in 9 patients, presenting with a distal myopathy phenotype without proximal or scapular weakness, has been also found in 2 of our patients (patient 3 and patient 5) with lower limb distal weakness at onset. However, this variant was previously reported in a patient with initial distal weakness involving the ankle extensors and a progression to both proximal and distal upper limb muscles with marked scapular wings 16. The R93H mutation found in patient 1, exhibiting lower limb and axial muscle weakness, was so far only been associated to Hereditary Spastic Paraplegia 17. One of the VCP hotspots is codon 155, in which three frequent missense mutations are present, R155C, R155H and R155P. According to model predictions, the most deleterious is R155C because it involves major conformational changes in the ATP binding site, even though all three variants cause a structural change affecting the ATP-ADP transition kinetics 18. In fact, R155 interacts with the N387 which is located within the D1 domain that binds and hydrolyses ATP 19. R93 and R155 are both surface-accessible residues located in the centre of cavities that may enable ligand-binding. The R155H variant present in patient 4, with mild increased parietal thicknesses of the left ventricle without cardiomyopathy, has been also reported in a patient with inclusion body myopathy and cardiomyopathy 20. In patient 2 the mutation R155C is associated with Paget’s disease (PDB). Moreover, the examination of the 31 cases reported in the literature and associated to the R155C mutation, reveals that 39% of them are inclusion body myopathy and 3% PDB only, while no patients present exclusively with FTD. Furthermore, 26% of patients show both inclusion body myopathy and PDB, 16% inclusion body myopathy and FTD, none has PDB and FTD, and 16% have inclusion body myopathy with PDB and FTD phenotypes 21.

It is known that VCP is overexpressed in many types of cancers probably due to its involvement in the DNA repair and stability as well as in the autophagy pathway for a proper proteostasis. However, despite 60% of our patients presented with cancer, no direct correlation with mutations in VCP has so far been reported, as also evident from the largest retrospective study published by the VCP International Study Group in 2022 22 analyzing 225 patients with known VCP mutations.

Our patient with Paget’s disease has R155C mutation as other patients reported in the literature by Watts, Al-Obeidi, Figuroa, Guyant, Stojovic 16,21,23-25. In contrast, FTD reported is associated with 6 different mutations (R93H, R155C, R155H, R159C, D395A, R155C), as reported in the Table II.

Among the cases reported in the literature with clinical data, the patients showing respiratory involvement were the 8% (39/503). Amid these, around 30% (11/39) required NIV, as shown in the Table II. Notably, 14 patients died due to respiratory complications. Cardiac involvement was reported in about 20% of the cases (11/503). Our data are substantially in line with these results, suggesting that cardiac involvement and need of NIV are not specific and rare, in particular the former. In addition, about 256 patients underwent muscle biopsies and rimmed vacuoles have been detected in 106 samples (40%). Conversely, all our patients except patient 3, showed rimmed vacuoles at muscle biopsy.

For an in-depth study of the muscle tissue and correlation with the VCP mutations we performed immunofluorescence analysis to evaluate the expressions of p62, TDP-43 along with those of VCP, desmin and myotilin. In fact, desmin and myotilin have demonstrated to be sensitive diagnostic tools to depict pathological protein aggregation in MFM 26, while different studies have reported the presence of aggregates of p62, TDP43 and VCP in patients with mutation in VCP gene. Additionally, Inoue and colleagues 27 showed co-localization of VCP and ubiquitin positive inclusions both in the nucleus and the cytoplasm in 2 patients. Also, Bersano et al. 28 described a IBMPFD patient with the R159C mutation which biopsy was characterized by the presence of some fibres containing aggregates that were positive for VCP, alpha B-crystallin, myotilin or desmin. Finally, VCP and ubiquitin-positive cytoplasmic and nuclear inclusions were described in a patient with R155C mutation 18. Conversely, in our patients, no significant positivity was observed for any of the tested proteins. The immunoassays of our patients were performed on quadriceps muscles, whereas in other works they used different muscles, e.g., Bersano et al. 28 biceps and the gastrocnemi and Hubbers et al. 19 biceps brachii, vastus lateralis, and tibialis anterior. Also, in one of the patients in the work of Bersano et al. no positivity for protein is shown, probably related to the lower severity of the phenotype at the time of biopsy. We could hypothesize that in our patients for the same reason, too, there is no signal in the muscle tissue.

Our report confirms that the R155C, P137L, R155H mutations present in our patients can be associated to a myopathic phenotype without any CNS involvement, as previously reported in the literature 21,15. Indeed, all our patients have a predominant skeletal muscular phenotype. On the other hand, R93H mutation found in patient 1 has only been reported in the literature in association with HSP 17 and not causative of a myopathy.

Further studies are needed to better clarify disease natural history and genotype-phenotype correlations in VCP-related myopathies.


This work was supported/partially supported by the Italian Ministry of Health (RRC).

We would like to thank all the patients and their families.

Lorenzo Maggi is member of the ERN-NMD.

Conflict of interest statement

The Authors declare no conflict of interest.


This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors’ contributions

EI: performed acquisition and analysis of data, revision of the literature and drafting of the manuscript; GR and FB: performed immunohistochemical analysis; SG and AC: acquired and analyzed genetic data; MC and LM: acquired and analyzed clinical data; SG, MC, LM and AR: revised the manuscript.

Ethical consideration

This study was approved by the Ethical Committee at the Fondazione IRCCS Istituto Neurologico C. Besta (project number 108/2020).

Informed consents were obtained from the participant patients.

Figures and tables

Figure 1. TRG staining (a-b) of patient 1. Desmin (green) and TDP-43 (red) double staining in the control tissue (c) and in the representative patient 1 (d); myotilin (green) and p62 (red) immunofluorescence in control (e) and patient 1 (f); VCP (green) staining in control (g) and patient 1’s tissue (h).

Figure 2. Muscle imaging at thigh level from patients 1-4. (a) T1-MRI axial images from patient 3 displayed minimal fatty degeneration in sartorious, semimembranous and semitendinosus muscles. (b) T1-MRI from patient 1 revealed asymmetric fatty changes of adductor magnus (red star), semimembranosus, semitendinosus and long head of biceps femoris on the left side and only initial changes of sartorious on both sides. The patient had a complete fatty replacement of tibialis anterior (data not shown). (c) CT scan from patient 2 demonstrating relevant symmetrical fatty changes mainly in vastus intermedius, medialis and adductor magnus (white arrows), while asymmetric changes are visible in the vastus lateralis, with the left side more involved. Gracilis muscles are involved on both side. (d) CT scan from patient 4, showing fatty changes mainly in vastus intermedius and medialis (white arrows), rectus, and adductor magnus.

Figure 3. Representation of the VCP gene with its domains and the localization of all the reported mutations. Our identified mutations are highlighted in red.

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
Sex/age at onset M/54 M/49 F/46 M/40 M/41
VCP mutations 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)
Symptoms at onset Distal lower limb and axial muscle weakness Proximal lower limb weakness Distal lower limb weakness Proximal upper limb weakness Distal lower limb weakness
Pattern of weakness distribution at last examination (age) Distal > proximal lower limbs > scapular asymmetric, left > right side (59y) Scapular and pelvic girdle > distal plus Beevor’s sign (54y) Distal > proximal lower limbs > scapular asymmetric, left > right side (56y) Scapular and pelvic > distal upper and lower limb plus Beevor’s sign (43y) Peroneal > pelvic and scapular (46y)
Scapular winging No Yes No Yes NA
Walton and Gardner & Medwin at last examination 4 8 4 4 4
Cranial nerve involvement No No No Mild tongue and orbicularis oculi muscle weakness No
Muscle biopsy (age) Mild unspecific changes (53y); moderate myopathic changes with degeneration/regeneration, rimmed vacuoles and inflammatory cells (58y) Moderate myopathic changes with degeneration/regeneration and rimmed vacuoles (53y) Moderate myopathic changes with degeneration and inflammatory cells (48y) Moderate myopathic changes with degeneration/regeneration and rimmed vacuoles (42y) Mild myopathic and neuropathic changes, rimmed vacuoles in 1 fibre (45y)
EMG Myopathic pattern plus SA (plus mild distal sensory axonopathy) Myopathic and neuropathic pattern with SA Myopathic pattern with SA Myopathic and neuropathic pattern with SA Neuropathic pattern with SA
Muscle imaging predominant pattern (age) Asymmetric (R > L) fatty replacement of TA and MG with gadolinium enhancement and asymmetric (L > R) fatty replacement of AM and AL and SM and ST (MRI, 53y) Severe fatty replacement of lumbar paravertebral, VL and VI and moderate of AM et AL (CT, 53y) Fatty replacement of TA (L > R), mild substitution of AM and AL and SM (MRI, 54 years) Severe fatty replacement of lumbar paravertebral, ileopsoas, MG, AM and VI (CT, 43y) Severe fatty replacement of peroneal muscles (CT, 45y)
PDB/FTD -/- +/- -/- -/- -/-
Familiarity for PDB/FTD No No Father with PDB No NA
Fractures Traumatic fractures No No No No
Cardiac involvement Mild atrial dilatation and diastolic dysfunction No Hypertensive cardiopathy No NA
Respiratory involvement No Mixed restrictive/obstructive pattern; NIV during night started at 54y No No NA
CNS involvement No (normal NCT+ brain MRI) No Normal brain MRI. NCT with mild revocation memory and attention-executive dysfunction No No (normal brain MRI)
CK levels (normal range 38-174) 300-1032 U/L 455-536 U/L 214 U/L Normal NA
Death No 55y – unknown reasons No No No
Other simptoms Well-differentiated papillary thyroid cancer Vascular hypertension, Renal cell carcinoma; major depressive disorder; obstructive pulmonary disease Depressive disorder; vascular hypertension; breast cancer Vascular hypertension NA
Table I. Summary of clinical features.
Reference Affected patients Prevalent phenotype Ethnicity Age at onset Rimmed vacuoles at biopsy VCP mutation (protein) Neuroimaging (muscle or brain MRI) or electromyography Immunohistochemistry Cardiac involvement Respiratory involvement Walking ability
Ayaki et al. (2014) 29 1M sporadic ALS Japanese 36 Not reported M158V CT scan showed osteolytic abnormalities and no brain atrophy. EMG: active and chronic denervation potentials Not reported Not reported NIV dependent at 38 years old, died of respiratory failure at the age of 41 Not reported
Al-Obeidi et al. (2018) 21 231 (118M, 113F) IBM, PDB, FTD, ALS and Parkinson’s disease. European, Brazilian, Hispanic/Apache, and African-American Myopathy (43) PDB (41.2) FTD (55.9) Muscle biopsy reports available for 115 of the symptomatic individuals. 46 (40%) out of 115 muscle biopsies showed rimmed vacuoles R155H R155C R155P R191Q R159C R159H L198W R95G R93C A232E N387H G97E A160P G128A M158I 138 myopathic individuals underwent EMG studies: 45/138 (32,6%) had pure myopathic changes, 16/138 (11,6%) had neurogenic alteration and 19/138 (13,7%) both Not reported Not reported Not reported Independent
Bersano et al. (2007) 28 1M IBM+FTD Italian 50 Yes R159C EMG: acute denervation in all examined muscles VCP-positive aggregates, alpha B-crystallin, myotilin, desmin Not reported Not reported Not reported
Bruno et al. (2021) 30 3 (1M,2F) Early onset FTD Italian 40 Not reported D395A Brain MRI suggestive of FTD Not reported Not reported Not reported Not reported
de Bot et al. (2012) 31 2 M Slowly progressive spastic paraplegia and PDB Dutch 55.5 Not reported R159C EMG: signs of active denervation, no myopathic changes, no neuropathy Not reported Not reported Not reported Not reported
DeJesus-Hernandez et al. (2011) 32 1 F Sporadic ALS African American 68 Not reported I151V EMG examination showed acute and chronic denervation Not reported hypertension NIV 19 months after onset of motor symptoms Not reported
Figueroa-Bonaparte et al. (2015) 24 42 (23M, 19F) 92.3% muscle weakness: 27% scapular/pelvic, 21.6% proximal UL, 13.5% proximal LL, 24.2 % both distal/proximal UL and/or LL. PDB first symptom (one case) English 42.05 9/17 (53%) biopsies revealed rimmed vacuoles G202W A439G R155H R191Q R155C R93C Not reported Not reported Not reported Not reported The mean time to loss of ambulation was 13.37 ± 6.6 years
Gang et al. (2016) 33 3 (2M, 1F) sIBM Not reported 69 Not reported I27V R159C Not reported Not reported Not reported Not reported Not reported
Gidaro et al. (2007) 34 2 (1M, 1F) Progressive myopathy Italian 42.5 Yes R155C Muscle MRI of the LL showed focal areas of fatty replacement of the gastrocnemius, quadriceps, and biceps femoris Not reported Subjects II-1 and II-2 died of a myocardial failure Not reported Independent, but waddling gait
Gu et al. (2013) 35 5 (3M, 2F) IBMFD Chinese 57.4 Not reported G97E Normal brain MRI Not reported Not reported Not reported Walking difficulty
Guyant-Maréchal et al. (2006) 25 2 families FTD in 100% (family 1), 70% (family 2). PDB more inconstant clinical feature Northern-European 56.5 Subsarcolemmal rimmed vacuoles in II-5 and II-8 R93C R155C Patients II-4, III-1 present myopathic alteration at EMG Not reported Not reported Respiratory distress (mean duration of 15 years, range 11 to 18 years). Death in 3 patients Not reported
Haubenberger et al. (2005) 36 4 (1M, 3F) Progressive proximal myopathy and PDB without dementia Austrian 48.5 Rimmed vacuoles only in patient 4 R159H Patient 2 EMG showed myopathic alterations Not reported Not reported Not reported Patients 1 and 4 lost ambulation
Hirano et al. (2015) 37 1 Sporadic ALS, with later dementia Japanese 65 Not reported R487H Marked atrophy of the frontal and temporal lobes by brain MRI Not reported Not reported Not reported Not reported
Hübbers et al. (2007) 19 3 IBMPFD Not reported 51.3 Yes R93C R155C R155H Frontal and temporal atrophy in brain MRI of patient II VCP and ubiquitin-positive aggregates Marked left ventricular dilatation and thickening of the left ventricular wall in patient II Not reported Not reported
Ikeda et al. (2020) 38 1M IBMPFD Japanese 42 Yes R155C Cerebral MRI revealed bilateral frontal and temporal atrophy Not reported Not reported Progressive respiratory involvement Walker at 52, wheelchair at 55 years
Ikenaga et al. (2020) 20 59 (28M, 31F) 53 IBM, 17 PDB, 8 patients with dementia, 6 with peripheral neuropathy, 4 with cardiomyopathy, 4 with cataracts, 2 with ALS, and 1 with parkinsonism American English Australian Canadian Netherlands German New Zealander Brazilian Thai 43.4 Not reported R155H R155C R159C R93C R159 R191Q G125D Not reported Not reported Cardiomyopathy (R155H, R191Q) 20 patients had orthopnea, 7 patients used assisted ventilation or oxygen supplementation Walking aid (n = 14), cane (n = 9), walker (n = 11), wheelchair (n = 5)
Inoue et al. (2017) 27 2M 1 patient with ALS, and 1 with parkinsonism Japanese 65 Yes V87F I126V EMG showed myopathic change VCP and ubiquitin-positive aggregates In patient 1 MIBG myocardial scintigraphy revealed reduced uptake Patient 2 respiratory failure at age 65 years, death at age 66 Independent
Jacquin et al. (2013) 39 1M IBMPFD French 41 Yes R155H Spontaneous activity and both myopathic or neurogenic at EMG. Frontal and internal temporal atrophy at brain MRI Not reported Not reported Not reported Wheelchair dependent
Jerath (2019) 40 3F The proband present proximal LL and distal UL weakness Caucasian 40 Not reported R155H Not reported Not reported Mildly abnormal cardiac stress test with mild ischemia of the anterior cardiac wall Not reported Independent
Kaleem et al. (2007) 41 3 LOAD Caucasian Not reported Not reported R92H Not reported Not reported Not reported Not reported Not reported
Koppers et al. (2012) 42 2F ALS Not reported 55.5 Not reported R159H I114V Not reported Not reported Not reported Not reported Patient B: unable to walk
Kumar et al. (2010) 43 6 (3M,3F) 1 myopathy 4 myopathy + PDB 1 IBMPFD Australian 37 2 patients’ muscle biopsies showed rimmed vacuoles R155C L198W EMG in 4 patients showed a myopathic pattern TDP-43 Not reported Not reported Progressive difficulty getting out of chairs and walking up and down stairs
Lévensque et al. (2016) 44 1 IBM Not reported 60 Not reported L386Q Not reported Not reported Not reported Not reported Not reported
Nakamura et al. (2021) 45 1F HSP with PDB Japanese 36 Not reported R155C Brain MRI was normal Not reported Not reported Not reported Independent
Neveling et al. (2013) 17 1 HSP Not reported Not reported Not reported R93H Not reported Not reported Not reported Not reported Not reported
Palmio et al. (2011) 15 9 (6M, 3F) 3 patients with distal myopathy and rapidly progressive dementia Finnish 46 3 patients’ muscle biopsies showed rimmed vacuolar myopathy P137L Abnormal findings in anterior LL muscles from subtle to severe replacement by fatty connective tissue in all others TDP-43 and p62 inclusions in rimmed vacuoles, granular cytoplasmic VCP in most fibres Not reported Not reported Walk with a stick until the age of 50
Papadimas et al. (2017) 46 4 (3M, 1F) LL myopathy and FTD(II-1), dementia(I-2) classical ALS (II-2), behavioural symptoms (II-3) Greek 62 Not reported R159H Brain MRI revealed frontal lobe atrophy. EMG showed diffuse myopathic changes and mild spontaneous activity. Muscle MRI showed extended atrophy and fatty degeneration Not reported Not reported Not reported Need of support
Pellerin et al. (2020) 47 3 (1M,2F) Initial proximal and distal LL weakness with loss of ambulation, 12 years later distal UL weakness, later proximal arm and neck extension weakness French Canadian 33.5 Biopsy of subjetc.2 revealed myopathic changes and scattered rimmed vacuoles G156S Brain MRI showed atrophy of the frontal and temporal lobes, slightly more significant over the left temporal lobe TDP-43 immunoreactive cytoplasmic deposits, and numerous COX-reduced fibres Not reported Subject II.2 present orthopnea, Subjects II.1 and II.3 died of aspiration pneumonia Subjects II.1 and II.3 became wheelchair-bound
Rohrer et al. (2011) 48 2 (1F, 1M) Male patient: deterioration in episodic memory and progressive behavioural disturbance later developing muscle weakness and tremor. Female patient: progressive speech disturbance Japanese 63.5 Not reported I27V Male patient brain MRI showed marked symmetrical cerebral atrophy involving the frontal and parietal lobes. Female MRI was normal Not reported Not reported Not reported Not reported
Shi et al. (2008) 49 2F FTD and AD Chinese 60.5 Not reported T127A N401S Brain MRI showed left temporal lobe atrophy at 58 years old, MRI at 62 years of age showed bilateral frontal and temporal lobe atrophy Not reported Not reported Not reported Not reported
Stojkovic et al. (2009) 16 19 (11M 8F) Early involvement of the proximal UL with scapular winging. Axial and LL muscles often affected. PDB observed in 8 and cognitive impairment in 9 patients French and Spanish 42 Yes P137L R155C R155S R155H A439S R159H G157R R191Q Muscle MRI showing fatty degeneration of VL, VM, RF and gluteus. At the scapular level, fatty degeneration is observed on supraspinatus, infraspinatus and deltoid. EMG: acute denervation either a myopathic pattern or a mixed myogenic/neurogenic pattern Not reported Not reported Two patients required NIV and 7 died as a consequence of weakness and respiratory distress 10 patients wheelchair bound after a mean disease course of 9 years and 6 required canes for walking
van der Zee et al. (2009) 50 2 families FTLD, PDB Belgian 54 (FTLD) 46 (PDB) Not reported R159H By brain MRI corticosubcortical and cerebellar atrophy (P5), periventricular leukoencephalopathy (P2) Not reported Not reported Not reported Not reported
Viassolo et al. (2008) 51 4 IBMPFD Italian 49 Rimmed vacuolar inclusion bodies in 3 biopsies R155H EMG of 2/4 patients: signs of diffuse acute and chronic denervation Not reported Not reported Not reported Independent
Watts et al. (2004) 23 13 families 82% patients with myopathy, 49% PDB and 30% early-onset FTD 12 from the United States and 1 from Canada 42 Yes R155H R155P R155C A232E R95G R191Q Not reported Not reported Not reported Not reported Not reported
Watts et al. (2007) 52 6 IBMPFD Poland and American 40 4 patients showed rimmed vacuoles N387H L198W EMG: Myopathic (3 patients), Mixed myopathic-neurogenic (1 patient) Not reported Cases 6 and 7 died of cardiac failure Case 6 died from respiratory failure Losing the ability to walk within a few years of onset
Weihl et al. (2015) 53 2 IBMPFD and Parkinson’s Disease Not reported > 45 2 patients showed rimmed vacuoles I27V R95C EMG: Myopathic (2 patients) Not reported Not reported Not reported Not reported
Table II. Reported clinical features.


  1. Halawani D, Latterich M. p97: The cell’s molecular purgatory?. Mol Cell. 2006;22:713-717. doi:https://doi.org/10.1016/j.molcel.2006.06.003
  2. Rabinovich E, Kerem A, Frohlich K. Bar-Nun AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Mol Cell Biol. 2002;22:626-634.
  3. Meyer H, Weihl C. The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis. J Cell Sci. 2014;127:3877-3883. doi:https://doi.org/10.1242/jcs.093831
  4. Dalal H, Evans P, Campbell J. Recent developments in secondary prevention and cardiac rehabilitation after acute myocardial infarction. Erratum in BMJ 2004;328:926. BMJ. 2004;328:693-697. doi:https://doi.org/10.1136/bmj.328.7441.693
  5. Wójcik C, DeMartino G. Intracellular localization of proteasomes. Int J Biochem Cell Biol. 2003;35:579-589. doi:https://doi.org/10.1016/s1357-2725(02)00380-1
  6. Nalbandian A, Donkervoort S, Dec E. The multiple faces of valosin-containing protein-associated diseases: inclusion body myopathy with Paget’s disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis. J Mol Neurosci. 2011;45:522-531.
  7. Harley J, Hagemann C, Serio A, Patani R. TDP-43 and FUS mislocalization in VCP mutant motor neurons is reversed by pharmacological inhibition of the VCP D2 ATPase domain. Brain Commun. 2021;3. doi:https://doi.org/10.1093/braincomms/fcab166
  8. Mehta S, Khare M, Ramani R. Genotype-phenotype studies of VCP-associated inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia. Clin Genet. 2013;83:422-431.
  9. Angelini C, Semplicini C, Ravaglia S. New motor outcome function measures in evaluation of late-onset Pompe disease before and after enzyme replacement therapy. Muscle Nerve. 2012;45:831-834. doi:https://doi.org/10.1002/mus.23340
  10. Matsubara S, Shimizu T, Komori T. Nuclear inclusions mimicking poly(A)-binding protein nuclear 1 inclusions in a case of inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia with a novel mutation in the valosin-containing protein gene. Neuromuscul Disord. 2016;26:436-440. doi:https://doi.org/10.1016/j.nmd.2016.05.001
  11. Eger K, Jordan B, Habermann S. Beevor’s sign in facioscapulohumeral muscular dystrophy: an old sign with new implications. J Neurol. 2010;257:436-438. doi:https://doi.org/10.1007/s00415-009-5342-9
  12. Garibaldi M, Diaz-Manera J, Gallardo E. Teaching video neuroimages: the beevor sign in late-onset pompe disease. Neurology. 2016;86:e250-e251. doi:https://doi.org/10.1212/WNL.0000000000002772
  13. Posey J, Harel T, Liu P. Resolution of disease phenotypes resulting from multilocus genomic variation. N Engl J Med. 2017;376:21-31. doi:https://doi.org/10.1056/NEJMoa1516767
  14. DeLaBarre B, Brunger A. Complete structure of p97/valosin-containing protein reveals communication between nucleotide domains. Nat Struct Biol. 2003;10:856-863. doi:https://doi.org/10.1038/nsb972
  15. Palmio J, Sandell S, Suominen T. Distinct distal myopathy phenotype caused by VCP gene mutation in a Finnish family. Neuromuscul Disord. 2011;21:551-555. doi:https://doi.org/10.1016/j.nmd.2011.05.008
  16. Stojkovic T, Hammouda el H, Richard P. Clinical outcome in 19 French and Spanish patients with valosin-containing protein myopathy associated with Paget’s disease of bone and frontotemporal dementia. Erratum in Neuromuscul Disord 2011;21:e1. Gonzalez, Pilar Camaño [corrected to Camaño, Pilar]. Neuromuscul Disord. 2009;19:316-323. doi:https://doi.org/10.1016/j.nmd.2009.02.012
  17. Neveling K, Feenstra I, Gilissen C. A post-hoc comparison of the utility of sanger sequencing and exome sequencing for the diagnosis of heterogeneous diseases. Hum Mutat. 2013;34:1721-1726. doi:https://doi.org/10.1002/humu.22450
  18. Wu R, Wei Z, Zhang L. Structural insight into mutations at 155 position of valosin containing protein (VCP) linked to inclusion body myopathy with Paget disease of bone and frontotemporal Dementia. Saudi J Biol Sci. 2021;28:2128-2138. doi:https://doi.org/10.1016/j.sjbs.2021.02.048
  19. Hübbers C, Clemen C, Kesper K. Pathological consequences of VCP mutations on human striated muscle. Brain. 2007;130:381-393. doi:https://doi.org/10.1093/brain/awl238
  20. Ikenaga C, Findlay A, Seiffert M. Phenotypic diversity in an international Cure VCP Disease registry. Orphanet J Rare Dis. 2020;15. doi:https://doi.org/10.1186/s13023-020-01551-0
  21. Al-Obeidi E, Al-Tahan S, Surampalli A. Genotype-phenotype study in patients with valosin-containing protein mutations associated with multisystem proteinopathy. Clin Genet. 2018;93:119-125. doi:https://doi.org/10.1111/cge.13095
  22. Schiava M, Ikenaga C, Villar-Quiles R. Genotype-phenotype correlations in valosin-containing protein disease: a retrospective muticentre study [published online ahead of print, 2022 Jul 27]. J Neurol Neurosurg Psychiatry. Published online 2022. doi:https://doi.org/10.1136/jnnp-2022-328921
  23. Watts G, Wymer J, Kovach M. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet. 2004;36:377-381. doi:https://doi.org/10.1038/ng1332
  24. Figueroa-Bonaparte S, Hudson J, Barresi R. Mutational spectrum and phenotypic variability of VCP-related neurological disease in the UK. J Neurol Neurosurg Psychiatry. 2016;87:680-681. doi:https://doi.org/10.1136/jnnp-2015-310362
  25. Guyant-Maréchal L, Laquerrière A, Duyckaerts C. Valosin-containing protein gene mutations: clinical and neuropathologic features. Neurology. 2006;67:644-651. doi:https://doi.org/10.1212/01.wnl.0000225184.14578.d3
  26. Schröder R, Schoser B. Myofibrillar myopathies: a clinical and myopathological guide. Brain Pathol. 2009;19:483-492. doi:https://doi.org/10.1111/j.1750-3639.2009.00289.x
  27. Inoue M, Iida A, Hayashi S. Two novel VCP missense variants identified in Japanese patients with multisystem proteinopathy. Hum Genome Var. 2018;5. doi:https://doi.org/10.1038/s41439-018-0009-7
  28. Bersano A, Del Bo R, Lamperti C. Inclusion body myopathy and frontotemporal dementia caused by a novel VCP mutation. Neurobiol Aging. 2009;30:752-758. doi:https://doi.org/10.1016/j.neurobiolaging.2007.08.009
  29. Ayaki T, Ito H, Fukushima H. Immunoreactivity of valosin-containing protein in sporadic amyotrophic lateral sclerosis and in a case of its novel mutant. Acta Neuropathol Commun. 2014;2. doi:https://doi.org/10.1186/s40478-014-0172-0
  30. Bruno F, Conidi M, Puccio G. A Novel Mutation (D395A) in valosin-containing protein gene is associated with early onset frontotemporal dementia in an Italian family. Front Genet. 2021;12. doi:https://doi.org/10.3389/fgene.2021.795029
  31. de Bot S, Schelhaas H, Kamsteeg E, van de Warrenburg B. Hereditary spastic paraplegia caused by a mutation in the VCP gene. Brain. 2012;135:e223-e224. doi:https://doi.org/10.1093/brain/aws201
  32. DeJesus-Hernandez M, Desaro P, Johnston A. Novel p.Ile151Val mutation in VCP in a patient of African American descent with sporadic ALS. Neurology. 2011;77:1102-1103. doi:https://doi.org/10.1212/WNL.0b013e31822e563c
  33. Gang Q, Bettencourt C, Machado P. Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis. Neurobiol Aging. 2016;47:218.e1-218.e9. doi:https://doi.org/10.1016/j.neurobiolaging.2016.07.024
  34. Gidaro T, Modoni A, Sabatelli M. An Italian family with inclusion-body myopathy and frontotemporal dementia due to mutation in the VCP gene. Muscle Nerve. 2008;37:111-114. doi:https://doi.org/10.1002/mus.20890
  35. Gu J, Ke Y, Yue H. A novel VCP mutation as the cause of atypical IBMPFD in a Chinese family. Bone. 2013;52:9-16. doi:https://doi.org/10.1016/j.bone.2012.09.012
  36. Haubenberger D, Bittner R, Rauch-Shorny S. Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene. Neurology. 2005;65:1304-1305. doi:https://doi.org/10.1212/01.wnl.0000180407.15369.92
  37. Hirano M, Nakamura Y, Saigoh K. VCP gene analyses in Japanese patients with sporadic amyotrophic lateral sclerosis identify a new mutation. Neurobiol Aging. 2015;36(3):1604.e1-1604.e16046. doi:https://doi.org/10.1016/j.neurobiolaging.2014.10.012
  38. Ikeda M, Kuwabara T, Takai E. Increased Neurofilament Light Chain and YKL-40 CSF Levels in One Japanese IBMPFD Patient With VCP R155C Mutation: A Clinical Case Report With CSF Biomarker Analyses. Front Neurol. 2020;11. doi:https://doi.org/10.3389/fneur.2020.00757
  39. Jacquin A, Rouaud O, Soichot P. Psychiatric presentation of frontotemporal dementia associated with inclusion body myopathy due to the VCP mutation (R155H) in a French family. Case Rep Neurol. 2013;5:187-194. doi:https://doi.org/10.1159/000356481
  40. Jerath N. Resolving a Multi-Generational neuromuscular mystery in a family presenting with a Variable Scapuloperoneal Syndrome in a c.464G > A, p.Arg155His VCP Mutation. Case Rep Genet. 2019;2019. doi:https://doi.org/10.1155/2019/2403024
  41. Kaleem M, Zhao A, Hamshere M, Myers A. Identification of a novel valosin-containing protein polymorphism in late-onset Alzheimer’s disease. Neurodegener Dis. 2007;4:376-381. doi:https://doi.org/10.1159/000105158
  42. Koppers M, van Blitterswijk M, Vlam L. VCP mutations in familial and sporadic amyotrophic lateral sclerosis. Neurobiol Aging. 2012;33:837.e7-13. doi:https://doi.org/10.1016/j.neurobiolaging.2011.10.006
  43. Kumar K, Needham M, Mina K. Two Australian families with inclusion-body myopathy, Paget’s disease of bone and frontotemporal dementia: novel clinical and genetic findings. Neuromuscul Disord. 2010;20:330-334. doi:https://doi.org/10.1016/j.nmd.2010.03.002
  44. Lévesque S, Auray-Blais C, Gravel E. Diagnosis of late-onset Pompe disease and other muscle disorders by next-generation sequencing. Orphanet J Rare Dis. 2016;11. doi:https://doi.org/10.1186/s13023-016-0390-6
  45. Nakamura T, Kawarabayashi T, Koh K. Spastic Paraplegia with Paget’s Disease of Bone due to a VCP Gene Mutation. Intern Med. 2021;60:141-144. doi:https://doi.org/10.2169/internalmedicine.4617-20
  46. Papadimas G, Paraskevas G, Zambelis T. The multifaceted clinical presentation of VCP-proteinopathy in a Greek family. Acta Myol. 2017;36:203-206.
  47. Pellerin D, Ellezam B, Korathanakhun P. Multisystem Proteinopathy Associated with a VCP G156S Mutation in a French Canadian Family. Can J Neurol Sci. 2020;47:412-415. doi:https://doi.org/10.1017/cjn.2020.25
  48. Rohrer J, Warren J, Reiman D. A novel exon 2 I27V VCP variant is associated with dissimilar clinical syndromes. J Neurol. 2011;258:1494-1496. doi:https://doi.org/10.1007/s00415-011-5966-4
  49. Shi Z, Liu S, Xiang L. Frontotemporal dementia-related gene mutations in clinical dementia patients from a Chinese population. J Hum Genet. 2016;61:1003-1008. doi:https://doi.org/10.1038/jhg.2016.92
  50. van der Zee J, Pirici D, Van Langenhove T. Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His. Neurology. 2009;73:626-632. doi:https://doi.org/10.1212/WNL.0b013e3181b389d9
  51. Viassolo V, Previtali S, Schiatti E. Inclusion body myopathy, Paget’s disease of the bone and frontotemporal dementia: recurrence of the VCP R155H mutation in an Italian family and implications for genetic counselling. Clin Genet. 2008;74:54-60. doi:https://doi.org/10.1111/j.1399-0004.2008.00984.x
  52. Watts G, Thomasova D, Ramdeen S. Novel VCP mutations in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia. Clin Genet. 2007;72:420-426. doi:https://doi.org/10.1111/j.1399-0004.2007.00887.x
  53. Weihl C, Baloh R, Lee Y. Targeted sequencing and identification of genetic variants in sporadic inclusion body myositis. Neuromuscul Disord. 2015;25:289-296. doi:https://doi.org/10.1016/j.nmd.2014.12.009



Eliana Iannibelli* - Department of Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; * These authors contributed equally to the study

Sara Gibertini* - Department of Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; *These authors contributed equally to the study

Marta Cheli - Department of Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Flavia Blasevich - Department of Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Andrea Cavaliere - Department of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Giorgia Riolo - Department of Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Alessandra Ruggieri - Department of Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Lorenzo Maggi - Department of Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

How to Cite
Iannibelli*, E., Gibertini*, S., Cheli, M., Blasevich, F., Cavaliere, A., Riolo, G., Ruggieri, A., & Maggi, L. (2022). VCP-related myopathy: a case series and a review of literature. Acta Myologica, 42(1). https://doi.org/10.36185/2532-1900-244
  • Abstract viewed - 872 times
  • PDF downloaded - 377 times