Neuromuscular Disorders 13 (2003) 166–172 www.elsevier.com/locate/nmd Workshop report 107th ENMC International Workshop: the management of cardiac involvement in and . 7th–9th June 2002, Naarden, the Netherlands

K. Bushby*, F. Muntoni, J.P. Bourke

Department of Neuromuscular Genetics, Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK Received 1 August 2002; accepted 16 August 2002

1. Introduction symptomatic presentation [13,14]. Although evidence in these rare conditions of the effect of treatment is lacking Sixteen participants from Austria, France, Germany, [15], extrapolation from other conditions causing heart fail- Italy, the Netherlands and the UK met to discuss the cardiac ure with means that there is a strong implications of the diagnosis of muscular dystrophy and case for the use of ACE inhibitors and potentially also beta myotonic dystrophy. The group included both myologists blockers, certainly in the presence of detectable abnormal- and cardiologists from nine different European centers. The ities and possibly preventatively [16–25]. aims of the workshop were to agree and report minimum The recommendations of the group are as follows. recommendations for the investigation and treatment of cardiac involvement in muscular and myotonic dystrophies, 2.1. DMD and define areas where further research is needed. During the workshop, all participants contributed to a review and † Patients should have a cardiac investigation (echo and assessment of the published evidence in each area and electrocardiogram (ECG)) at diagnosis. current practice amongst the group. Consensus statements † DMD patients should have cardiac investigations before for the management of , myotonic dystro- any surgery, every 2 years to age 10 and annually after phy, limb-girdle muscular dystrophy, Emery Dreifuss age 10. muscular dystrophy, facio-scapulo-humeral muscular † Respiratory failure is also common in DMD and assess- dystrophy and congenital muscular dystrophy were ment and treatment of respiratory function should be produced. The need for further research to extend the performed in parallel with the cardiological investiga- evidence-base in certain key areas was also highlighted tions [26]. and outline proposals to resolve these deficiencies put † Patients should be treated with angiotensin-converting forward. A summary of the cardiac implications of the enzyme (ACE) inhibitors initially in the presence of disorders discussed is presented in Table 1. progressive abnormalities [15–19]. Subsequently the addition of beta blockers should be considered [20–23]. † There is no evidence that the currently used steroid treat- 2. Dystrophinopathy [Duchenne and Becker muscular ment regimes have a detrimental effect on cardiac invol- dystrophy (DMD and BMD) and carriers of DMD and vement or are a contraindication for the concurrent use of BMD] ACE inhibitors [27]. † The multiple other complications of DMD including There is strong evidence of frequent progressive cardiac and respiratory failure mean that these patients involvement in these disorders, characterized ultimately by are rarely fit for cardiac transplantation. the development of dilated cardiomyopathy [1–12]. † There is an urgent need for multi-centre clinical trials to Abnormalities on investigation are more common than determine whether treatment of patients with cardiomyo- pathy, prior to the onset of symptoms, improves prog- * Corresponding author. Tel.: 144-191-241-8737; fax: 144-191-241- 8799. nosis and quality of life. There is also unpublished E-mail address: [email protected] (K. Bushby). evidence to suggest that treatment even before any

0960-8966/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. doi:10.1016/S0960-8966(02)00213-4 K. Bushby et al. / Neuromuscular Disorders 13 (2003) 166–172 167 Stevenson et al. [83]; De Visser et al. [77]; Laforetal. et [81] de Kermadec et al. [2]; Corrado et al. [3]; Farah et[4]; al. Backman et al. [6] al. [9]; Nigro et al.Hoogerwaard [8]; et al. [10] Brockington et al. [74]; Poppe et al. [73] Brockington et al. [74] Bonne et al. [57]; vanKooi der [60]; Fatkin et al.Becane [61]; et al. [62] Graham et al. [67]; Davies [68]; Becane et al. [62]; Fatkin et al. [61] Politano et al. [33]; Hoogerwaard et al. [34]; Grain et al. [35] Hayashi et al. [38]; Olofsson et al. [36]; Hawley et al.Antonini [43]; et al. [46]; Clarkeal. et [44] Van der Kooi et al.Politano [72]; et al. [71]; Gnecchi- Ruscone et al. [76] Emery et al. [52]; Merlinial. et [55]; Bione et al.Funakoshi [53]; et al. [54] – 35) – 11%. Several – cant cardiomyopathy fi 57) years; 50% of deaths – signi Few reports of clinically relevant cardiac involvement Cardiac death in approx 10 20%, usually in teens Cardiac death in up to 50% Melachini et al. [7]; Saito et DCM in 7 1/3 of adult cases have symptomatic cardiomyopathy. Further data needed on natural history May be a major contributory factor to early death 19 are sudden despite pacing common if not transplanted reports of successful cardiac transplantation individuals (mean age at pacing 24 years, range 14 Approx 5% require pacemaker insertion. Risk of SCD. unclear a 52 Mean age at pacing 32 (range 55 Death from heart failure 39 SCD common in non-paced – – – Age range Morbidity/mortality References Further work needed to establish prevalence of cardiac involvement in severe childhood onset disease ECG abnormalities detectable from age 6, progressive thereafter Variable, may be disproportionate to skeletal involvement proportion to skeletal muscle involvement LGMD2I/MDC1C relates to severity of overall disease Present from early childhood in most severe cases Earliest age at which abnormalities become clinically relevant is unclear. Greatest risk is in middle adulthood 90% Variable, may be out of – sudden cardiac death. 90%; ¼ 90% 90%, Echo . . – 65% – cant fi 95% by age 30 years 15 95% by age 30 years 10 . . % of patients in whom abnormality likely Abnormal ECG abnormal Echo ECG abnormal abnormal Variable estimates 21 signi Minor ECG changes in up to 30% 18.7% Not established Impact on overall prognosis Approximately 65% of the adult myotonic dystrophy population have abnormal ECG utter brillation brillation, fl fi fi hypertrophic cardiomyopathy; and SCD ¼ brillation/ utter and utter and fi fl fl and DCM increasing order of severity) and DCM ECG abnormalities: HCM and DCM AV block; atrial paralysis; atrial Dilated cardiomyopathy 35% of all cases 19 Conduction defects, atrial arrhythmias atrial ECG abnormalities; HCM and DCM ventricular tachy-arrhythmias atrial dilated cardiomyopathy; HCM ¼ DCM a MDC1A Reduced ejection fraction No reports to date of clinically Duchenne muscular dystrophy ECG abnormalities: HCM Table 1 Frequency, type and implications of cardiac involvement inDisease different forms of muscular dystrophy and myotonic dystrophy Cardiac involvement (in Becker muscular dystrophy ECGManifesting abnormalities: carriers HCM of DMD/ BMD MDC1C Dilated cardiomyopathy Invariable and clinically Laminopathies (including AD- EDMD, LGMD1B) Laminopathies (including AD- EDMD, LGMD1B) Facioscapulohumeral muscular dystrophy XL-EDMD AV block; atrial paralysis; Sarcoglycanopathies (LGMD2C-2F) LGMD2I ECG abnormalities, DCM 1/3 of adult onset cases Over whole spectrum of Myotonic dystrophy AV-conduction disturbances; 168 K. Bushby et al. / Neuromuscular Disorders 13 (2003) 166–172 impairment of ventricular function is detectable on echo- When invasive electrophysiology testing is performed in cardiogram may delay the onset and progression of cardi- patients with abnormal ECGs, it typically detects more omyopathy [28]. Concerns about the possible impact of widespread conduction abnormalities that that suggested ACE-inhibition on left ventricular development in very by the surface recording [45,46]. Electrophysiological young children, means that treatment in the very young tests and MRI may help to predict those at particular risk should only be undertaken in the context of a formal of severe arrhythmia [45,47,48]. Ventricular arrhythmias clinical trial, at the present time. are likely to explain some cases of sudden death. However, † There is a case for continued evaluation of more sophis- in patients with pacemakers implanted, the best predictor of ticated tools (echo tissue Doppler imaging, cardiac death is deteriorating respiratory function. magnetic resonance imaging (MRI), etc.) for earlier Cardiac investigation in these patients should include. detection of abnormalities, but these are not required for routine management [29]. † Annual ECG from diagnosis. † Holter monitoring may also be valuable at diagnosis in 2.2. BMD adult patients. † Echocardiogram should be performed at diagnosis in Cardiac involvement in BMD is common and is congenital myotonic dystrophy. frequently out of proportion to the skeletal muscle involve- † Additional investigations should include Holter monitor- ment [7–10]. ing, if annual ECG shows increasing PR interval or other evidence of increased risk of bradycardia. Invasive † BMD patients should have cardiac evaluation (ECG and measurement of the HV interval (infra-nodal conduction echo) at diagnosis. delay: HV .70 ms) may help decide the need for pacing † BMD patients should be screened for the development of in borderline cases. cardiomyopathy at least every 5 years. † Atrial tachyarrhythmias (atrial flutter, fibrillation) are † They should be seen more regularly and treated with common and, if symptomatic, may justify antiarrhythmic ACE inhibitors and, if indicated, beta blockers when treatment. However, antiarrhythmic drugs may aggravate progressive abnormality is found [15–25]. any preexisting tendency to bradycardia or ventricular † Cardiac transplantation may be a viable treatment in this tachy-arrhythmias. group of patients [30,31]. † Treatment with pacemaker is indicated when a progres- sive arrhythmia is detected even prior to symptoms. 2.3. Female carriers of DMD and BMD † Despite reports of ventricular tachy-arrhythmias the inci- dence is not sufficiently high to justify implantable defi- There is unequivocal evidence that approximately 10% of brillator therapy routinely when permanent pacing is female carriers of dystrophin mutations, either DMD or indicated. BMD develop overt cardiac failure even in the absence of † There is a need to collect data on cardiac involvement in any skeletal muscle involvement [32–35]. young patients to determine the incidence of cardiac complications in this group [49,50]. † All carriers of DMD or BMD should have echo and ECG at diagnosis or after the age of 16 years and at least every 3. Congenital muscular dystrophy 5 years thereafter, or more frequently in patients with abnormalities on investigation. The congenital muscular dystrophies are a heterogeneous † Carriers manifesting severe skeletal muscle symptoms or group of disorders, and cardiac involvement depends on the cardiac symptoms require more frequent investigation. type [49,50]. In congenital muscular dystrophy therefore it † Once significant abnormalities are detected patients may is necessary to define the genetic basis of the disease as the benefit from treatment with ACE inhibitors and addi- different types carry different cardiac risks. MDC1C (due to tional medication as indicated. fukutin-related protein gene (FKRP) mutations) needs to be † Ultimately cardiac transplantation may be appropriate. followed closely as cardiac involvement is common [51]. There are reports of cardiomyopathy in primary merosin 2.4. Myotonic dystrophy type 1 deficient congenital muscular dystrophy (CMD) but to date this has been non-progressive. In other types of CMD, echo There is clear evidence of conduction disease in myotonic and ECG is recommended at diagnosis and thereafter prior dystrophy, but not of ischaemic heart disease or of impaired to surgery or as clinically indicated. myocardial function [36–41]. In many patients, conduction defects progress in a predictable way over time [42–44]. Surface ECG may be normal despite the presence of impor- 4. Emery Dreifuss muscular dystrophy (EDMD) tant intra-Hisian conduction delay but the role of electro- physiological testing in patients with normal ECG is not EDMD is a genetically heterogeneous condition. X linked established [45]. This could be addressed in a trial setting. EDMD is due to mutations in the STA gene encoding the K. Bushby et al. / Neuromuscular Disorders 13 (2003) 166–172 169 protein emerin [52–56]. Autosomal dominant EDMD is due with XLEDMD, long term prognosis is directly related to to mutations in the lamin A/C gene [57–65]. Lamin A/C cardiac status, and investigation of these patients should be mutations are also found in a range of other conditions performed as outlined above. However, the cardiac manage- including autosomal recessive EDMD [66], LGMD1B, ment of this group is more complex than XLEDMD. Dilated familial dilated cardiomyopathy [67,68], partial lipodystro- cardiomyopathy may develop as well as conduction defects phy and peripheral neuropathy (AR CMT2). Variable [58–61]. Sudden death is seen in patients even after pacing phenotypes may be seen in the same family. [61–65]. As a result of accumulating evidence of sudden Because of the different implications of laminopathy and death even in patients who have been paced, the consensus emerinopathy both from the point of view of management recommendation at present is that implantable defibrillators and genetic counseling, a precise diagnosis should be sought may be a more appropriate form of management than pace- in all patients. makers in this group. However, management of these cases is complex and the complications of implantable defibrilla- 4.1. XLEDMD tors may be greater than with pacemakers. These patients should be managed in specialized centers and their data There is strong evidence for cardiac involvement in collated to contribute to further evidence in the future. In XLEDMD and in this condition long term prognosis is the meantime there is a strong indication for defibrillator entirely dependent on cardiac status [52–56]. The major implantation to be considered when anti-bradycardia pacing problem is that of atrioventricular (AV) conduction defects is indicated [62]. This interim recommendation needs to be and there are only very rare reports of development of validated over time through the collection of high quality dilated cardiomyopathy, congestive heart failure or death prospective data. after pacemaker insertion. Recommended investigations in this group include. 4.3. The role of anticoagulation

† Follow up by a cardiologist as ECG changes may be In both XLEDMD and ADEDMD atrial fibrillation/flutter subtle and difficult to interpret. and atrial standstill occur frequently, even after pacemaker † Twelve lead ECG (preferably at 50 mm/s) at diagnosis implantation, and this carries a substantial risk of thrombo- and annually thereafter. embolic events, including ischaemic stroke. When atrial † Holter monitoring for tachy- or brady-arrhythmias fibrillation or atrial standstill are recognised, antithrom- annually. boembolic prophylaxis with warfarin should be considered. † Echocardiography on a less regular basis. † Permanent pacemaker implantation is justified, even in asymptomatic patients, when ECG begins to show 5. The limb-girdle muscular dystrophies (LGMD) abnormalities of sinus node or AV node disease. However, nocturnal AV-Wenkebach may be a normal The limb-girdle muscular dystrophies are a very hetero- finding in young people. geneous group of disorders with variable underlying genetic † In the presence of sino-atrial or AV-nodal conduction abnormalities [69,70]. Cardiac involvement may be present abnormalities on surface ECG, the role of electrophysiol- in any type of sarcoglycanopathy (LGMD2C-F) [70–72]. ogy is unclear. Invasive electrophysiology testing prob- For example, LGMD2I due to mutations in the FKRP ably adds little to the decision to or timing of pacemaker gene appears to have a frequent association with cardiomyo- implantation. However, such testing may have a role in pathy [73,74]. In contrast, there is no evidence that cardiac determining the optimum mode of and sites for pacing. involvement occurs commonly in (LGMD2A) or dysferlinopathy (LGMD2B) [75]. Cardiac As with DMD, there may be some female carriers of this involvement has not been described to date in the rarer X-linked disease who manifest cardiac disease. Published LGMD2H (TRIM 32), LGMD2G (telethoninopathy) or cases of manifesting carriers may have been diluted by cases LGMD2J (titin) nor in the dominant forms of LGMD, of dominant disease. Carrier status should be established in LGMD1A (myotolin) and LGMD1C (caveolin). Therefore, females at risk. These women should be offered periodic the recommendations for cardiac surveillance in this group ECG surveillance to detect atrial or AV-nodal conduction depend very much on the particular type of LGMD. disease. There is a need for more systematic study of the † natural history of cardiac involvement in XLEDMD There is evidence to suggest that cardiac surveillance is carriers. not indicated routinely in LGMD2A, 2B, 2G, 2H, 2J, 1A, 1C. Occasional cardiac review might be useful, for exam- 4.2. Laminopathies ple at diagnosis and when patients lose independent ambulation. Apart from the partial lipodystrophy and CMT pheno- † Sarcoglycanopathy patients should be investigated with types, there is strong evidence for cardiac involvement in the same intensity as in patients with DMD/BMD (see laminopathy and this is progressive with age [57–65]. As above). 170 K. Bushby et al. / Neuromuscular Disorders 13 (2003) 166–172 † LGMD2I patients are at risk of cardiomyopathy and the basis for further studies. Anyone interested in taking part should be assessed as for DMD/BMD. The severity of in such studies are encouraged to contact the workshop cardiomyopathy may be out of proportion to that of organisers. skeletal muscle involvement. † ECG and echo appear to be appropriate investigative 1. When and how to treat cardiac abnormalities in dystro- tools for standard initial clinical assessment and follow- phinopathy. up. 2. The prevalence of cardiac abnormalities or cardiac symp- † Present perception is that the incidence of tachy- or toms in young patients with myotonic dystrophy. brady-arrhythmias in sarcoglycanopathies is low but the 3. The pathogenesis of cardiomyopathy in sarcoglycanopa- issue is not fully resolved. Some arrhythmia surveillance thies – the role of smooth muscle involvement. with Holter ECG or similar recordings is still justified. 4. The natural history of cardiac involvement in LGMD2I † Standard therapy should be effective in these patients and response to therapy. with evidence of cardiomyopathy, but trial-based 5. The natural history of cardiac involvement after implan- evidence of efficacy is lacking. table defibrillator in laminopathy. † Cardiac transplantation may be indicated in selected 6. Cardiac involvement in young patients with severe patients with cardiac failure progressing despite anti-fail- FSHD. ure therapy. † Further research studies are needed to determine: – Whether prophylactic therapy will prevent or delay the onset of cardiomyopathy in patients with LGMD2I. Acknowledgements – The natural history of cardiac involvement in LGMD2I and genotype-phenotype correlations. This Workshop was made possible thanks to the financial – Involvement of smooth muscle in coronary artery support of the European Neuromuscular Centre (ENMC) walls contributes to the development of cardiomyopa- and ENMC main sponsors: Association Franc¸aise contre thy in patients with sarcoglycanopathy. Data from les (France); Deutsche Gesellschaft fu¨r Musk- mouse models of the condition suggest a role for elkranke (Germany); Telethon Foundation (Italy); Muscular calcium antagonists as a specific treatment to reduce Dystrophy Campaign (United Kingdom); Muskelsvindfon- abnormalities of coronary artery flow and the devel- den (Denmark); Prinses Beatrix Fonds (The Netherlands); opment of related myocardial damage [76]. Given the Schweizerische Stiftung fu¨r die Erforschung der Muskelk- ¨ rarity of this condition, evidence of benefit from any rankheiten (Switzerland); Osterreichische Muskelforschung treatment in humans could only come from a well (Austria); Vereniging Spierziekten Nederland (The Nether- coordinated multi-centre collaborative study. lands); and ENMC associate member: Muscular Dystrophy Association of Finland. 6. Facioscapulohumeral muscular dystrophy (FSHD) Participants: FSHD is probably not a major cause of cardiac disease [77,78]. The older literature reporting atrial paralysis in † Prof. Corrado Angelini (Italy) FSHD may have represented cases of probably misdiag- † Dr John Bourke (UK) nosed EDMD [79]. There are few large series and few † Prof. Kate Bushby (UK) papers with secure genetic data [80,81]. Severe cardiac † Prof. Denis Duboc (France) involvement is exceptional (or not related to the FSHD). † Prof. Victor Dubowitz (ENMC) There appears to be a low incidence of conduction defect † Dr Josef Finsterer (Austria) and atrial arrhythmia potentially complicated by embolism † Dr Colin Forfar (UK) [82,83]. Data are lacking on the prevalence of cardiac † Dr Nickolaos Giatrakos (UK) problems in severe childhood disease, and these data should † Dr David Hilton-Jones (UK) be collected on a collaborative basis. † Dr Pascal Laforeˆt (France) For classical FSHD, echocardiography and ECG should † Dr Paola Melacini (Italy) be performed as a baseline investigation at diagnosis. † Prof. Francesco Muntoni (UK) Further cardiac follow up should be dictated by the clinical † Dr Ulrich Neudorf (Germany) situation. † Prof. Giovanni Nigro (Italy) † Prof. Thomas Voit (Germany) † Prof. Arthur Wilde (The Netherlands). 7. Future work The authors wish to thank Dr. G. Boriani for his helpful There are a number of questions which were identified as comments. K. Bushby et al. / Neuromuscular Disorders 13 (2003) 166–172 171

References vention trial in congestive heart failure (MERIT-HF). Lancet 1999;353:2001–2007. [1] Heymsfield SB, McNish T, Perkins JV, et al. Sequence of cardiac [23] McMurray JJ. Major beta-blocker mortality trials in chronic heart changes in Duchenne muscular dystrophy. Am Heart J failure: a critical review. Heart 1999;82(Suppl. IV):IV14–IV22. 1978;95:283–294. [24] Zannad F, Alla F, Dousset B, et al. Limitation of excessive extracel- [2] de Kermadec JM, Becane HM, Chenard A, et al. Prevalence of left lular matrix turn over may contribute to survival benefit of spirono- ventricular systolic dysfunction in Duchenne muscular dystrophy: an lactone therapy in patients with congestive heart failure: insights from echocardiographic study. Am Heart J 1994;127:618–623. the randomized aldosterone evaluation study (RALES). RALES [3] Corrado G, Lissoni A, Beretta S, et al. Prognositc value of electro- Investigators Circ 2001;102:2700–2706. cardiograms, ventricular late potentials, ventricular arrhythmias and [25] Locolley P, Safar ME, Lucet B, et al. Prevention of aortic and cardiac left ventricular systolic dysfunction in patients with Duchenne muscu- fibrosis by spironolactone in old normotensive rats. J Am Coll Cardiol lar dystrophy. Am J Cardiol 2002;89:838–841. 2001;37:662–667. [4] Farah MG, Evans EB, Vignos Jr PJ. Echocardiographic evaluation of [26] Eagle M, Baudouin SV, Chandler C, et al. Survival in Duchenne left ventricular function in Duchenne’s muscular dystrophy. Am J muscular dystrophy: improvements in life expectancy since 1967 Med 1980;69:248–254. and the impact of home nocturnal ventilation. Neuromuscul Disord [5] Takenaka A, Yokota M, Iwase M, et al. Discrepancy between systolic 2002;12:926–929. and diastolic dysfunction of the left ventricle in patients with Duch- [27] Dubrovsky AL, Angelini C, Bonifati DM, et al. Steroids in muscular enne muscular dystrophy. Eur Heart J 1993;14:669–676. dystrophy: where do we stand? Neuromuscul Disord 1998;8:380–384. [6] Backman E, Nylander E. The heart in Duchenne muscular dystrophy: [28] Denis DUBOC et al., Trial of ACE inhibition in preventing onset of a non-invasive longitudinal study. Eur Heart J 1992;13:1239–1244. cardiomyopathy in Duchenne & Becker Muscular Dystrophy (Presen- [7] Melacini P, Fanin M, Danieli GA, et al. Cardiac involvement in tation to ENMC 107th Workshop 7–9th June 002: ‘The management Becker muscular dystrophy. J Am Coll Cardiol 1993;22:1927–1934. of cardiac complications in muscular dystrophy and myotonic dystro- [8] Nigro G, Comi LI, Politano L, et al. Evaluation of the cardiomyopathy phy’ [personal communication]. in Becker muscular dystrophy. Muscle Nerve 1995;18:283–291. [29] Crilley JG, Boehm EA, Rajagopalan B, et al. Magnetic resonance [9] Saito M, Kawai H, Akaike M, et al. Cardiac dysfunction with Becker spectroscopy evidence of abnormal cardiac energetics in Xp21 muscular dystrophy. Am Heart J 1996;132:642–647. muscular dystrophy. J Am Coll Cardiol 2000;15:1953–1958. [10] Hoogerwaard EM, de Voogt WG, Wilde AA, et al. Evolution of [30] Piccolo G, Azan G, Tonin P, et al. Dilated cardiomyopathy requiring cardiac abnormalities in Becker muscular dystrophy over a 13-year cardiac transplantation as initial manifestation of Xp21 Becker type period. J Neurol 1997;244:657–663. muscular dystrophy. Neuromuscul Disord 1994;4:143–146. [11] Boland BJ, Silbert PL, Groover RV, et al. Skeletal, cardiac, and [31] Rees W, Schuler S, Hummel M, et al. Heart transplantation in smooth muscle failure in Duchenne muscular dystrophy. Pediatr patientswith muscular dystrophy associated with end-stage cardio- Neurol 1996;14:7–12. . J Heart Lung Transplant 1993;12:804–807. [12] Melacini P, Vianello A, Villanova C, et al. Cardiac and respiratory [32] Mirabella M, Servidei S, Manfredi G, et al. Cardiomyopathy may be involvement in advanced stage Duchenne muscular dystrophy. the only clinical manifestation in female carriers of Duchenne muscu- Neuromuscul Disord 1996;6:367–376. lar dystrophy. 1993;43:2342–2345. [13] Koyama J, Ray-Sequin PA, Davidoff R, et al. Usefulness of pulsed [33] Politano L, Nigro V, Nigro V, et al. Development of cardiomyopathy tissue Doppler imaging for evaluating systolic and diastolic left in female carriers of Duchenne and Becker muscular dystrophies. J ventricular function in patients with AL (primary) amyloidosis. Am Am Med Assoc 1996;275:1335–1338. J Cardiol 2002;89:1067–1071. [34] Hoogerwaard EM, van der Wouw PA, Wilde AA, et al. Cardiac [14] Miller S, Simonetti OP, Carr J, et al. MR Imaging of the heart with involvement in carriers of Duchenne and Becker muscular dystrophy. cine true fast imaging with steady-state precession: influence of Neuromuscul Disord 1999;9:347–351. spatial and temporal resolutions on left ventricular functional para- [35] Grain L, Cortina-Borja M, Forfar C, et al. Cardiac abnormalities and meters. Radiology 2002;223:263–269. skeletal muscle weakness in carriers of Duchenne and Becker muscu- [15] Ishikawa Y, Bach JR, Minami R. Cardioprotection for Duchenne’s lar dystrophies and controls. Neuromuscl Disord 2001;11:186–191. muscular dystrophy. Am Heart J 1999;137:895–902. [36] Olofsson BO, Forsberg H, Andersson S, et al. Electrocardiographic [16] Kober L, Torp-Petersen C, Carlsen JE, et al. A clinical trial of the findings in myotonic dystrophy. Br Heart J 1988;59:47–52. angiotensin-converting-enzyme inhibitor, trandolapril in patients with [37] Groh WJ, Miriam R, Lowe MS, et al. Severity of cardiac conduction left ventricular dysfunction after myocardial infarction. N Engl J Med involvement and arrhythmias in myotonic dystrophy type 1 correlates 1995;333:1670–1676. with age and CTG repeat length. J Cardiovasc Electrophysiol [17] Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on 2002;13:444–448. mortality and morbidity in patients with left ventricular dysfunction [38] Hayashi Y, Ikeda U, Kojo T, et al. Cardiac abnormalities and cyto- after myocardial infarction: results of the Survival and Ventricular sine-thyminie-guanine repeats in myotonic dystrophy. Am Heart J Enlargement Trial. N Engl J Med 1992;327:669–677. 1997;134:292–297. [18] Thuillez C, Richer C, Loueslati H, et al. Systemic and regional [39] Milner MR, Hawley RJ, Jachim M, et al. Ventricular late potentials in haemodynamic effects of perindopril in congestive heart failure. J myotonic dystrophy. Ann Int Med 1991;115:607–613. Cardiovasc Pharmacol 1990;15:527–535. [40] Melacini P, Villanova C, Menegazzo E, et al. Correlation between [19] SOLVD. The effect of enalapril on survival in patients with reduced cardiac involvement and the CTG trinucleotide repeat length in left ventricular ejection fraction and congestive cardiac failure. N myotonic dystrophy. J Am Coll Cardiol 1995;25:239–245. Engl J Med 1991;325:293–302. [41] Badano L, Autore C, Fragola PV, et al. Left ventricular myocardial [20] Anonymous. The cardiac insufficiency bisoprolol study II (CIBIS II): function in myotonic dystrophy. Am J Cardiol 1993;71:987–991. a randomized trial. Lancet 1999,11:138–142. [42] Finsterer J, Gharehbaghi-Schnell E, Stollberger C, et al. Relation of [21] MacMahon S, Sharpe N, Doughty R, et al. Randomized, placebo- cardiac abnormalities and CTG-repeat size in myotonic dystrophy. controlled trial of carvedilol in patients with congestive heart failure Clin Genet 2001;59:350–355. due to ischaemic heart disease. Lancet 1997;349:375–380. [43] Hawley RJ, Milner MR, Gottdiener JS, et al. Myotonic heart disease: [22] Hjalmarson A, Goldstein S, Fagerberg B, et al. Effect of metoprolol a clinical follow-up. Neurology 1991;41:259–262. CR/XL in chronic heart failure: metoprolol CR/XL randomized inter- [44] Clarke NRA, Kelion AD, Nixon J, et al. Does cytosine-thymine- 172 K. Bushby et al. / Neuromuscular Disorders 13 (2003) 166–172

guanine (CTG) expansion size predict cardiac events and electr-ocar- [64] Bharati S, Surawicz B, Vidaillet Jr HJ, Lev M. Familial congenital diographic progression in myotonic dystrophy? Heart 2001;86:1–5. sinus rhythm abnormalities: clinical and pathological correlates. [45] Lazarus A, Varin J, Ounnoughene Z, et al. Relationship among elec- Pacing Clin Electrophysiol 1992;15:1720–1729. trophysiological findings and clinical status, heart function and extent [65] Bonne G, Mercuri E, Murchir A, et al. Clinical and molecular genetic of DNA mutation in myotonic dystrophy. Circulation 1999;99:1041– spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy 1046. due to mutations of the lamin A/C gene. Ann Neurol 2000;48:170– [46] Antonini G, Giubilei F, Mammaarella A, et al. Natural history of 180. cardiac involvement in myotonic dystrophy: correlation with CTG [66] DiBarletta RM, Ricci E, Galluzzi G, et al. Different mutations in the repeats. Neurology 2000;55:1207–1209. LMNA gene cause autosomal dominant and autosomal recessive [47] De Ambroggi L, Raisaro A, Marchiano V, et al. Cardiac involvement Emery-Dreifuss muscular dystrophy. Am J Genet 2000;66:1407– in patients with myotonic dystrophy: characteristic features of 1412. magnetic resonance imaging. Eur Heart J 1995;16:1007–1010. [67] Graham RM, Owens WA. Pathogenesis of inherited forms of dilated [48] Vignaux O, Lazarus A, Varin J, et al. Right ventricular MR abnorm- cardiomyopathy. N Engl J Med 1999;341:1759–1762. alities in myotonic dystrophy and relationship with intracardiac elec- [68] Davies MJ. The cardiomyopathies: an overview. Heart 2000;83:469– trophysiology test findings: initial results. Radiology 2002;224:231– 474. 235. [69] Bushby KMD. The limb-girdle muscular dystrophies. In: Emery [49] Forsberg H, Olofsson BO, Eriksson A, et al. Cardiac involvement in AEH, editor. The muscular dystrophies, Oxford: Oxford University congenital myotonic dystrophy. Br Heart J 1990;63:119–121. Press, 2001. pp. 109–136. [50] Reardon W, Newcombe R, Fenton I, et al. The natural history of [70] Bushby KMD. The limb-girdle muscular dystrophies: multiple genes, congenital myotonic dystrophy: mortality and long term clinical multiple mechanisms. Hum Mol Genet 1999;8:1875–1882. aspects. Arch Dis Child 1993;68:177–181. [71] Politano L, Nigro V, Passamano L, et al. Evaluation of cardiac and [51] Brockington M, Blade DJ, Prandini P, et al. Mutations in the fukutin- respiratory involvement in sarcoglycanopathies. Neuromuscul Disord related protein gene (FKRP) cause a form of congenital muscular 2001;11:178–185. dystrophy with secondary laminin alpha-2 deficiency and abnormal [72] van der Kooi AJ, de Voogt WG, Barth PG, et al. The heart in limb- glycosilation of alpha-dystroglycan. Am J Hum Gen 2001;69:1189– girdle muscular dystrophy. Heart 1998;79:73–77. 1209. [73] Poppe MJ, Eagle M, Bourke J, Bullock R, Cree L, Buddles M, Bushby [52] Emery AED, Dreifuss FE. Unusual type of benign X-linked muscular K. Respiratory and cardiac involvement are an important part of limb- dystrophy. J Neurol Neurosurg Psychiatry 1966;29:338–342. girdle muscular dystrophy. Neuromuscul Disord 2002;12:732–733. [53] Bione S, Maestrini E, Rivella S, et al. Identification of a novel X- [74] Brockington M, Yuva Y, Prandini P, et al. Mutations in the fukutin- linked gene responsible for Emery-Dreifuss muscular dystrophy. Nat related protein gene (FKRP) identify limb-girdle muscular dystrophy Genet 1994;8:323–327. 21 as a milder allelic variant of congenital muscular dystrophy [54] Funakoshi M, Tsuchiya Y, Arahata K. Emerin and cardiomyopathy in MDC1C. Hum Mol Gen 2001;10:2851–2859. Emery-Dreifuss muscular dystrophy [Review]. Neuromuscul Disord [75] Pollitt C, Anderson LV, Pogue R, Davison K, Pyle A, Bushby KMD. 1999;9:108–114. The phenotype of calpainopathy: diagnosis based on multidisciplinary [55] Merlini L, Granata C, Dominici P, et al. Emery-Dreifuss muscular approach. Neuromuscul Disord 2001;11:287–296. dystrophy: report of five cases of a family and review of the literature. [76] Gnecchi-Ruscone T, Taylor J, Mercuri E, et al. Cardiomyopathy in Muscle Nerve 1986;9:481–485. Duchenne, Becker, and sarcoglycanopathies: a role for coronary [56] Wehnert M, Muntoni F. 60th ENMC International Workshop: non-X- linked Emery-Dreifuss muscular dystrophy 5–7 June 1998, Naarden, dysfunction?. Muscle Nerve 1999;22:1549–1556. The Netherlands. Neuromuscul Disord 1999;9:115–121. [77] De Visser M, de Voogt WG, la Riviere GV. The heart in muscular [57] Bonne G, Di Barletta MR, Varnous S, et al. Mutations in the gene dystrophy, fascioscapulohumeral dystrophy and . encoding lamin A/C cause autosomal dominant Emery-Dreifuss Muscle Nerve 1992;15:591–596. muscular dystrophy. Nat Genet 1999;21:285–288. [78] Faustmann PM, Farahati J, Rupilius B, et al. Cardiac involvement in [58] Buckley AE, Dean J, Mahy IR. Cardiac involvement in Emery-Drei- fascio-scapulo-humeral muscular dystrophy: a family study using fuss muscular dystrophy: a case series. Heart 1999;82:105–108. Thallium-201 single-photon-emission-computer tomography. J [59] Vohanka S, Vytopil M, Beanarik J, et al. A mutation in the X-linked Neurol Sci 1996;144:59–63. Emery-Dreifuss muscular dystrophy gene in a patient affected with [79] Baldwin BJ, Talley RC, Johnson C, Nutter DO. Permanent paralysis conduction cardiomyopathy. Neuromuscul Disord 2001;11:411–413. of the atrium in a patient with fascioscapulohumeral muscular dystro- [60] Van der Kooi AJ, van Meegen M, Ledderhof TM, et al. Genetic phy. Am J Cardiol 1973;31:649–653. localization of a newly recognized autosomal dominant limb-girdle [80] Kimura T, Moriwaki T, Sawada J, et al. A family with fascioscapu- muscular dystrophy with cardiac involvement (LGMD1B) to chromo- lohumeral muscular dystrophy and hereditary long-QT syndrome some 1q11–21. Am J Hum Gen 1997;60:891–895. [Japanese]. Rinsho Shinkeigaku 1997;37:690–692. [61] Fatkin D, MacRae C, Sasaki T, et al. Missense mutations in the rod [81] Laforet P, de Toma C, Eymard B, et al. Cardiac involvement in domain of the lamin A/C gene as causes of dilated cardiomyopathy genetically confirmed fascioscapulohumeral muscular dystrophy. and conduction-system disease. N Engl J Med 1999;341:1715–1724. Neurology 1998;51:1454–1456. [62] Becane HM, Bonne G, Varnous S, et al. High incidence of sudden [82] Woelfel A, Cascio W, Smith SW. Cerebral embolization in two young death with conduction system and myocardial disease due to lamin A patients with fascioscapulohumeral muscular dystrophy and atrial and C gene mutation. Pacing Clin Electrophysiol 2000;23:1661– dysrhythmias. Am Heart J 1989;118:632–633. 1666. [83] Stevenson WG, Perloff JK, Weiss JN, et al. Fascioscapulohumeral [63] Nelson SD, Sparks EA, Graber HL, et al. Clinical characteristics of muscular dystrophy: evidence for selective genetic electrophysiologic sudden death victims in heritable (Chromosome 1p1-1q1) conduction cardiac involvement. J Am Coll Cardiol 1990;15:292–299. and myocardial disease. J Am Coll Cardiol 1998;32:1717–1723.