Muscle Disorders
Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw in Hankey's Clinical Neurology, 2020
Skeletal muscle tissue is unique in several regards. It comprises individual, large, multinucleated, tube-shaped syncytial structures called myofibers. These develop through fusion of mononucleated precursors. Myofibers are grouped into fascicles that, in turn, are arranged into individual muscles. The basic contractile units of myofibers are sarcomeres, composed of actin and myosin filaments, which give muscles their striated appearance. An acquired inflammatory myopathy characterized by progressive muscle weakness and the presence of inflammatory infiltrates and degenerating or regenerating fibers in the muscle. Dermatomyositis is an inflammatory myopathy with characteristic cutaneous manifestations. Childhood dermatomyositis is more common than childhood and adolescent polymyositis. Sporadic inclusion body myositis is a slowly progressive, often asymmetric myopathy. Degenerative and inflammatory factors may play a role in its pathogenesis. Metabolic and endocrine myopathies are a large, heterogeneous group of inherited and acquired disorders of muscle due to a disturbance of metabolism.
Autologous Hematopoietic Stem Cell Transplantation for Idiopathic Inflammatory Myositis
Richard K. Burt, Alberto M. Marmont in Stem Cell Therapy for Autoimmune Disease, 2019
The term idiopathic inflammatory myopathies (IIM) refers to a group of disorders of unknown cause in which immune-mediated inflammation results in muscle injury and complaints of weakness. IIM consist of six distinct subtypes including: type I- primary idiopathic polymyositis (PM), type II- primary idiopathic dermatomyositis (DM), type III- dermatomyositis or polymyositis associated with malignancy, type IV-juvenile dermatomyositis or polymyositis (JDM), type V- myositis associated with another connective tissue disease, and type VI- inclusion body myositis (IBM). 1 IIM is believed to be triggered by environmental factors in genetically susceptible individuals. Response to immunosuppressive therapies, frequent coexisting autoimmune diseases, existence of autoantibodies in patients’ serum, and experimental animal models all suggest an autoimmune pathogenesis. Patients develop proximal muscle weakness with or without tenderness of involved muscle. Laboratory tests reveal elevated serum muscle enzymes, myopathic changes by electromyography (EMG) and biopsy evidence of mononuclear cell infiltration with lymphocytes and plasma cells. Treatment includes corticosteroids, immunosuppressive drugs such as azathioprine, methotrexate, cyclophosphamide, cyclosporin and IVIG. While the overall prognosis for patients with IIM has improved in the last 20 years, there remain subsets of patients who continue to have active disease despite conventional therapy, for whom effects from long-term corticosteroids or immunosuppressive therapies are of concern, and for whom hematopoietic stem cell transplantation (HSCT) may be considered.
Hereditary inclusion body myopathies: clinical and genetic features Zohar Argov
Oded Abramsky, D. Alastair S. Compston, Ariel Miller, Gerard Said in Brain Disease, 2002
The term inclusion body myositis (IBM) was introduced three decades ago to describe an adult-onset, acquired (sporadic) inflammatory myopathy with two unique histological features:1 cytoplasmic ‘rimmed’ vacuoles containing whorls of cytomembranes, and typical cytoplasmic and nuclear inclusions. Electron microscopy (EM) shows that these inclusions are composed of clusters of tubular filaments with a diameter of 14-18 nm. The vacuoles are not membrane bound, for the term rimmed refers to the extra basophilic stain around many of these vacuoles on hematoxylin and eosin staining. During the same period, a group of hereditary myopathies, each with its unique clinical features and ethnic cluster, was described. The histological and ultrastructural picture in these diverse myopathies is very reminiscent of sporadic IBM, with one clear exception: the absence of inflammation.1 This heterogeneous group is now called hereditary inclusion body myopathy (HIBM).
Formation of Gelsolin Amyloid Fibrils in the Rough Endoplasmic Reticulum of Skeletal Muscle in the Gelsolin Mouse Model of Inclusion Body Myositis: Comparative Analysis to Human Sporadic Inclusion Body Myositis
Published in Ultrastructural Pathology, 2013
Sergei I. Bannykh, William E. Balch, Jeffery W. Kelly, Lesley J. Page, G. Diane Shelton
Sporadic inclusion body myositis has a significant impact on the life of the elderly. Despite some similarities to other myopathies with established genetic defects, little is known about mechanisms of its development and no effective treatment is available. Therefore, there is a need for animal models that can faithfully reconstitute important aspects of this human disease. The authors recently expressed a mutant form of human gelsolin in mice under the control of a muscle-specific promoter. This induced myopathic changes reminiscent of human inclusion body myositis. In this study, immunogold labeling is used to further characterize this model. The study demonstrates a presence of gelsolin amyloid deposits within the rough endoplasmic reticulum. It further compares this mouse model to human sporadic inclusion body myositis.
Advances in inclusion body myositis: genetics, pathogenesis and clinical aspects
Published in Expert Opinion on Orphan Drugs, 2017
Merrilee Needham, Frank Mastaglia
Introduction: Inclusion body myositis is the most common acquired muscle disease affecting older adults. It has an insidious onset with a very specific pattern of muscle involvement, but the aetiopathogenesis is still unknown. Pathologically the combination of inflammatory changes, degenerative changes as well as mitochondrial and nuclear changes are seen, and probably all contribute to the loss of muscle, however the primary abnormality remains a mystery. Treatment is currently supportive, but clinical trials are ongoing and are directed at new targets. Areas covered: Clinical profile, genetic susceptibility, pathogenesis and treatment Expert opinion: Understanding the aetiopathogeneis is vital to identify future treatment targets. In addition, understanding the natural history and the roles of biomarkers including the anti-CN1a antibody is vital for designing future clinical trials in IBM, to be properly designed and of sufficient duration to detect clinically significant changes.
Inclusion body myositis: from immunopathology and degenerative mechanisms to treatment perspectives
Published in Expert Review of Clinical Immunology, 2013
Jens Schmidt, Marinos C Dalakas
Inclusion body myositis is the most common inflammatory myopathy above the age of 50. It becomes clinically apparent around the fourth decade and leads to a slowly, but relentlessly progressive decline in muscular wasting and weakness. The pathology consists of a complex network of inflammatory and degenerative mechanisms, which lead to an attack of muscle fibers by auto-reactive T cells and possibly antibodies. At the same time, various aberrant proteins accumulate within the muscle fibers, including β-amyloid, tau and α-synuclein. Several key components of proinflammatory cell stress mechanisms such as nitric oxide production and macroautophagic processing contribute to the muscle fiber damage. So far, none of the anti-inflammatory or immunomodulatory treatment efforts have been able to halt the disease progression and help the patients. In this summary, the current concept of the complex disease pathology of IBM is reviewed with a focus on recent findings as well as future treatment perspectives.
Related Knowledge Centers
- Arm
- Inclusion Bodies
- Inflammation
- Muscle
- Myositis
- Hereditary Inclusion Body Myopathy
- T Cell