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      Cardiac Involvement in Primary Myopathies

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          Abstract

          Simultaneous or temporarily staggered affection of both the skeletal as well as the cardiac muscle (cardiac involvement, CI) is a frequent finding in primary myopathies (MPs). CI leads to impulse generation defects, impulse conduction defects, thickened myocardium, left ventriculalr hypertrabeculation, dilatation of the cardiac cavities, secondary valve insufficiency, reduction of coronary vasodilative reserve, intracardial thrombus formation, and heart failure with systolic and diastolic dysfunction. CI has been found in Duchenne muscular dystrophy (MD), Becker MD, Emery-Dreifuss MD, facioscapulohumeral MD, sarcoglycanopathies, myotubular congenital MD, myotonic dystrophies type 1 and 2, proximal myotonic myopathy, myoadenylate deaminase deficiency, glycogenosis type II, III, IV, VII and IX, carnitine deficiency, mitochondriopathy, desmin MP, nemaline MP, central core disease, multicore MP, congenital fiber-type disproportion MP, Barth syndrome, McLeod syndrome and Bethlem MP. Patients with any of the above-mentioned myopathies should be cardiologically investigated as soon as their diagnosis is established, since sufficient cardiac therapy improves CI in MPs and since management of these patients is influenced by the degree of CI.

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          Most cited references 29

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          Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy.

          Muscle contraction results from the force generated between the thin filament protein actin and the thick filament protein myosin, which causes the thick and thin muscle filaments to slide past each other. There are skeletal muscle, cardiac muscle, smooth muscle and non-muscle isoforms of both actin and myosin. Inherited diseases in humans have been associated with defects in cardiac actin (dilated cardiomyopathy and hypertrophic cardiomyopathy), cardiac myosin (hypertrophic cardiomyopathy) and non-muscle myosin (deafness). Here we report that mutations in the human skeletal muscle alpha-actin gene (ACTA1) are associated with two different muscle diseases, 'congenital myopathy with excess of thin myofilaments' (actin myopathy) and nemaline myopathy. Both diseases are characterized by structural abnormalities of the muscle fibres and variable degrees of muscle weakness. We have identified 15 different missense mutations resulting in 14 different amino acid changes. The missense mutations in ACTA1 are distributed throughout all six coding exons, and some involve known functional domains of actin. Approximately half of the patients died within their first year, but two female patients have survived into their thirties and have children. We identified dominant mutations in all but 1 of 14 families, with the missense mutations being single and heterozygous. The only family showing dominant inheritance comprised a 33-year-old affected mother and her two affected and two unaffected children. In another family, the clinically unaffected father is a somatic mosaic for the mutation seen in both of his affected children. We identified recessive mutations in one family in which the two affected siblings had heterozygous mutations in two different exons, one paternally and the other maternally inherited. We also identified de novo mutations in seven sporadic probands for which it was possible to analyse parental DNA.
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            Mitochondrial defects in cardiomyopathy and neuromuscular disease.

            Over the past 11 years, a considerable body of evidence has accumulated implicating defects in the mitochondrial energy-generating pathway, oxidative phosphorylation, in a wide variety of degenerative diseases including myopathy and cardiomyopathy. Most classes of pathogenic mitochondrial DNA mutations affect the heart, in association with a variety of other clinical manifestations that can include skeletal muscle, the central nervous system (including eye), the endocrine system, and the renal system. To better understand the pathophysiologic basis of mitochondrial diseases and their role in myopathy and cardiomyopathy, several mouse models of mitochondrial disease have been prepared. Mitochondrial DNA mutations from cultured cells have been introduced into mice; nuclear DNA genes involved in mitochondrial energy production and reactive oxygen species detoxification have been genetically inactivated, which resulted in mice with hypertrophic and dilated cardiomyopathy, respectively. Physiologic characterization of these mice has confirmed the importance of decreased mitochondrial energy production, increased mitochondrial reactive oxygen species production, and the mitochondrial initiation of apoptosis in mitochondrial disease. With these insights, new therapeutic approaches for neuromuscular and cardiac disease have been suggested.
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              Decreased myocardial nNOS, increased iNOS and abnormal ECGs in mouse models of Duchenne muscular dystrophy.

              Duchenne muscular dystrophy is a devastating neuromuscular disease caused by lack of the protein, dystrophin, in skeletal muscle and heart, although the biochemical mechanism by which dystrophin loss causes muscle dysfunction is unknown. Here we show that the dystrophin-deficient mdx mouse and a mouse lacking both dystrophin and the dystrophin-related protein, utrophin (dko), have abnormal electrocardiograms (ECGs). In skeletal muscle, dystrophin is normally associated with neuronal nitric oxide synthase (nNOS) at the sarcolemma. Consequently, we have measured NOS isoform activities in hearts from control, mdx and dko mice. In control mouse hearts, eNOS and nNOS activities increased by 120% and 47%, respectively, between 2 and 6 months of age. In mdx mice, myocardial nNOS activity was decreased by 60%, 84% and 80% at 2, 6 and 12 months of age, respectively. Similarly, hearts from dko mice showed a 65% decrease in nNOS activity compared to controls at 2 months of age. Endothelial NOS (eNOS) activity was not affected by dystrophin loss, but inducible NOS (iNOS) activity was seven-fold higher than control in the mdx mouse heart by 12 months of age. We conclude that lack of dystrophin in the mdx mouse results in abnormal ECGs that are associated with decreased myocardial nNOS and increased iNOS activities. Copyright 1999 Academic Press.
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                Author and article information

                Journal
                CRD
                Cardiology
                10.1159/issn.0008-6312
                Cardiology
                S. Karger AG
                0008-6312
                1421-9751
                2000
                November 2000
                22 November 2000
                : 94
                : 1
                : 1-11
                Affiliations
                aLudwig Boltzmann Institute for Research in Epilepsy and Neuromuscular Disorders, Vienna, and bMedical Department, Krankenanstalt Rudolfstiftung, Vienna, Austria
                Article
                7039 Cardiology 2000;94:1–11
                10.1159/000007039
                11111138
                © 2000 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 2, Tables: 4, References: 123, Pages: 11
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