The management of individuals with a neuromuscular disorder is usually focused on the skeletal muscle weakness and resulting complications, such as respiratory failure. Long-term prognosis of a number of neuromuscular conditions is, however, also determined by the type and severity of cardiac involvement. Early recognition and treatment of the cardiovascular complications are part of the task of the multidisciplinary team involved in the care of these patients. Although for several of the common conditions, there is general consensus on the cardiac investigations and treatments, in the rarer disorders, evidence-based recommendations are not available, and suggestions from experts provide an acceptable solution. This review summarizes the recent advances in our understanding of the pathogenesis and phenotypic diversity of cardiac complications associated with pediatric myopathies and provides a rational framework for planning the monitoring and therapeutic intervention in individual conditions. (J Child Neurol 2003; 18: 191—202).
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References
1.
Bushby K., Muntoni F., Bourke JP: 107th ENMC International Workshop: The Management of Cardiac Involvement in Muscular Dystrophy and Myotonic Dystrophy. 7th-9th June 2002 , Naarden, the Netherlands. Neuromuscul Disord in press.
Slucka C.: The electrocardiogram in Duchenne's progressive muscular dystrophy. Circulation1968;38:933—940.
4.
Nigro G., Comi LI, Politano L. et al: The incidence and evolution of cardiomyopathy in Duchenne muscular dystrophy. Int J Cardiol1990;26:271—277.
5.
Perloff JK: Cardiac rythm and conduction in Duchenne muscular dystrophy. J Am Coll Cardiol1984;3:1263—1267.
6.
Heymsfield SB , McNish T., Perkins JV, et al: Sequence of cardiac c h a n g e s i n D u c h e n n e m u s c u l a r d y s t r o p h y. A m H e a r t J1978;95:283—294.
7.
de Kermadec JM , Becane HM, Chenard A., et al: Prevalence of left ventricular systolic dysfunction in Duchenne muscular dystrophy: An echocardiographic study. Am Heart J1994; 127: 618—623.
8.
Corrado G., Lissoni A., Beretta S., et al: Prognostic value of electrocardiograms, ventricular late potentials, ventricular arrhythmias and left ventricular systolic dysfunction in patients with Duchenne muscular dystrophy. Am J Cardiol2002;89:838—841.
9.
Farah MG, Evans EB, Vignos PJ Jr: Echocardiographic evaluation of left ventricular function in Duchenne's muscular dystrophy. Am J Med1980; 69: 248—254.
10.
Takenaka A. , Yokota M., Iwase M., et al: Discrepancy between systolic and diastolic dysfunction of the left ventricle in patients with Duchenne muscular dystrophy . Eur Heart J1993;14:669—676.
11.
Backman E., Nylander E.: The heart in Duchenne muscular dyst r o p h y: A n o n i n v a s i v e l o n g i t u d i n a l study. E u r H e a r t J1992,13:1239-44.
12.
Eagle M., Baudouin SV, Chandler C., et al:Survival in Duchenne muscular dystrophy: Improvements in life expectancy since 1967 and the impact of home nocturnal ventilation. Neuromuscul Disord2002;12:926—929.
13.
Ishikawa Y. , Bach JR, Minami R.: Cardioprotection for Duchenne's muscular dystrophy. Am Heart J1999; 137: 895—902.
14.
Kober L., Torp-Petersen C., Carlsen JE, et al: A clinical trial of the angiotensin-converting-enzyme inhibitor, trandolapril, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med1995; 333: 1670—1676.
15.
Pfeffer MA, Braunwald E., Moye LA, et al: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: Results of the Survival and Ventricular Enlargement Trial. N Engl J Med1992;327:669—677.
16.
Thuillez C. , Richer C., Loueslati H., et al: Systemic and regional haemodynamic effects of perindopril in congestive heart failure. J Cardiovasc Pharmacol1990;15:527—535.
17.
TheSOLVD Investigators: Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive cardiac failure. N Engl J Med1991; 325: 293—302.
18.
TheCardiac Insufficiency Bisoprolol Study II (CIBIS II): A randomized trial. Lancet1999;353:9—13.
19.
MacMahon S. , Sharpe N., Doughty R., et al: Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet1997;349:375—380.
20.
Hjalmarson A., Goldstein S., Fagerberg B., et al: Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Lancet1999;353:2001—2007.
21.
McMurray JJ : Major beta-blocker mortality trials in chronic heart failure: A critical review. Heart1999 ;82(Suppl IV):14—22.
22.
Zannad F., Alla F., Dousset B., et al: Limitation of excessive extracellular matrix turn over may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: Insights from the Randomized Aldosterone Evaluation Study (RALES). RALES investigators. Circulation2001;102:2700—2706.
23.
Locolley P. , Safar ME, Lucet B., et al: Prevention of aortic and cardiac fibrosis by spironolactone in old normotensive rats. J Am Coll Cardiol2001; 37: 662—667.
24.
Dubrovsky AL , Angelini C., Bonifati DM, et al: Steroids in muscular d y s t r o p h y: W h e r e d o w e s t a n d ? N e u r o m u s c u l D i s o r d1998;8:380—384.
25.
Simonds AK, Muntoni F., Heather S., Fielding S.: Impact of nasal ventilation on survival in hypercapnic Duchenne muscular dystrophy . Thorax1998;53:949—952.
26.
Melacini P. , Fanin M., Danieli GA, et al: Cardiac involvement in Becker muscular dystrophy. J Am Coll Cardiol1993; 22: 1927—1934.
27.
Nigro G., Comi LI, Politano L., et al:Evaluation of the cardiomyo p a t h y i n B e c k e r m u s c u l a r d y s t r o p h y. M u s c l e N e r v e1995;18:283—291.
28.
Saito M., Kawai H., Akaike M., et al: Cardiac dysfunction with Becker muscular dystrophy. Am Heart J1996;132:642—647.
29.
Hoogerwaard EM, de Voogt WG, Wilde AA, et al: Evolution of cardiac abnormalities in Becker muscular dystrophy over a 13-year period. J Neurol1997;244:657—663.
Piccolo G., Azan G., Tonin P., et al:Dilated cardiomyopathy requiring cardiac transplantation as initial manifestation of Xp21 Becker type muscular dystrophy. Neuromuscul Disord1994;4:143—146.
32.
Nigro G., Politano L., Nigro V., et al:Mutation of dystrophin gene and cardiomyopathy. Neuromuscul Disord1994;4:371—379.
33.
Rees W., Schuler S., Hummel M., et al: Heart transplantation in patients with muscular dystrophy associated with end-stage cardiomyopathy. J Heart Lung Transplant1993;12:804—807.
34.
Towbin JA, Hejtmancik JF, Brink P., et al: X-linked cardiomyopathy. Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus. Circulation1993;87:1854—1865.
35.
Muntoni F., Cau M., Congiu R., et al: Deletion of the dystrophin muscle-promoter region associated with X-linked dilated cardiomyopathy. N Engl J Med1993;329:921—925.
36.
Ferlini A., Sewry CA, Melis MA, et al: X-linked dilated cardiomyo p a t h y a n d t h e d y s t r o p h i n g e n e . N e u r o m u s c u l D i s o r d1999;9:339—346.
37.
Muntoni F., Di Lenarda A, Porcu M., et al: Dystrophin gene abnormalities in two patients with idiopathic dilated cardiomyopathy. Heart1997;78:608—612.
38.
Milasin J., Muntoni F., Severini GM, et al: A point mutation in the 5' splice site of the dystrophin gene first intron responsible for X-linked dilated cardiomyopathy. Hum Mol Genet1996;5:73—79. 39. Grain L., Cortina-Borja M., Forfar C., et al: Cardiac abnormalities and skeletal muscle weakness in carriers of Duchenne and Becker muscular dystrophies and controls. Neuromuscul Disord2001;11: 186-191.
39.
Politano L., Nigro V., Nigro V., et al: Development of cardiomyopathy in female carriers of Duchenne and Becker muscular dystrophies. JAMA1996 ;275:1335—1338.
40.
Hoogerwaard EM , van der Wouw PA, Wilde AA, et al: Cardiac involvement in carriers of Duchenne and Becker muscular dystrophy. Neuromuscul Disord1999;9:347—351.
41.
Mirabella M., Servidei S., Manfredi G., et al: Cardiomyopathy may be the only clinical manifestation in female carriers of Duchenne muscular dystrophy. Neurology1993;43:2342—2345.
42.
Bushby Kmd: The limb-girdle muscular dystrophies, in Emery AEH (ed): The Muscular Dystrophies. Oxford, Oxford University Press, 2001, 109—136.
43.
Bushby Kmd: The limb-girdle muscular dystrophies: Multiple genes, multiple mechanisms . Hum Mol Genet1999;8:1875—1882. 45. Campbell KP: Three muscular dystrophies: Loss of cytoskeletonextracellular matrix linkage. Cell1995;80:675—679.
44.
Melacini P. , Fanin M., Duggan DJ, et al: Heart involvement in muscular dystrophies due to sarcoglycan gene mutations. Muscle Nerve1999;22:473—479.
45.
Calvo F., Teijeira S., Fernandez JM, et al: Evaluation of heart involvement in gamma-sarcoglycanopathy (LGMD2C). A study of ten patients. Neuromuscul Disord2000; 10: 560—566.
46.
Politano L. , Nigro V., Passamano L., et al: Evaluation of cardiac and respiratory involvement in sarcoglycanopathies. Neuromuscul Disord2001,11: 178—185.
47.
Barresi R., Di Blasi C, Negri T., et al: Disruption of heart sarcoglycan complex and severe cardiomyopathy caused by β sarcoglycan mutations. J Med Genet2000; 37: 102—107.
48.
Gnecchi-Ruscone T., Taylor J., Mercuri E., et al: Cardiomyopathy in Duchenne, Becker, and sarcoglycanopathies: A role for coronary dysfunction?Muscle Nerve1999;22:1549—1556.
49.
Coral-Vazquez R., Chohn RD, Moore SA, et al: Disruption of the sarcoglycan-sarcospan complex in vascular smooth muscle: A novel mechanism for cardiomyopathy and muscular dystrophy. Cell1999;98:465—474.
50.
Cohn RD, Durbeej M., Moore SA, et al: Prevention of cardiomyopathy in mouse models lacking the smooth muscle sarcoglycan complex. J Clin Invest2001;107:R1—R7.
51.
Brockington M., Yuva Y., Prandini P., et al: Mutations in the fukutin-related protein gene (FKRP) identify limb-girdle muscular dystrophy 21 as a milder allelic variant of congenital muscular dystrophy MDC1C. Hum Mol Genet2001; 10: 2851—2859.
52.
Poppe M., Cree L., Bourke JP, et al: FKRP mutations are an important cause of limb-girdle muscular dystrophy (LGMD2I). Neurology, in press.
53.
Muntoni F., Brockington M., Blake D., et al: Defective glycosylation in muscular dystrophy. Lancet2002; 360: 1419—1421.
54.
Emery Aed, Dreifuss FE: Unusual type of benign X-linked muscular dystrophy. J Neurol Neurosurg Psychiatry1966;29:338—342.
55.
Bione S., Maestrini E., Rivella S., et al: Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. Nat Genet1994;8:323—327.
56.
Bonne G., Di Barletta MR, Varnous S., et al: Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet1999;21:285—288.
57.
Di Barletta RM, Ricci E., Galluzzi G., et al: Different mutations in the LMNA gene cause autosomal dominant and autosomal recess i v e E m e r y - D r e i f u s s m u s c u l a r d y s t r o p h y. A m J G e n e t2000;66:1407—1412.
58.
Van der Kooi AJ, van Meegen M., Ledderhof TM, et al: Genetic localization of a newly recognized autosomal dominant limb-girdle muscular dystrophy with cardiac involvement (LGMD1B) to chromosome 1q11-21. Am J Hum Genet1997;60:891—895.
59.
Funakoshi M. , Tsuchiya Y., Arahata K.: Emerin and cardiomyopathy in Emery-Dreifuss muscular dystrophy. Neuromuscul Disord1999 ;9:108—114.
60.
Merlini L., Granata C., Dominici P., et al: Emery-Dreifuss muscular dystrophy: Report of five cases of a family and review of the literature. Muscle Nerve1986;9:481—485.
61.
Buckley AE, Dean J., Mahy IR: Cardiac involvement in Emery-Dreifuss muscular dystrophy: a case series. Heart1999;82:105—108.
62.
Vohanka S., Vytopil M., Beanarik J., et al: A mutation in the X-linked Emery-Dreifuss muscular dystrophy gene in a patient affected with conduction cardiomyopathy. Neuromuscul Disord2001;11:411—413.
63.
Waters DD, Nutter DO, Hopkins LD, Dorney ER: Cardiac features of an unusual X-linked humeroperoneal neuromuscular disease . N Engl J Med1975; 293: 1017—1022.
64.
Bensaid J., Vallat JM, Amsallem D., et al: La paralysie auriculaire permanente totale. Revue de la litterature a propos de 109 cas. Ann Cardiol Angeiol1995 ;44:139—145.
65.
Wehnert M., Muntoni F.: 60th ENMC International Workshop: Non X-linked Emery-Dreifuss Muscular Dystrophy , 5—7 June, 1998, Naarden, The Netherlands. Neuromuscul Disord1999;9:115—121.
66.
Bonne G., Mercuri E., Murchir A., et al: Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene. Ann Neurol2000;48:170—180.
67.
Becane HM, Bonne G., Varnous S., et al: High incidence of sudden death with conduction system and myocardial disease due to lamin A and C gene mutation. PACE2000;23:1661—1666.
68.
Nelson SD, Sparks EA, Graber HL, et al: Clinical characteristics of sudden death victims in heritable (chromosome 1p1-1q1) con-d u c t i o n a n d m y o c a r d i a l d i s e a s e . J A m C o l l C a r d i o l1998;32:1717—1723.
69.
Brodsky GL, Muntoni F., Miocic S., et al: Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement. Circulation2000;101:473—476.
70.
Fatkin D., MacRae C., Sasaki T., et al: Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med1999;341:1715—1724.
71.
Mercuri E., Muntoni F.: Congenital muscular dystrophies, in Emery AEH (ed): The Muscular Dystrophies. Oxford, Oxford University Press, 2001, 10—38.
72.
Spyrou N., Philpot J., Muntoni F., et al: Evidence of left ventricular dysfunction in children with merosin deficient congenital muscular dystrophy. Am Heart J1998;136:474—476.
73.
Saito K., Kobayashi M.: Fukuyama muscular dystrophies, in Emery AEH (ed): The Muscular Dystrophies. Oxford , Oxford University Press, 2001, 39—54.
74.
Brockington M., Blade DJ, Prandini P., et al: Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha-2 deficiency and abnormal glycosilation of alpha-dystroglycan. Am J Hum Genet2001;69:1189—1209.
75.
Salih Mam, Al Rayess M., Cutshall S., et al: A novel form of familial congenital muscular dystrophy in two adolescents. Neuropediatrics1998;29:289—293.
76.
Olofsson BO , Forsberg H., Andersson S., et al: Electrocardiographic findings in myotonic dystrophy. Br Heart J1988; 59: 47—52.
77.
Groh WJ, Miriam R., Lowe MS, et al: Severity of cardiac conduction involvement and arrhythmias in myotonic dystrophy type 1 correlates with age and CTG repeat length. J Cardiovasc Electrophysiol2002; 13: 444—448.
78.
Hayashi Y., Ikeda U., Kojo T., et al: Cardiac abnormalities and cytosine-thymine-guanine repeats in myotonic dystrophy. Am Heart J1997;134:292—297.
79.
Milner MR, Hawley RJ, Jachim M., et al: Ventricular late potentials in myotonic dystrophy. Ann Intern Med1991;115:607—613.
80.
Melacini P., Villanova C., Menegazzo E., et al: Correlation between cardiac involvement and the CTG trinucleotide repeat length in myotonic dystrophy. J Am Coll Cardiol1995; 25: 239—245.
81.
Badano L., Autore C., Fragola PV, et al: Left ventricular myocardial function in myotonic dystrophy. Am J Cardiol1993; 71:987—991.
82.
Finsterer J., Gharehbaghi-Schnell E., Stollberger C., et al: Relation of cardiac abnormalities and CTG-repeat size in myotonic dystrophy. Clin Genet2001; 59: 350—355.
83.
Hawley RJ, Milner MR, Gottdiener JS, et al: Myotonic heart disease: A clinical follow-up. Neurology1991;41:259—262.
84.
Clarke Nra, Kelion AD, Nixon J., et al: Does cytosine-thymine-guanine (CTG) expansion size predict cardiac events and electrocardiographic progression in myotonic dystrophy?Heart2001;86:1—5.
85.
Lazarus A., Varin J., Ounnoughene Z., et al: Relationship among electrophysiological findings and clinical status, heart function and extent of DNA mutation in myotonic dystrophy. Circulation1999;99:1041—1046.
86.
Antonini G. , Giubilei F., Mammaarella A., et al: Natural history of cardiac involvement in myotonic dystrophy: Correlation with CTG repeats. Neurology2000; 55: 1207—1209.
87.
De Ambrogi L, Raisaro A., Marchiano V., et al: Cardiac involvement in patients with myotonic dystrophy: Characteristic features of magnetic resonance imaging . Eur Heart J1995; 16:1007—1010.
88.
Vignaux O., Lazarus A., Varin J., et al: Right ventricular MR abnormalities in myotonic dystrophy and relationship with intracardiac electrophysiology test findings: Initial results . Radiology2002;224:231—235.
89.
Reardon W., Newcombe R., Fenton I., et al: The natural history of congenital muscular dystrophy: Mortality and long term clinical aspects. Arch Dis Child1993;68:177—181.
90.
Annane D., Merlet P., Radvanyi H., et al: Blunted coronary reserve in myotonic dystrophy. An early and gene-related phenomenon. Circulation1996;94:973—977.
91.
Igarashi H. , Momoi MY, Yamagata T., et al: Hypertrophic cardiomyopathy in congenital myotonic dystrophy. PaediatrNeurol1998;18:366—369.
92.
Timchenko LT : Myotonic dystrophy: The role of RNA CUG triplet repeats. Am J Hum Genet1999;64:360—364.
93.
Miller JW, Urbinati CR, Teng-Umnuay P., et al: Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J2000; 19: 4439—4448.
94.
Philips AV, Cooper TA: RNA processing and human disease. Cell Mol Life Sci2000;57:235—249.
95.
Savkur RS, Philips AV, Cooper TA: Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet2001; 29: 40—47.
96.
Philips AV, Timchenko LT, Cooper TA: Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy . Science1998;280:737—741.
97.
De Visser M, de Voogt WG, la Riviere GV: The heart in muscular dystrophy, fascioscapulohumeral dystrophy and Bethlem myopathy. Muscle Nerve1992;15:591—596.
98.
Faustmann PM, Farahati J., Rupilius B., et al: Cardiac involvement in fascio-scapulo-humeral muscular dystrophy: a family study using thallium-201 single-photon emission-computed tomography. J Neurol Sci1996;144:59—63.
99.
Baldwin BJ , Talley RC, Johnson C., Nutter DO: Permanent paralysis of the atrium in a patient with fascioscapulohumeral muscular dystrophy. Am J Cardiol1973;31:649—653.
100.
Kimura T., Moriwaki T., Sawada J., et al: A family with fascioscapulohumeral muscular dystrophy and hereditary long-QT syndrome. Rinsho Shinkeigaku1997;37:690—692.
101.
Laforet P. , de Toma C., Eymard B., et al: Cardiac involvement in genetically confirmed fascioscapulohumeral muscular dystrophy. Neurology1998;51:1454—1456.
102.
Woelfel A. , Cascio W., Smith SW: Cerebral embolization in two young patients with fascioscapulohumeral muscular dystrophy and atrial dysrhythmias. Am Heart J1989;118:632—633.
103.
Stevenson WG, Perloff JK, Weiss JN, et al: Facioscapulohumeral muscular dystrophy: Evidence for selective genetic electrophysiologic cardiac involvement. J Am Coll Cardiol1990; 15: 292—299.
104.
Airenne AL , Wallgren-Pettersson C.: Normal cardiac contractility in patients with congenital nemaline myopathy. Neuropediatrics1988;19:115—117.
105.
Skyllouriotis ML, Marx M., Skyllouriotis P., et al: Nemaline myopathy and cardiomyopathy . Pediatr Neurol1999;20:319—321
106.
Gospe SM Jr, Armstrong DL, Gresik MV, Hawkins HK: Life-threatening congestive heart failure as the presentation of centronuclear myopathy. Pediatr Neurol1987; 3: 117—120.
107.
Banwell BL , Becker LE, Jay V., et al: Cardiac manifestations of congenital fiber-type disproportion myopathy. J Child Neurol1999;14:83—87.
108.
Engel AG: Myofibrillar myopathy. Ann Neurol1999; 46: 681—683.
109.
Goldfarb LG , Park KY, Cervenakova L., et al: Missense mutations in desmin associated with famililar cardiac and skeletal myopathy. Nat Genet1998;19:402—403.
110.
Vicart P., Caron A., Guicheney P., et al: A missense mutation in the alpha-B-crystallin chaperone gene causes a desmin-related myopathy. Nat Genet1998;20:92—95.
111.
Melberg A. , Oldfors A., Blomstrom-Lundqvist C., et al: Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy linked to chromosome 10q. Ann Neurol1999;46:684—692.
112.
Danon MJ, Oh SJ, DiMauro S., et al: Lysosomal glycogen storage disease with normal acid maltase . Neurology1981;31:51—57.
113.
Muntoni F. , Catani G., Mateddu A., et al: Familial cardiomyopathy, mental retardation and myopathy associated with desmin-type intermediate filaments. Neuromuscul Disord1994;4:233—242.
114.
Morisawa Y. , Fujieda M., Murakami N., et al: Lysosomal glycogen storage disease with normal acid maltase with early fatal outcome. J Neurol Sci1998;160:175—179.
115.
Nishino I. , Fu J., Tanji K., et al: Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature2000;406:906—910.
116.
Andersen ED , Krasilnikoff PA, Overvad H.: Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies: A new syndrome?Acta Paediatr Scand1971;60:559—564.
117.
Plaster NM , Tawil R., Tristani-Firouzi M.: Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome . Cell2001; 105: 511—519.
