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Journal of Neuromuscular Diseases 2018Anti-HMGCR myopathy was first recognized and characterized in patients with a history of statin exposure and immune-mediated necrotizing myopathy. After the discovery of... (Review)
Review
Anti-HMGCR myopathy was first recognized and characterized in patients with a history of statin exposure and immune-mediated necrotizing myopathy. After the discovery of anti-HMGCR autoantibodies, several international groups identified and characterized more patients, expanding the phenotypic spectrum of this disease to include pediatric patients and young adults without statin exposure and those with a chronic myopathy resembling limb-girdle muscular dystrophy. We provide a summary of clinical findings, pathologic features, muscle imaging, and immunogenetic risk factors of the disease. We also discuss the current treatment strategies and approaches to monitoring the therapeutic response. Lastly, we briefly summarize the current understanding of the pathophysiology of the disease and postulate a model for autoimmunity initiation and propagation in this disease.
Topics: Autoantibodies; Autoimmune Diseases; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Muscular Diseases; Myositis
PubMed: 29480216
DOI: 10.3233/JND-170282 -
Continuum (Minneapolis, Minn.) Dec 2022Metabolic myopathies are disorders that affect skeletal muscle substrate oxidation. Although some drugs and hormones can affect metabolism in skeletal muscle, this... (Review)
Review
PURPOSE OF REVIEW
Metabolic myopathies are disorders that affect skeletal muscle substrate oxidation. Although some drugs and hormones can affect metabolism in skeletal muscle, this review will focus on the genetic metabolic myopathies.
RECENT FINDINGS
Impairments in glycogenolysis/glycolysis (glycogen storage disease), fatty acid transport/oxidation (fatty acid oxidation defects), and mitochondrial metabolism (mitochondrial myopathies) represent most metabolic myopathies; however, they often overlap clinically with structural genetic myopathies, referred to as pseudometabolic myopathies. Although metabolic myopathies can present in the neonatal period with hypotonia, hypoglycemia, and encephalopathy, most cases present clinically in children or young adults with exercise intolerance, rhabdomyolysis, and weakness. In general, the glycogen storage diseases manifest during brief bouts of high-intensity exercise; in contrast, fatty acid oxidation defects and mitochondrial myopathies usually manifest during longer-duration endurance-type activities, often with fasting or other metabolic stressors (eg, surgery, fever). The neurologic examination is often normal between events (except in the pseudometabolic myopathies) and evaluation requires one or more of the following tests: exercise stress testing, blood (eg, creatine kinase, acylcarnitine profile, lactate, amino acids), urine (eg, organic acids, myoglobin), muscle biopsy (eg, histology, ultrastructure, enzyme testing), and targeted (specific gene) or untargeted (myopathy panels) genetic tests.
SUMMARY
Definitive identification of a specific metabolic myopathy often leads to specific interventions, including lifestyle, exercise, and nutritional modifications; cofactor treatments; accurate genetic counseling; avoidance of specific triggers; and rapid treatment of rhabdomyolysis.
Topics: Young Adult; Infant, Newborn; Child; Humans; Muscular Diseases; Metabolism, Inborn Errors; Mitochondrial Myopathies; Rhabdomyolysis; Glycogen Storage Disease; Fatty Acids
PubMed: 36537979
DOI: 10.1212/CON.0000000000001182 -
International Journal of Molecular... Oct 2021Hyperlipidemia is a major risk factor for cardiovascular morbidity and mortality. Statins are the first-choice therapy for dyslipidemias and are considered the... (Review)
Review
Hyperlipidemia is a major risk factor for cardiovascular morbidity and mortality. Statins are the first-choice therapy for dyslipidemias and are considered the cornerstone of atherosclerotic cardiovascular disease (ASCVD) in both primary and secondary prevention. Despite the statin-therapy-mediated positive effects on cardiovascular events, patient compliance is often poor. Statin-associated muscle symptoms (SAMS) are the most common side effect associated with treatment discontinuation. SAMS, which range from mild-to-moderate muscle pain, weakness, or fatigue to potentially life-threatening rhabdomyolysis, are reported by 10% to 25% of patients receiving statin therapy. There are many risk factors associated with patient features and hypolipidemic agents that seem to increase the risk of developing SAMS. Due to the lack of a "gold standard", the diagnostic test for SAMS is based on a clinical criteria score, which is independent of creatine kinase (CK) elevation. Mechanisms that underlie the pathogenesis of SAMS remain almost unclear, though a high number of risk factors may increase the probability of myotoxicity induced by statin therapy. Some of these, related to pharmacokinetic properties of statins and to concomitant therapies or patient characteristics, may affect statin bioavailability and increase vulnerability to high-dose statins.
Topics: Animals; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Muscular Diseases; Prevalence
PubMed: 34769118
DOI: 10.3390/ijms222111687 -
Arquivos de Neuro-psiquiatria May 2022Idiopathic inflammatory myopathies (IIM) are a heterogenous group of treatable myopathies. Patients present mainly to the rheumatologist and neurologists, complaining of... (Review)
Review
Idiopathic inflammatory myopathies (IIM) are a heterogenous group of treatable myopathies. Patients present mainly to the rheumatologist and neurologists, complaining of acute or subacute onset of proximal weakness. Extramuscular manifestations may occur, including involvement of the lungs, skin, and joints. Classically, the diagnosis used to be made based on the creatine kinase level increase, abnormalities in electroneuromyography and presence of inflammatory infiltrates in the muscle biopsy. Recently, the importance of autoantibodies has increased, and now they may be identified in more than half of IIM patients. The continuous clinicoseropathological improvement in IIM knowledge has changed the way we see these patients and how we classify them. In the past, only polymyositis, dermatomyositis and inclusion body myopathy were described. Currently, immune-mediated necrotizing myopathy, overlap myositis and antisynthetase syndrome have been considered the most common forms of IIM in clinical practice, increasing the spectrum of classification. Patients previously considered to have polymyositis, in fact have these other forms of seropositive IIM. In this article, we reviewed the new concepts of classification, a practical way to make the diagnosis and how to plan the treatment of patients suffering from IIM.
Topics: Autoantibodies; Dermatomyositis; Humans; Muscular Diseases; Myositis; Neurologists; Polymyositis
PubMed: 35976321
DOI: 10.1590/0004-282X-ANP-2022-S131 -
Endocrinology and Metabolism Clinics of... Sep 2022This article reviews the safety of statins and non-statin medications for management of dyslipidemia. Statins have uncommon serious adverse effects: myopathy/... (Review)
Review
This article reviews the safety of statins and non-statin medications for management of dyslipidemia. Statins have uncommon serious adverse effects: myopathy/ rhabdomyolysis, which resolve with statin discontinuation, and diabetes, usually in people with risk factors for diabetes. The CVD benefit of statins far exceeds the risk of diabetes. Statin myalgia, without CK elevation, is likely caused by muscle symptoms with another etiology, or the nocebo effect. Notable adverse effects of non-statin medicines include injection site reactions (alirocumab, evolocumab, inclisiran), increased uric acid and gout (bempedoic acid), atrial fibrillation/flutter (omega-3-fatty acids), and myopathy in combination with a statin (gemfibrozil).
Topics: Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Muscular Diseases; Rhabdomyolysis
PubMed: 35963634
DOI: 10.1016/j.ecl.2022.01.004 -
International Journal of Molecular... Mar 2023Collagen VI exerts several functions in the tissues in which it is expressed, including mechanical roles, cytoprotective functions with the inhibition of apoptosis and... (Review)
Review
Collagen VI exerts several functions in the tissues in which it is expressed, including mechanical roles, cytoprotective functions with the inhibition of apoptosis and oxidative damage, and the promotion of tumor growth and progression by the regulation of cell differentiation and autophagic mechanisms. Mutations in the genes encoding collagen VI main chains, and , are responsible for a spectrum of congenital muscular disorders, namely Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM) and myosclerosis myopathy (MM), which show a variable combination of muscle wasting and weakness, joint contractures, distal laxity, and respiratory compromise. No effective therapeutic strategy is available so far for these diseases; moreover, the effects of collagen VI mutations on other tissues is poorly investigated. The aim of this review is to outline the role of collagen VI in the musculoskeletal system and to give an update about the tissue-specific functions revealed by studies on animal models and from patients' derived samples in order to fill the knowledge gap between scientists and the clinicians who daily manage patients affected by collagen VI-related myopathies.
Topics: Humans; Collagen Type VI; Muscular Dystrophies; Muscular Diseases; Contracture; Muscle, Skeletal; Mutation; Myopathies, Structural, Congenital
PubMed: 36982167
DOI: 10.3390/ijms24065095 -
Journal of Atherosclerosis and... Mar 2019Statins are the main treatment for hypercholesterolemia and the cornerstone of atherosclerotic cardiovascular disease prevention. Many patients taking statins report... (Review)
Review
Statins are the main treatment for hypercholesterolemia and the cornerstone of atherosclerotic cardiovascular disease prevention. Many patients taking statins report muscle-related symptoms, one of the most important causes of statin treatment discontinuation, which is associated with an increased risk of cardiovascular events. Therefore, it is important to identify patients who are truly statin intolerant to avoid unnecessary discontinuation of this beneficial treatment. Some studies indicate that not all muscle complaints are caused by statins, and most patients can tolerate a statin upon re-challenge, down-titration of dose, or switching to another statin. In this paper, we review the definitions of statin intolerance and approaches to reducing cardiovascular risk among individuals reporting statin-associated muscle symptoms.
Topics: Animals; Cardiovascular Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hyperlipidemias; Muscular Diseases
PubMed: 30662020
DOI: 10.5551/jat.RV17030 -
Neurotherapeutics : the Journal of the... Oct 2018Ryanodine receptor type 1-related myopathies (RYR1-RM) are the most common class of congenital myopathies. Historically, RYR1-RM classification and diagnosis have been... (Review)
Review
Ryanodine receptor type 1-related myopathies (RYR1-RM) are the most common class of congenital myopathies. Historically, RYR1-RM classification and diagnosis have been guided by histopathologic findings on muscle biopsy. Main histological subtypes of RYR1-RM include central core disease, multiminicore disease, core-rod myopathy, centronuclear myopathy, and congenital fiber-type disproportion. A range of RYR1-RM clinical phenotypes has also emerged more recently and includes King Denborough syndrome, RYR1 rhabdomyolysis-myalgia syndrome, atypical periodic paralysis, congenital neuromuscular disease with uniform type 1 fibers, and late-onset axial myopathy. This expansion of the RYR1-RM disease spectrum is due, in part, to implementation of next-generation sequencing methods, which include the entire RYR1 coding sequence rather than being restricted to hotspot regions. These methods enhance diagnostic capabilities, especially given historic limitations of histopathologic and clinical overlap across RYR1-RM. Both dominant and recessive modes of inheritance have been documented, with the latter typically associated with a more severe clinical phenotype. As with all congenital myopathies, no FDA-approved treatments exist to date. Here, we review histopathologic, clinical, imaging, and genetic diagnostic features of the main RYR1-RM subtypes. We also discuss the current state of treatments and focus on disease-modulating (nongenetic) therapeutic strategies under development for RYR1-RM. Finally, perspectives for future approaches to treatment development are broached.
Topics: Animals; Humans; Muscular Diseases; Ryanodine Receptor Calcium Release Channel
PubMed: 30406384
DOI: 10.1007/s13311-018-00677-1 -
Autoimmunity Reviews Feb 2022This review is focused on the myopathological spectrum of immune mediated necrotizing myopathies (IMNMs) and its differentiation with other, potentially mimicking,... (Review)
Review
This review is focused on the myopathological spectrum of immune mediated necrotizing myopathies (IMNMs) and its differentiation with other, potentially mimicking, inflammatory and non-inflammatory myopathies. IMNMs are a subgroup of idiopathic inflammatory myopathies (IIMs) characterized by severe clinical presentation with rapidly progressive muscular weakness and creatine kinase elevation, often requiring early aggressive immunotherapy, associated to the presence of muscle specific autoantibodies (MSA) against signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). Muscle biopsy usually shows unspecific features consisting in prominent necrosis and regeneration of muscle fibres with mild or absent inflammatory infiltrates, inconstant and faint expression of major histocompatibility complex (MHC) class I and variable deposition of C5b-9 on sarcolemma. Several conditions could present similar histopathological findings leading to possible misdiagnosis of IMNM with other IIMs or non-inflammatory myopathies (nIMs) and viceversa. This review analyses the muscle biopsy data in IMNMs through a systematic revision of the literature from the last five decades. Several histopathological variables have been considered in both SRP- and HMGCR-IMNM, and compared to other IIMs - as dermatomyositis (DM) and anti-synthethase syndrome (ASS) - or other nIMs -as toxic myopathies (TM), critical illness myopathy (CIM) and muscular dystrophy (MD) - to elucidate similarities and differences among these potentially mimicking conditions. The major histopathological findings of IMNMs were: very frequent necrosis and regeneration of muscle fibres (93%), mild inflammatory component mainly constituted by scattered isolated (65%) CD68-prevalent (68%) cells, without CD8 invading/surrounding non-necrotic fibres, variable expression of MHC-I in non-necrotic fibres (56%) and constant expression of sarcoplasmic p62, confirming those that are widely considered the major histological characteristics of IMNMs. Conversely, only 42% of biopsies showed a sarcolemmal deposition of C5b-9 component. Few differences between SRP and HMGCR IMNMs consisted in more severe necrosis and regeneration in SRP than in HMGCR (p = 0.01); more frequent inflammatory infiltrates (p = 0.007) with perivascular localization (p = 0.01) and clustered expression of MHC-I (p = 0.007) in HMGCR; very low expression of sarcolemmal C5b-9 in SRP (18%) compared to HMGCR (56%) (p = 0.0001). Milder necrosis and regeneration, detection of perifascicular pathology, presence of lymphocytic inflammatory infiltrates and myofibre expression of MxA help to distinguish DM or ASS from IMNM. nIMs can present signs of inflammation at muscle biopsy. Low fibre size variability with overexpression of both MHC-I and II, associated with C5b-9 deposition, could could be observed in CIM, while increased connective tissue should lead to consider MD, or TM in absence of C5b-9 deposition. Nevertheless, these features are not constantly detected and muscle biopsy could not be diriment. For this reason, muscle biopsy should always be critically considered in light of the clinical context before concluding for a definite diagnosis of IMNM, only based on histopathological findings. More rigorous collection and analysis of muscle biopsy is warranted to obtain a higher quality and more homogeneous histopathological data in inflammatory myopathies.
Topics: Autoantibodies; Autoimmune Diseases; Humans; Muscle, Skeletal; Muscular Diseases; Myositis; Necrosis
PubMed: 34798316
DOI: 10.1016/j.autrev.2021.102993 -
The New England Journal of Medicine Feb 2016
Review
Topics: Algorithms; Autoimmune Diseases; Glucocorticoids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Muscle, Skeletal; Muscular Diseases; Prednisone
PubMed: 26886523
DOI: 10.1056/NEJMra1515161