-
Orphanet Journal of Rare Diseases Sep 2020Dominant mutations in valosin-containing protein (VCP) gene cause an adult onset inclusion body myopathy, Paget's disease of bone, and frontotemporal dementia also...
BACKGROUND
Dominant mutations in valosin-containing protein (VCP) gene cause an adult onset inclusion body myopathy, Paget's disease of bone, and frontotemporal dementia also termed multisystem proteinopathy (MSP). The genotype-phenotype relationships in VCP-related MSP are still being defined; in order to understand this better, we investigated the phenotypic diversity and patterns of weakness in the Cure VCP Disease Patient Registry.
METHODS
Cure VCP Disease, Inc. was founded in 2018 for the purpose of connecting patients with VCP gene mutations and researchers to help advance treatments and cures. Cure VCP Disease Patient Registry is maintained by Coordination of Rare Diseases at Sanford. The results of two questionnaires with a 5-point Likert scale questions regarding to patients' disease onset, symptoms, and daily life were obtained from 59 participants (28 males and 31 females) between June 2018 and May 2020. Independent of the registry, 22 patients were examined at the Cure VCP Disease annual patient conference in 2019.
RESULTS
In the questionnaires of the registry, fifty-three patients (90%) reported that they were with inclusion body myopathy, 17 patients (29%) with Paget's disease of bone, eight patients (14%) with dementia, two patients (3%) with amyotrophic lateral sclerosis, and a patient with parkinsonism. Thirteen patients (22%) reported dysphagia and 25 patients (42%) reported dyspnea on exertion. A self-reported functional rating scale for motor function identified challenges with sit to stand (72%), walking (67%), and climbing stairs (85%). Thirty-five (59%) patients in the registry answered that their quality of life is more than good. As for the weakness pattern of the 22 patients who were evaluated at the Cure VCP Disease annual conference, 50% of patients had facial weakness, 55% had scapular winging, 68% had upper proximal weakness, 41% had upper distal weakness, 77% had lower proximal, and 64% had lower distal weakness.
CONCLUSIONS
The Cure VCP Disease Patient Registry is useful for deepening the understanding of patient daily life, which would be a basis to develop appropriate clinical outcome measures. The registry data is consistent with previous studies evaluating VCP patients in the clinical setting. Patient advocacy groups are essential in developing and maintaining disease registries.
Topics: Adult; Female; Frontotemporal Dementia; Humans; Male; Mutation; Myositis, Inclusion Body; Osteitis Deformans; Phenotype; Quality of Life; Registries; Valosin Containing Protein
PubMed: 32993728
DOI: 10.1186/s13023-020-01551-0 -
Calcified Tissue International Feb 2021Paget's disease of bone (PDB) is characterized by focal or multifocal increase in bone turnover. One of the most well-established candidate genes for susceptibility to...
Paget's disease of bone (PDB) is characterized by focal or multifocal increase in bone turnover. One of the most well-established candidate genes for susceptibility to PDB is Sequestosome 1 (SQSTM1). Mutations in SQSTM1 have been documented among Western-European, British and American patients with PDB. However, there is no information on SQSTM1 mutation status in PDB patients from the Central- and Eastern-European regions. In this study, we conducted a mutation screening for SQSTM1 gene variants in 82 PDB patients and 100 control participants in Hungary. Mutations of SQSTM1 were detected in 18 PDB patients (21.95%); associations between genotype and clinical characteristics were also analyzed. Altogether, six different exonic alterations, including two types of UTR variants in the SQSTM1 gene, were observed in our PDB patients. Similarly, to previous genetic studies on Paget's disease, our most commonly detected variant was the c.1175C > T (p.Pro392Leu) in nine cases (four in monostotic and five in polyostotic form). We have surveyed the germline SQSTM1 variant distribution among Hungarian patients with PDB. We also highlighted that the pattern of the analyzed disease-associated pathophysiological parameters could partially discriminate PDB patients with normal or mutant SQSTM1 genotype. However, our findings also underline and strengthen that not solely SQSTM1 stands in the background of the complex PDB etiology.
Topics: Aged; Aged, 80 and over; Exons; Female; Humans; Hungary; Male; Middle Aged; Mutation; Osteitis Deformans; Sequestosome-1 Protein
PubMed: 32978683
DOI: 10.1007/s00223-020-00758-4 -
Internal Medicine (Tokyo, Japan) Jan 2021Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder clinically characterized by slowly progressing spastic paraparesis. We herein report a 50-year-old...
Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder clinically characterized by slowly progressing spastic paraparesis. We herein report a 50-year-old Japanese woman who presented with slowly progressing spastic paraplegia and a history of Paget's disease of bone (PDB). Genetic testing revealed a mutation of the Valosin-containing protein (VCP) gene (p.Arg155Cys; c.436C>T). This mutation has not been reported to cause HSP with PDB.
Topics: Female; Genetic Predisposition to Disease; Humans; Middle Aged; Mutation; Osteitis Deformans; Paraplegia; Pedigree; Spastic Paraplegia, Hereditary
PubMed: 32893227
DOI: 10.2169/internalmedicine.4617-20 -
The Journal of Clinical Endocrinology... Dec 2020Nephrolithiasis (NL) and primary hyperparathyroidism (HPTH) are metabolic complications of Paget disease of bone (PDB), but recent data regarding their prevalence in PDB...
CONTEXT
Nephrolithiasis (NL) and primary hyperparathyroidism (HPTH) are metabolic complications of Paget disease of bone (PDB), but recent data regarding their prevalence in PDB patients are lacking.
OBJECTIVES
Study 1: To compare the prevalence of primary HPTH and NL in 708 patients with PDB and in 1803 controls. Study 2: To evaluate the prevalence of NL-metabolic risk factors in 97 patients with PDB and NL, 219 PDB patients without NL, 364 NL patients without PDB, and 219 controls, all of them without HPTH.
DESIGN
Cross-sectional multicentric study.
SETTING
Italian referral centers for metabolic bone disorders.
PARTICIPANTS
Patients with PDB from the Associazione Italiana malati di osteodistrofia di Paget registry. Participants in the Olivetti Heart and the Siena Osteoporosis studies.
MAIN OUTCOME MEASURES
HPTH; NL; NL-metabolic risk factors.
RESULTS
Patients with PDB showed higher prevalence of primary HPTH and NL compared with controls (P < 0.01). The NL recurrence occurs more frequently in patients with polyostotic PDB. About one-half of patients with PDB but without NL showed 1 or more NL-related metabolic risk factors. The hyperoxaluria (HyperOx) prevalence was higher in patients with PDB and NL compared with patients with NL but without PDB and in patients with PDB without NL compared with controls (P = 0.01). Patients with PDB and HyperOx showed a longer lapse of time from the last aminobisphosphonate treatment.
CONCLUSIONS
NL and HPTH are frequent metabolic complication of PDB. The NL occurrence should be evaluated in patients with PDB, particularly in those with polyostotic disease and/or after aminobisphosphonate treatment to apply an adequate prevention strategy.
Topics: Aged; Cross-Sectional Studies; Female; Humans; Hyperoxaluria; Hyperparathyroidism; Male; Middle Aged; Nephrolithiasis; Osteitis Deformans; Prevalence; Risk Factors
PubMed: 32827434
DOI: 10.1210/clinem/dgaa576 -
American Family Physician Aug 2020
Topics: Humans; Osteitis Deformans
PubMed: 32803938
DOI: No ID Found -
American Family Physician Aug 2020Paget disease of bone is a benign disorder characterized by focal areas of increased bone turnover in one or more skeletal sites. It usually affects older adults, and...
Paget disease of bone is a benign disorder characterized by focal areas of increased bone turnover in one or more skeletal sites. It usually affects older adults, and men are at a higher risk than women. Any bone may be affected, but the disease has a high preference for the pelvis, spine, skull, and long bones. Pain is the most common symptom, and presentation of the disease may depend on which bones are affected, the extent of involvement, and the presence of complications. Paget disease of bone may be asymptomatic, and suspicion arises from incidental findings of elevated serum alkaline phosphatase levels on routine blood work or abnormalities on imaging tests performed for an unrelated cause. Evidence-based guidelines recommend the use of plain radiography and serum alkaline phosphatase testing for initial diagnosis and radionuclide scans for delineation of the extent of disease. Treatment with nitrogen-containing bisphosphonates is recommended in active disease or when risk of complications is possible. Complications of the disease include arthritis, gait changes, hearing loss, nerve compression syndromes, and osteosarcoma. Total serum alkaline phosphatase is the suggested marker for assessing treatment response when high bone turnover occurs, and it should be measured at three to six months to evaluate initial response. Early diagnosis of Paget disease of bone remains key to its management because patients generally have a good prognosis if treatment is initiated before major complications arise. The primary care physician may need to consult with a specialist for confirmation of diagnosis and initiation of treatment.
Topics: Alkaline Phosphatase; Analgesics; Arthritis; Bone Density Conservation Agents; Bone Neoplasms; Collagen Type I; Diphosphonates; Fractures, Compression; Gait; Hearing Loss; Humans; Nerve Compression Syndromes; Osteitis Deformans; Osteosarcoma; Pain; Pain Management; Peptides; Practice Guidelines as Topic; Primary Health Care; Radiography; Radionuclide Imaging
PubMed: 32803929
DOI: No ID Found -
International Journal of Molecular... Aug 2020The maintenance of bone mass is a dynamic process that requires a strict balance between bone formation and resorption. Bone formation is controlled by osteoblasts,... (Review)
Review
The maintenance of bone mass is a dynamic process that requires a strict balance between bone formation and resorption. Bone formation is controlled by osteoblasts, while osteoclasts are responsible for resorption of the bone matrix. The opposite functions of these cell types have to be tightly regulated not only during normal bone development, but also during adult life, to maintain serum calcium homeostasis and sustain bone integrity to prevent bone fractures. Disruption of the control of bone synthesis or resorption can lead to an over accumulation of bone tissue in osteopetrosis or conversely to a net depletion of the bone mass in osteoporosis. Moreover, high levels of bone resorption with focal bone formation can cause Paget's disease. Here, we summarize the steps toward isolation and characterization of the osteopetrosis associated trans-membrane protein 1 () gene and protein, essential for proper osteoclast maturation, and responsible when mutated for the most severe form of osteopetrosis in mice and humans.
Topics: Animals; Bone Resorption; Humans; Membrane Proteins; Mice; Osteitis Deformans; Osteoclasts; Osteogenesis; Osteopetrosis
PubMed: 32764302
DOI: 10.3390/ijms21165600 -
Frontiers in Endocrinology 2020Bone biopsies have been obtained for many centuries and are one of the oldest known medical procedures in history. Despite the introduction of new noninvasive...
Bone biopsies have been obtained for many centuries and are one of the oldest known medical procedures in history. Despite the introduction of new noninvasive radiographic imaging techniques and genetic analyses, bone biopsies are still valuable in the diagnosis of bone diseases. Advanced techniques for the assessment of bone quality in bone biopsies, which have emerged during the last decades, allows in-depth tissue analyses beyond structural changes visible in bone histology. In this review, we give an overview of the application and advantages of the advanced techniques for the analysis of bone biopsies in the clinical setting of various rare metabolic bone diseases. A systematic literature search on rare metabolic bone diseases and analyzing techniques of bone biopsies was performed in PubMed up to 2019 week 34. Advanced techniques for the analysis of bone biopsies were described for rare metabolic bone disorders including Paget's disease of bone, osteogenesis imperfecta, fibrous dysplasia, Fibrodysplasia ossificans progressiva, X-linked osteoporosis, Loeys-Diets syndrome, osteopetrosis, Erdheim-Chester disease, and Cherubism. A variety of advanced available analytical techniques were identified that may help to provide additional detail on cellular, structural, and compositional characteristics in rare bone diseases complementing classical histopathology. To date, these techniques have only been used in research and not in daily clinical practice. Clinical application of bone quality assessment techniques depends upon several aspects such as availability of the technique in hospitals, the existence of reference data, and a cooperative network of researchers and clinicians. The evaluation of rare metabolic bone disorders requires a repertoire of different methods, owing to their distinct bone tissue characteristics. The broader use of bone material obtained from biopsies could provide much more information about pathophysiology or treatment options and establish bone biopsies as a valuable tool in rare metabolic bone diseases.
Topics: Biopsy; Bone Diseases; Fibrous Dysplasia of Bone; Humans; Loeys-Dietz Syndrome; Myositis Ossificans; Osteitis Deformans; Osteogenesis Imperfecta; Osteopetrosis; Osteoporosis; Rare Diseases
PubMed: 32714279
DOI: 10.3389/fendo.2020.00399 -
Journal of Bone and Mineral Research :... Aug 2020
Topics: Bone and Bones; Genetic Predisposition to Disease; Humans; Osteitis Deformans; Profilins
PubMed: 32589291
DOI: 10.1002/jbmr.4090 -
Biochimica Et Biophysica Acta.... Oct 2020MicroRNA (miRs) are small, non-coding RNA that post-transcriptionally regulate DNA expression. We hypothesized that specific miR profiles may be a feature of overactive...
MicroRNA (miRs) are small, non-coding RNA that post-transcriptionally regulate DNA expression. We hypothesized that specific miR profiles may be a feature of overactive osteoclasts in Paget's disease of bone (PDB), a disorder characterized by an increased and disorganized bone remodeling that typically begins with excessive bone resorption. We compared the expression profile of 13 miRs in human osteoclasts differentiated in vitro from peripheral blood mononuclear cells (PBMCs) of patients with PDB (n = 10) or age- and sex- matched healthy subjects (n = 10). We selected 13 miRs for testing, on the basis of their previously reported roles either in human osteoclast differentiation, in bone diseases, or in osteoclast important signaling pathways. From those expression results, 3 miRNAs were further selected for in-vitro studies aiming at modulating miR expression in human cord blood monocyte derived osteoclasts: 2 miRs (miR-146a-3p and miR-155-5p) whose expression was significantly reduced in pagetic osteoclasts, as well as miRNA-133a-3p, stable in PDB relative to controls, but with known regulatory importance within osteoclasts. We demonstrated a positive (miR-133a-3p) or negative (miR-155-5p, miR-146a-3p) impact of those miRs on the formation of osteoclasts and/or their bone resorption capacity in this human model. Signaling pathways were significantly affected, including p38 MAP-kinase (miR-133a-3p), RANKL-induced TRAF6/NFκB signaling (miR-146a-3p), and MITF expression (miR-155-5p). Osteoclast miRNA profiles might have an important value to yield significant new insights into the osteoclast phenotype in PDB and in other bone diseases with hyperactive osteoclasts.
Topics: Aged; Aged, 80 and over; Antagomirs; Bone Resorption; Cell Differentiation; Cells, Cultured; Down-Regulation; Female; Gene Expression Profiling; Humans; Leukocytes, Mononuclear; Male; MicroRNAs; Middle Aged; NF-kappa B; Osteitis Deformans; Osteoclasts; Primary Cell Culture; RANK Ligand; Signal Transduction; p38 Mitogen-Activated Protein Kinases
PubMed: 32485219
DOI: 10.1016/j.bbadis.2020.165852