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Metabolic bone disease
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
Philip E. Harris, Pierre-Marc G. Bouloux
Genome-wide linkage studies have identified several susceptibility loci for Paget’s disease. Mutations have been identified in four genes that are all involved in the RANK–NF-κB pathway.49,50 The most important gene identified so far is sequestome 1 (SQSTM1), located at 5q35, a scaffold protein encoding p62 (Figure 12.5). Heterozygous mutations affecting the ubiquitin-associated domain, causing loss of ubiquitin binding, account for approximately 40% of cases of familial disease and a smaller proportion of patients with sporadic disease.50 Other rare genetic causes have also been identified. Familial expansile osteolysis, early-onset familial Paget’s disease, and expansile skeletal hyperphosphatasia are autosomal dominant disorders caused by insertion mutations in exon 1 of the TNFRSF1A gene that encodes the RANK receptor. Juvenile Paget’s disease is an autosomal recessive disorder, caused by inactivating mutations of TNFRSF11B that encodes osteoprotegerin. Hereditary inclusion body myopathy, Paget’s disease, and frontotemporal dementia (IBMPFD) is a dominant progressive disorder, caused by mutations in the valosin-containing protein VCP gene, clustered around a domain involved in ubiquitin binding.49,50
Ophthalmological Manifestations of Hereditary Myopathies
Published in Journal of Binocular Vision and Ocular Motility, 2022
Marta Saint-Gerons, Miguel Angel Rubio, Gemma Aznar, Ana Matheu
The causative gene, the hereditary inclusion-body myopathy (IBM3) gene, has been mapped to chromosome region 17p13.1. Inheritance is autosomal dominant.91 This disease is characterized by congenital joint contractures (normalizing during early childhood), external ophthalmoplegia, and proximal muscle weakness. In adult cases, muscular weakness is progressive. Nineteen affected individuals have been described from one large family.91
A review on the treatment of sporadic inclusion body myositis with Bimagrumab and Alemtuzumab
Published in International Journal of Neuroscience, 2019
Mavroudis Ioannis, Petridis Foivos, Kazis Dimitrios
We considered cohort studies, randomised or quasi‐randomised trials of treatment for IBM with Bimagrumad or Alemtuzumab in adults compared to placebo or any other treatment for inclusion in the review. We specifically excluded people with familial IBM and hereditary inclusion body myopathy, but we included people who had connective tissue and autoimmune diseases associated with IBM, which may or may not be identified in trials.
Paget’s disease of bone: an update on epidemiology, pathogenesis and pharmacotherapy
Published in Expert Opinion on Orphan Drugs, 2018
Luigi Gennari, Domenico Rendina, Tommaso Picchioni, Simone Bianciardi, Maria Materozzi, Ranuccio Nuti, Daniela Merlotti
Despite the remarkable progresses of the last two decades, the pathogenetic mechanisms leading to these alterations in osteoclast phenotype and the development of PDB remain in part unknown and probably include either genetic or environmental causes. The possibility that heredity might play an important role in the pathogenesis of PDB was first raised in the 1949 [41], following the initial clinical reports of familial cases of PDB [42]. The presence of ethnic differences in prevalence rates of PDB, which persists after migration to other countries, further supports a genetic etiology of the disease [43]. Most of the following epidemiological observations provided additional support to the genetic hypothesis, evidencing a positive family history for PDB accounting from 10 to 40% of cases [31,44–47]. Indeed, the late onset of the symptoms and the high frequency of asymptomatic bony involvement make it impossible to obtain a real estimate of familial and sporadic cases. In a large survey of 864 patients in the USA, the cumulative risk for PDB development in a first-degree relative of a patient was 9%, compared with 2% for individuals with unaffected relatives [46]. It is also estimated that at least one third of patients have an autosomal dominant form of the disease. In this form, the risk of PDB for each first-degree relative was close to 50% (penetrance being estimated at 80%). As a counterpart to the genetic hypothesis, the focal nature of skeletal lesions together with the decline in prevalence rates and the incomplete penetrance of the disease among family members all suggest that one or more environmental triggers may play a role in the pathophysiology of PDB. The exact nature of these triggers and how they might interact with the genetic factors in the pathogenesis of PDB is less understood [48]. Another hypothesis is that the genetic version of the disease represents only one group of patients and that the other cases have a form of PDB that originates from viral exposure or other unknown factors. Moreover, different rare inherited bone disorders have also been described that show phenotypic overlap with classical PDB in that they are also characterized by increased bone turnover, bone deformity, bone expansion, and elevated serum alkaline phosphatase concentrations. These PDB-related disorders include juvenile PDB (JPD), early-onset PDB, familial expansile osteolysis (FEO), expansile skeletal hyperphosphatasia (ESH), and the syndrome of hereditary inclusion-body myopathy, PDB, and frontotemporal dementia (IBMPFD), that has more recently defined as multisystem proteinopathy [49,50]. In these disorders a more clear familial clustering has been identified.