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.
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.
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.
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.
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).
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.
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.
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
|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)|
|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)|
|Familiarity for PDB/FTD||No||No||Father with PDB||No||NA|
|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|
|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|
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