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Orphanet Journal of Rare Diseases Aug 2013RYR1 mutations are typically associated with core myopathies and are the most common overall cause of congenital myopathy. Dominant mutations are most often associated...
BACKGROUND
RYR1 mutations are typically associated with core myopathies and are the most common overall cause of congenital myopathy. Dominant mutations are most often associated with central core disease and malignant hyperthermia, and genotype-phenotype patterns have emerged from the study of these mutations that have contributed to the understanding of disease pathogenesis. The recent availability of genetic testing for the entire RYR1 coding sequence has led to a dramatic expansion in the identification of recessive mutations in core myopathies and other congenital myopathies. To date, no clear patterns have been identified in these recessive mutations, though no systematic examination has yet been performed.
METHODS
In this study, we investigated genotype-phenotype correlations in a large combined cohort of unpublished (n = 14) and previously reported (n = 92) recessive RYR1 cases.
RESULTS
Overall examination of this cohort revealed nearly 50% of cases to be non-core myopathy related. Our most significant finding was that hypomorphic mutations (mutations expected to diminish RyR1 expression) were enriched in patients with severe clinical phenotypes. We also determined that hypomorphic mutations were more likely to be encountered in non-central core myopathies. With analysis of the location of non-hypomorphic mutations, we found that missense mutations were generally enriched in the MH/CCD hotspots and specifically enriched in the selectivity filter of the channel pore.
CONCLUSIONS
These results support a hypothesis that loss of protein function is a key predictive disease parameter. In addition, they suggest that decreased RyR1 expression may dictate non-core related pathology though, data on protein expression was limited and should be confirmed in a larger cohort. Lastly, the results implicate abnormal ion conductance through the channel pore in the pathogenesis in recessive core myopathies. Overall, our findings represent a comprehensive analysis of genotype-phenotype associations in recessive RYR1-myopathies.
Topics: Cohort Studies; Female; Genes, Recessive; Genetic Association Studies; Humans; Male; Muscular Diseases; Mutation; Ryanodine Receptor Calcium Release Channel; Severity of Illness Index
PubMed: 23919265
DOI: 10.1186/1750-1172-8-117 -
Nature Communications Feb 2020Idiopathic inflammatory myopathies cause progressive muscle weakness and degeneration. Since high-dose glucocorticoids might not lead to full recovery of muscle...
Idiopathic inflammatory myopathies cause progressive muscle weakness and degeneration. Since high-dose glucocorticoids might not lead to full recovery of muscle function, physical exercise is also an important intervention, but some exercises exacerbate chronic inflammation and muscle fibrosis. It is unknown how physical exercise can have both beneficial and detrimental effects in chronic myopathy. Here we show that senescence of fibro-adipogenic progenitors (FAPs) in response to exercise-induced muscle damage is needed to establish a state of regenerative inflammation that induces muscle regeneration. In chronic inflammatory myopathy model mice, exercise does not promote FAP senescence or resistance against tumor necrosis factor-mediated apoptosis. Pro-senescent intervention combining exercise and pharmacological AMPK activation reverses FAP apoptosis resistance and improves muscle function and regeneration. Our results demonstrate that the absence of FAP senescence after exercise leads to muscle degeneration with FAP accumulation. FAP-targeted pro-senescent interventions with exercise and pharmacological AMPK activation may constitute a therapeutic strategy for chronic inflammatory myopathy.
Topics: Aging; Animals; Apoptosis; Exercise Therapy; Female; Humans; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Muscle, Skeletal; Muscular Diseases; Regeneration
PubMed: 32060352
DOI: 10.1038/s41467-020-14734-x -
Nutrients Apr 2016Resveratrol is a natural polyphenolic compound produced by plants under various stress conditions. Resveratrol has been reported to exhibit antioxidant,... (Review)
Review
Resveratrol is a natural polyphenolic compound produced by plants under various stress conditions. Resveratrol has been reported to exhibit antioxidant, anti-inflammatory, and anti-proliferative properties in mammalian cells and animal models, and might therefore exert pleiotropic beneficial effects in different pathophysiological states. More recently, resveratrol has also been shown to potentially target many mitochondrial metabolic pathways, including fatty acid β-oxidation or oxidative phosphorylation, leading to the up-regulation of the energy metabolism via signaling pathways involving PGC-1α, SIRT1, and/or AMP-kinase, which are not yet fully delineated. Some of resveratrol beneficial effects likely arise from its cellular effects in the skeletal muscle, which, surprisingly, has been given relatively little attention, compared to other target tissues. Here, we review the potential for resveratrol to ameliorate or correct mitochondrial metabolic deficiencies responsible for myopathies, due to inherited fatty acid β-oxidation or to respiratory chain defects, for which no treatment exists to date. We also review recent data supporting therapeutic effects of resveratrol in the Duchenne Muscular Dystrophy, a fatal genetic disease affecting the production of muscle dystrophin, associated to a variety of mitochondrial dysfunctions, which likely contribute to disease pathogenesis.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Energy Metabolism; Gene Expression Regulation; Humans; Muscular Diseases; Resveratrol; Stilbenes
PubMed: 27136581
DOI: 10.3390/nu8050254 -
Human Mutation Dec 2014A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types...
A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types of variants, and a widening in the spectrum of clinical and histological phenotypes associated with this gigantic, 183 exons containing gene. Recessive pathogenic variants in NEB are the major cause of nemaline myopathy (NM), one of the most common congenital myopathies. Moreover, pathogenic NEB variants have been identified in core-rod myopathy and in distal myopathies. In this update, we present the disease-causing variants in NEB in 159 families, 143 families with NM, and 16 families with NM-related myopathies. Eighty-eight families are presented here for the first time. We summarize 86 previously published and 126 unpublished variants identified in NEB. Furthermore, we have analyzed the NEB variants deposited in the Exome Variant Server (http://evs.gs.washington.edu/EVS/), identifying that pathogenic variants are a minor fraction of all coding variants (∼7%). This indicates that nebulin tolerates substantial changes in its amino acid sequence, providing an explanation as to why variants in such a large gene result in relatively rare disorders. Lastly, we discuss the difficulties of drawing reliable genotype-phenotype correlations in NEB-associated disease.
Topics: Alternative Splicing; Animals; Chromosomes, Human, Pair 2; Databases, Genetic; Exons; Genotype; Humans; Models, Animal; Muscle Proteins; Muscular Diseases; Mutation; Phenotype
PubMed: 25205138
DOI: 10.1002/humu.22693 -
Acta Neuropathologica Communications Jan 2019Several morphological phenotypes have been associated to RYR1-recessive myopathies. We recharacterized the RYR1-recessive morphological spectrum by a large monocentric...
Several morphological phenotypes have been associated to RYR1-recessive myopathies. We recharacterized the RYR1-recessive morphological spectrum by a large monocentric study performed on 54 muscle biopsies from a large cohort of 48 genetically confirmed patients, using histoenzymology, immunohistochemistry, and ultrastructural studies. We also analysed the level of RyR1 expression in patients' muscle biopsies. We defined "dusty cores" the irregular areas of myofibrillar disorganisation characterised by a reddish-purple granular material deposition with uneven oxidative stain and devoid of ATPase activity, which represent the characteristic lesion in muscle biopsy in 54% of patients. We named Dusty Core Disease (DuCD) the corresponding entity of congenital myopathy. Dusty cores had peculiar histological and ultrastructural characteristics compared to the other core diseases. DuCD muscle biopsies also showed nuclear centralization and type1 fibre predominance. Dusty cores were not observed in other core myopathies and centronuclear myopathies. The other morphological groups in our cohort of patients were: Central Core (CCD: 21%), Core-Rod (C&R:15%) and Type1 predominance "plus" (T1P+:10%). DuCD group was associated to an earlier disease onset, a more severe clinical phenotype and a lowest level of RyR1 expression in muscle, compared to the other groups. Variants located in the bridge solenoid and the pore domains were more frequent in DuCD patients. In conclusion, DuCD is the most frequent histopathological presentation of RYR1-recessive myopathies. Dusty cores represent the unifying morphological lesion among the DuCD pathology spectrum and are the morphological hallmark for the recessive form of disease.
Topics: Adolescent; Adult; Aged; Biopsy; Child; Child, Preschool; Cohort Studies; Female; Genes, Recessive; Humans; Infant; Infant, Newborn; Male; Middle Aged; Muscle, Skeletal; Muscular Diseases; Ryanodine Receptor Calcium Release Channel; Young Adult
PubMed: 30611313
DOI: 10.1186/s40478-018-0655-5 -
Continuum (Minneapolis, Minn.) Dec 2016This article provides guidelines for diagnosing and treating the different subtypes of autoimmune myopathies. (Review)
Review
PURPOSE OF REVIEW
This article provides guidelines for diagnosing and treating the different subtypes of autoimmune myopathies.
RECENT FINDINGS
The most common subtypes of autoimmune myopathies are dermatomyositis, immune-mediated necrotizing myopathy, antisynthetase syndrome, and overlap syndromes; isolated polymyositis is an exceptionally rare disease. Specific autoantibodies are associated with unique clinical phenotypes and may be used for diagnostic and prognostic purposes, such as to assess the risk of coexisting malignancy.
SUMMARY
Diagnosing the specific subtype of autoimmune myopathy can be achieved by combining relevant features of the history, neuromuscular examination, muscle biopsy, and serologic studies.
Topics: Aged; Autoantibodies; Autoimmune Diseases; Dermatomyositis; Electromyography; Female; Humans; Male; Middle Aged; Muscular Diseases; Myositis
PubMed: 27922497
DOI: 10.1212/01.CON.0000511070.50715.ab -
Neuromuscular Disorders : NMD Jan 2021Dysphagia (impaired swallowing) is not a rare problem in various neuromuscular disorders, both in the pediatric and the adult patient population. On many occasions such... (Review)
Review
Dysphagia (impaired swallowing) is not a rare problem in various neuromuscular disorders, both in the pediatric and the adult patient population. On many occasions such patients are first presented to other medical specialists or health professionals. Disorders of deglutition are probably underrecognized in patients with a neuromuscular disease as a result of patient's and doctor's delay. This review will focus on dysphagia in adults suffering from a myopathy. Dysphagia in myopathies usually affects the oropharyngeal phases which rely mostly on voluntary muscle activity of the mouth, pharynx and upper esophageal sphincter. Dysphagia is known to contribute to a reduction of quality of life and may also lead to increased morbidity and mortality. The review includes an overview on symptomatology and tools of assessments, and elaborates on dysphagia in specific hereditary and acquired myopathies.
Topics: Deglutition; Deglutition Disorders; Esophagus; Humans; Mouth; Muscular Diseases; Pharynx; Quality of Life
PubMed: 33334661
DOI: 10.1016/j.nmd.2020.11.001 -
Journal of Korean Medical Science Nov 2017
Topics: Arabinofuranosyluracil; Humans; Mitochondria; Mitochondrial Myopathies; Muscular Diseases
PubMed: 28960021
DOI: 10.3346/jkms.2017.32.11.1732 -
Indian Journal of Pathology &... May 2022Within the history of neuromuscular diseases (NMD), congenital myopathies (CM) represent a relatively new category introduced in the mid-nineteen hundreds upon advent... (Review)
Review
Within the history of neuromuscular diseases (NMD), congenital myopathies (CM) represent a relatively new category introduced in the mid-nineteen hundreds upon advent and subsequent application of enzyme histochemistry and electron microscopy by establishing the three major CM, central core disease, nemaline myopathy, and centronuclear myopathy which later pluralized each when the molecular era began at the end of last century. Quickly, during the following 5 decades, many new CM entities were described, based on muscle biopsies and their CM-characteristic myopathology, the former a prerequisite to recognizing an individual CM, the latter of the nosological hallmark of the individual CM. When the molecular era ushered in immunohistochemistry the spectrum and nosography of CM altered in that some CM became allelic to other cohorts of NMD, e.g., congenital muscular dystrophies, other muscular dystrophies, distal myopathies based on different or identical mutations in the same gene. The nosological spectrum of a defective gene also enlarged by recognizing several entities with mutations in the same gene, and same or similar nosological conditions originated from mutations in different genes. Lately, however, CM were reported which lacked any individual myopathological hallmarks, but were clearly based on molecular defects, a fair number of them being newly identified ones. Few CM still remain without any molecular clarification. This nosographic development rendered the original definition of such new CM questionable and brought uncertainty to their classification and nomenclature.
Topics: Biopsy; Histocytochemistry; Humans; Microscopy, Electron; Muscular Diseases; Mutation
PubMed: 35562159
DOI: 10.4103/ijpm.ijpm_1031_21 -
Neurologic Clinics Aug 2014Muscle tissue is highly sensitive to many substances. Early recognition of toxic myopathies is important, because they potentially are reversible on removal of the... (Review)
Review
Muscle tissue is highly sensitive to many substances. Early recognition of toxic myopathies is important, because they potentially are reversible on removal of the offending drug or toxin, with greater likelihood of complete resolution the sooner this is achieved. Clinical features range from mild muscle pain and cramps to severe weakness with rhabdomyolysis, renal failure, and even death. The pathogenic bases can be multifactorial. This article reviews some of the common toxic myopathies and their clinical presentation, histopathologic features, and possible underlying cellular mechanisms.
Topics: Anticholesteremic Agents; Creatine Kinase; Female; Humans; Immunosuppressive Agents; Male; Muscular Diseases; Propofol; Toxins, Biological
PubMed: 25037083
DOI: 10.1016/j.ncl.2014.04.009