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Neuromuscular Disorders : NMD May 2009Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM) associated with Paget's disease of the bone (PDB) and fronto-temporal dementia (FTD) or... (Review)
Review
Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM) associated with Paget's disease of the bone (PDB) and fronto-temporal dementia (FTD) or IBMPFD. Although IBMPFD is a multisystem disorder, muscle weakness is the presenting symptom in greater than half of patients and an isolated symptom in 30%. Patients with the full spectrum of the disease make up only 12% of those affected; therefore it is important to consider and recognize IBMPFD in a neuromuscular clinic. The current review describes the skeletal muscle phenotype and common muscle histochemical features in IBMPFD. In addition to myopathic features; vacuolar changes and tubulofilamentous inclusions are found in a subset of patients. The most consistent findings are VCP, ubiquitin and TAR DNA-binding protein 43 (TDP-43) positive inclusions. VCP is a ubiquitously expressed multifunctional protein that is a member of the AAA+ (ATPase associated with various activities) protein family. It has been implicated in multiple cellular functions ranging from organelle biogenesis to protein degradation. Although the role of VCP in skeletal muscle is currently unknown, it is clear that VCP mutations lead to the accumulation of ubiquitinated inclusions and protein aggregates in patient tissue, transgenic animals and in vitro systems. We suggest that IBMPFD is novel type of protein surplus myopathy. Instead of accumulating a poorly degraded and aggregated mutant protein as seen in some myofibrillar and nemaline myopathies, VCP mutations disrupt its normal role in protein homeostasis resulting in the accumulation of ubiquitinated and aggregated proteins that are deleterious to skeletal muscle.
Topics: Adenosine Triphosphatases; Cell Cycle Proteins; DNA-Binding Proteins; Dementia; Humans; Muscle Fibers, Skeletal; Mutation; Myositis, Inclusion Body; Osteitis Deformans; Phenotype; Syndrome; Ubiquitin; Valosin Containing Protein
PubMed: 19380227
DOI: 10.1016/j.nmd.2009.01.009 -
Brazilian Journal of Medical and... Apr 2011Inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD) is a progressive and usually misdiagnosed autosomal dominant disorder. It is... (Review)
Review
Inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD) is a progressive and usually misdiagnosed autosomal dominant disorder. It is clinically characterized by a triad of features: proximal and distal myopathy, early onset Paget disease of bone (PDB), and frontotemporal dementia (FTD). It is caused by missense mutations in the valosin-containing protein (VCP) gene. We describe here the clinical and molecular findings of the first Brazilian family identified with IBMPFD. Progressive myopathy affecting the limb girdles was detected by clinical examination followed by muscle biopsy and creatine kinase measurement. PDB was suggested after anatomopathological bone examination and FTD was diagnosed by clinical, neuropsychological and language evaluations. Brain magnetic resonance revealed severe atrophy of the anterior temporal lobes, including the hippocampi. A R93C mutation in VCP was detected by direct sequencing screening in subject W (age 62) and in his mother. Four more individuals diagnosed with "dementia" were reported in this family. We also present a comprehensive genotype-phenotype correlation analysis of mutations in VCP in 182 patients from 29 families described in the literature and show that while IBM is a conspicuously penetrant symptom, PDB has a lower penetrance when associated with mutations in the AAAD1 domain and FTD has a lower penetrance when associated with mutations in the Junction (L1-D1) domain. Furthermore, the R93C mutation is likely to be associated with the penetrance of all the clinical symptoms of the triad.
Topics: Adenosine Triphosphatases; Aged; Aged, 80 and over; Cell Cycle Proteins; Female; Frontotemporal Dementia; Genetic Association Studies; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Mutation; Myositis, Inclusion Body; Osteitis Deformans; Pedigree; Valosin Containing Protein
PubMed: 21412659
DOI: 10.1590/s0100-879x2011007500028 -
Reumatismo 2007Paget's disease of bone is a chronic focal abnormality of bone turnover that remains totally asymptomatic over a very long period of time but that eventually ensue in... (Review)
Review
Paget's disease of bone is a chronic focal abnormality of bone turnover that remains totally asymptomatic over a very long period of time but that eventually ensue in bone pain and skeletal deformities. Although, in the last decade new insights have been obtained on its etiology, this remains largely obscure. Effective medical treatment (based on the use of bisphosphonates) has become available and the diagnostic procedures are now well defined. However, there remains considerable controversy regarding the hierarchy of diagnostic procedures and the medical treatment threshold. In the last few years different institution have published national guidelines, reflecting local national health systems and the available medical treatment. In this review, a working group derived from members of the SIOMMMS has examined the information available regarding the diagnosis and treatment of Paget's disease in order to develop guidelines to assist in the management of this condition. The first draft was then extensively reviewed by experts derived from the most representative scientific societies of rheumatology, internal medicine, and orthopaedic surgery. The document provides the most updated recommendations based primarily on the "evidence-based- medicine" but also on the Italian regulation for the diagnostic procedures and on the available medical treatments.
Topics: Humans; Osteitis Deformans
PubMed: 17603696
DOI: No ID Found -
Frontiers in Endocrinology 2022To evaluate the clinical features of sporadic Paget's disease of bone (PDB) in China and further explore the underlying genetic abnormalities of the disease.
OBJECTIVE
To evaluate the clinical features of sporadic Paget's disease of bone (PDB) in China and further explore the underlying genetic abnormalities of the disease.
METHODS
Clinical characteristics, biochemical indices, bone turnover markers and radiographic examinations of the patients were collected. Genomic DNA was extracted from peripheral blood and whole-exome sequencing was carried out to identify the potential pathogenic genes. The pathogenicity of the variants was thereafter investigated by bioinformatics analysis.
RESULTS
A total of 50 patients (57.20 ± 15.52 years, male/female: 1.63: 1) with PDB were included and the mean onset age was 48.34 years (48.34 ± 17.24 years). 94.0% of the patients exhibited symptomatic patterns described as bone pain (86.0%), elevated skin temperature at the lesion site (26.0%), bone deformity (22.0%) and local swelling (18.0%). The most frequently involved lesion sites were pelvis (52.0%), femur (42.0%), tibia (28.0%), skull (28.0%) and spine (18.0%), respectively. Additionally, 40.0% of them accompanied with osteoarthritis, 14.0% with pathological fractures, and the misdiagnosis rate of PDB was as high as 36.0%. Serum level of alkaline phosphatase was significantly increased, with the mean value of 284.00 U/L (quartiles, 177.00-595.00 U/L). Two heterozygous missense mutations of gene (c.1211T>C, M404T) and one novel heterozygous missense mutation in gene (c.989C>T, p. P330L) were identified in our study. Moreover, several potential disease-causing genes were detected and markedly enriched in the pathways of neurodegeneration (including , and genes) and amyotrophic lateral sclerosis (ALS, including , , and genes).
CONCLUSION
In contrast to Western patients, Chinese patients have an earlier onset age, more severe symptoms, and lower frequency of gene mutation (4.0%). Moreover, a novel heterozygous missense mutation in gene was identified in one male patient with isolated bone phenotype. As for other genetic factors, it was indicated that , , , , and genes may be potential pathogenic genes, pathways of neurodegeneration and ALS may play a vital role in the pathogenesis of PDB.
Topics: Amyotrophic Lateral Sclerosis; Asian People; Female; Heterozygote; Humans; Male; Mutation; Osteitis Deformans
PubMed: 35355568
DOI: 10.3389/fendo.2022.850462 -
International Journal of Paleopathology Sep 2022This study explores the validity of Paget's disease of bone (PDB) reported in unpublished skeletal reports, based on macroscopic analysis alone.
OBJECTIVE
This study explores the validity of Paget's disease of bone (PDB) reported in unpublished skeletal reports, based on macroscopic analysis alone.
MATERIALS
The high prevalence of 'suspected' Paget's disease (10.7%) in an early modern sample from St John's the Evangelist Church in Redhill, Surrey is reassessed.
METHODS
Signs of PDB were examined in 53 well-preserved adults aged 35 + years using macroscopic, radiographic and histological techniques.
RESULTS
Macroscopic features of PDB were identified in 8 individuals (15%), with 5 individuals later rejected using radiography. Two individuals showed classic radiographic features of PDB, with a third presenting possible features in radiography (5.7%). These three cases were confirmed by histological analysis.
CONCLUSIONS
PDB should not be suggested as a single diagnosis in cases of bone hypertrophy without confirmation using radiography.
SIGNIFICANCE
The growing popularity of 'big data' projects and limited collections access means that unpublished cases of PDB are often included in large scale analyses, impacting our understanding of the evolution of this disease. Using macroscopic analysis alone leads to overdiagnosis. Histological analysis is unnecessary when radiographic features are present, but provides a useful diagnostic step in long bones in advanced cases of PBD.
LIMITATIONS
The radiographic sample in this study was limited to three individuals.
SUGGESTIONS FOR FURTHER RESEARCH
The conclusion that radiography alone can be used to identify PDB in archaeological cases merits further research on a larger number of cases.
Topics: Adult; Bone and Bones; Humans; Osteitis Deformans; Overdiagnosis; Prevalence; Radiography
PubMed: 35816770
DOI: 10.1016/j.ijpp.2022.07.001 -
Journal of Endocrinological... Jun 2024Paget's disease of bone is a focal skeletal disorder causing bone deformities and impairing bone quality. Despite the prevalence of asymptomatic cases is increasing, the... (Review)
Review
INTRODUCTION
Paget's disease of bone is a focal skeletal disorder causing bone deformities and impairing bone quality. Despite the prevalence of asymptomatic cases is increasing, the progression of the disease can lead to invalidating complications that compromise the quality of life. Doubts on clinical and therapeutic management aspects exist, although beneficial effects of antiresorptive drugs, particularly bisphosphonates are known. However, limited information is available from randomized controlled trials on the prevention of disease complications so that somewhat contrasting positions about treatment indications between expert panels from the main scientific societies of metabolic bone diseases exist. This task force, composed by expert representatives appointed by the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases and members of the Italian Association of Paget's disease of bone, felt the necessity for more specific and up to date indications for an early diagnosis and clinical management.
METHODS
Through selected key questions, we propose evidence-based recommendations for the diagnosis and treatment of the disease. In the lack of good evidence to support clear recommendations, available information from the literature together with expert opinion of the panel was used to provide suggestions for the clinical practice.
RESULTS AND CONCLUSION
Description of the evidence quality and support of the strength of the statements was provided on each of the selected key questions. The diagnosis of PDB should be mainly based on symptoms and the typical biochemical and radiological features. While treatment is mandatory to all the symptomatic cases at diagnosis, less evidence is available on treatment indications in asymptomatic as well as in previously treated patients in the presence of biochemical recurrence. However, given the safety and long-term efficacy of potent intravenous bisphosphonates such as zoledronate, a suggestion to treat most if not all cases at the time of diagnosis was released.
Topics: Humans; Osteitis Deformans; Italy; Bone Density Conservation Agents; Societies, Medical; Diphosphonates
PubMed: 38488978
DOI: 10.1007/s40618-024-02318-1 -
Calcified Tissue International Aug 2017Paget's disease of bone (PDB) is a common skeletal disorder characterised by focal abnormalities of increased and disorganised bone turnover. Genetic factors play a...
Paget's disease of bone (PDB) is a common skeletal disorder characterised by focal abnormalities of increased and disorganised bone turnover. Genetic factors play a central role in the pathogenesis of PDB but environmental factors also contribute. Measles virus (MV), respiratory syncytial virus (RSV) and canine distemper virus (CDV) have all been implicated as potential disease triggers but the data are conflicting. Since chronic paramyxovirus infection with measles is known to be accompanied by increased production of antiviral antibodies, we have analysed circulating concentrations of antibodies to MV, CDV, and RSV as well as mumps, rubella and varicella zoster virus (VZV) in 463 patients with PDB and 220 aged and gender-matched controls. We also studied the relation between viral antibody concentrations and various markers of disease severity and extent in 460 PDB patients. A high proportion of cases and controls tested positive for antiviral antibodies but there was no significant difference in circulating antibody concentrations between PDB cases and controls for MV, CDV, RSV, rubella or VZV. However, mumps virus antibody levels were significantly higher in the PDB cases (mean ± SD = 3.1 ± 0.84 vs. 2.62 ± 0.86. p < 0.001). There was no association between disease severity and circulating antibody concentrations to any of the viruses. In conclusion, we found no evidence to suggest that PDB is associated with abnormalities of immune response to measles or other paramyxoviruses, although there was evidence of a greater antibody response to mumps. The results do not support that hypothesis that PDB is associated with a persistent infection with measles or other paramyxoviruses.
Topics: Aged; Aged, 80 and over; Antibody Formation; Bone and Bones; Female; Humans; In Situ Hybridization; Male; Middle Aged; Osteitis Deformans; Osteoclasts; Paramyxovirinae
PubMed: 28361207
DOI: 10.1007/s00223-017-0265-4 -
BMJ (Clinical Research Ed.) Dec 1992
Topics: Bone Resorption; Humans; Osteitis Deformans
PubMed: 1486297
DOI: 10.1136/bmj.305.6866.1379 -
Journal of Bone and Mineral Research :... Oct 1999Orthopedic complications of Paget's disease occur commonly and arise as a result of chronically accelerated bone remodeling in focal regions of the skeleton.... (Review)
Review
Orthopedic complications of Paget's disease occur commonly and arise as a result of chronically accelerated bone remodeling in focal regions of the skeleton. Complications include pathologic fractures with delayed union, progressive skeletal deformity, chronic bone pain and pagetic arthritis. The new bisphosphonates have transformed the treatment of Paget's disease in the past decade but have not yet been studied in depth for their ability to prevent orthopaedic complications. Although few patients with Paget's disease ever require surgical intervention, successful operative management of orthopaedic complications has dramatically improved the quality of life for many sufferers. Selected modalities with promising results include total hip replacement for end-stage pagetic arthritis of the hip, total knee replacement for end-stage pagetic arthritis of the knee, proximal tibial osteotomy for painful malalignment of the knees, internal fixation for pathological fractures, and decompressive laminectomy for spinal stenosis. Complications of surgery on pagetic bone include hemorrhage, infection, pathologic fracture, delayed union, nonunion, and aseptic loosening of hardware. Medical, surgical, and rehabilitative modalities provide a wide array of options in managing orthopaedic complications of Paget's disease and are useful in improving quality of life for sufferers of the condition. Prospective studies are needed to assess the ability of antipagetic medications to prevent severe long-term complications such as deformity, arthritis, and malignancy. Localization of susceptibility genes for Paget's disease may accelerate identification of targets for gene therapy and disease prevention.
Topics: Arthroplasty; Humans; Osteitis Deformans; Osteotomy; Spinal Stenosis
PubMed: 10510211
DOI: 10.1002/jbmr.5650140208 -
American Journal of Medical Genetics.... Apr 2016We report auricular ossification (AO) affecting the elastic cartilage of the ear as a newly recognized feature of osteoprotegerin (OPG)-deficiency juvenile Paget disease... (Review)
Review
We report auricular ossification (AO) affecting the elastic cartilage of the ear as a newly recognized feature of osteoprotegerin (OPG)-deficiency juvenile Paget disease (JPD). AO and auricular calcification refer interchangeably to rigid pinnae, sparing the ear lobe, from various etiologies. JPD is a rare Mendelian disorder characterized by elevated serum alkaline phosphatase activity accompanied by skeletal pain and deformity from rapid bone turnover. Autosomal recessive transmission of loss-of-function mutations within TNFRSF11B encoding OPG accounts for most JPD (JPD1). JPD2 results from heterozygous constitutive activation of TNFRSF11A encoding RANK. Other causes of JPD remain unknown. In 2007, we reported a 60-year-old man with JPD1 who described hardening of his external ears at age 45 years, after 4 years of treatment with bisphosphonates (BPs). Subsequently, we noted rigid pinnae in a 17-year-old boy and 14-year-old girl, yet pliable pinnae in a 12-year-old boy, each with JPD1 and several years of BP treatment. Cranial imaging indicated cortical bone within the pinnae of both teenagers. Radiologic studies of our three JPD patients without mutations in TNFRSF11B showed normal auricles. Review of the JPD literature revealed possible AO in several reports. Two of our JPD1 patients had experienced difficult tracheal intubation, raising concern for mineralization of laryngeal elastic cartilage. Thus, AO is a newly recognized feature of JPD1, possibly exacerbated by BP treatment. Elastic cartilage at other sites in JPD1 might also ossify, and warrants investigation.
Topics: Adolescent; Aged; Bone and Bones; DNA Mutational Analysis; Ear Auricle; Female; Genetic Association Studies; Humans; Male; Mutation; Ossification, Heterotopic; Osteitis Deformans; Osteoprotegerin; Phenotype; Tomography, X-Ray Computed; Young Adult
PubMed: 26762549
DOI: 10.1002/ajmg.a.37536