Cardiac Manifestations in Emery–Dreifuss Muscular Dystrophy

PRACTICE | CASES CPD

Cardiac manifestations in Emery–Dreifuss muscular dystrophy

Whitney Faiella MD, Ricardo Bessoudo MD n Cite as: CMAJ 2018 December 3;190:E1414-7. doi: 10.1503/cmaj.180410

35-year-old man with a known history of Emery–Dreifuss muscular dystrophy called emergency medical services KEY POINTS (EMS) while at work one morning, reporting palpitations, • Emery–Dreifuss muscular dystrophy is one of many lightheadedness,A fatigue and a rapid heart rate. On arrival by neuromuscular diseases with cardiac involvement, including EMS, his pulse was documented at 195–200 beats/min, and his bradyarrhythmia, tachyarrhythmia and cardiomyopathy, and rhythm strips showed ventricular tachycardia (Figure 1A). He involves an increased risk of sudden cardiac death. underwent cardioversion and was given a bolus of amiodarone, • A recently published scientific statement highlights key cardiac 150 mg intravenously. In the emergency department and during manifestations in various forms of neuromuscular diseases and includes detailed recommendations regarding screening, admission, his symptoms persisted with rhythm strips showing follow-up and treatment for each individual disease. recurrent episodes of sustained ventricular tachycardia (Fig- • Medical optimization of cardiac function and early detection of ure 1B). He was subsequently started on an amiodarone drip and arrhythmias with subsequent insertion of a pacemaker or oral metoprolol. Echocardiography performed during admission defibrillator can be life-saving in this patient population. showed dilated cardiomyopathy with severe systolic dysfunction and an estimated ejection fraction of 23%. Cardiac catheteriza- tion was performed to rule out an ischemic cause of the cardio- With respect to the patient’s diagnosis of Emery–Dreifuss mus- myopathy and showed normal coronary arteries. The patient cular dystrophy, he first saw a neurologist at age 14 years after received an implantable cardioverter–defibrillator and was dis- multiple operations to lengthen his Achilles tendon owing to per- charged with prescriptions for an oral β-blocker and amiodarone. sistent “toe walking,” which is characteristic of the disease. He was As an outpatient, his amiodarone is slowly being weaned because subsequently referred to a muscular dystrophy specialist at age he has had no recurrent episodes of ventricular tachycardia. 15, when the diagnosis of Emery–Dreifuss muscular dystrophy was confirmed. Aside from the contractures of his Achilles tendons, he also has substantial difficulty with neck flexion sec- ondary to contractures in his neck extensors. The patient lives in a community with limited access to specialist care and has therefore not followed up with a muscular dystrophy specialist since age 15, because it would require substantial travel to a larger tertiary care centre. The patient’s first echocardiogram at age 15 showed a dilated cardiomyopathy with an ejection fraction of 45%– 50%. He was subsequently started on an angiotensin- converting enzyme (ACE) inhibitor by a cardiologist. He elected not to start a β-blocker because of potential adverse effects, including fatigue. Subsequently, he had a total of 4 follow-up appointments over the next 20 years with his cardiologist, where he remained completely asymptomatic from a cardiac perspective. He underwent serial echocardiography tests, which ultimately showed progression of his cardiomyopathy. His next echocardio- Figure 1: Rhythm strips in a 35-year-old man with Emery–Dreifuss muscular dystrophy, gram almost 10 years later showed a dilated left ventricle documenting wide complex tachycardia consistent with ventricular tachycardia. A) Ini- tial 3-lead rhythm strip performed on site by emergency medical services, with a docu- with mild global systolic dysfunction (ejection fraction of mented heart rate of 195 beats/min. B) Initial 12-lead electrocardiogram performed in 45%), which progressed to moderate left ventricular sys- the emergency department, with a documented heart rate of 186 beats/min. tolic dysfunction (ejection fraction of 35%–40%) over the

E1414 CMAJ | DECEMBER 3, 2018 | VOLUME 190 | ISSUE 48 © 2018 Joule Inc. or its licensors PRACTICE myo- E1415 8 Follow-up visits should Follow-up visits should 6 The AHA statement pro- The AHA statement 8 8

8 8 7 The AHA statement recommends, at minimum, Ambulatory monitoring can potentially help Ambulatory monitoring can potentially help be decided on an individual patient basis be decided on an individual patient basis according to symptoms and rate of disease progression. annual evaluations with ECG and ambulatory ECG monitoring in patients with autosomal recessive Emery–Dreifuss muscular dystrophy, with an additional annual echocardiography test in patients with autosomal dominant or X-linked subtypes of the condition. detect arrhythmia at an earlier stage because detect arrhythmia at an earlier stage because sudden cardiac death can often be the first presenting cardiac feature. tions once they become symptomatic or meet certain ECG criteria. ISSUE 48 ISSUE | The AHA statement provides specific recommendations regard- The AHA statement provides specific recommendations In 2017, the American Heart Association (AHA) published a sci- Heart Association (AHA) American In 2017, the tion often present with substantial conduction disease by age 20 20 age by disease conduction with substantial present tion often or implantable cardioverter– requiring pacing or 30 years, defibrillator placement to control symptoms and prevent sud- symptoms and placement to control defibrillator death. den cardiac ing follow-up, which are summarized in Box 1. In general, patientsing follow-up, which are summarized in Box years with either ECG,should be followed regularly every 1 to 2 depending on theechocardiogram or ambulatory ECG monitoring, For example, patientsparticular type of neuromuscular disease. 1B are at increased riskwith Limb-girdle muscular dystrophy type additional ambulatoryof sudden cardiac death and should have are asymptomatic orECG monitoring at least every 2 years if they they have cardiac findings such as a cardiomyopathyevery year if (DM1) are also ator arrhythmia. Patients with myotonic dystrophy should undergo serialincreased risk of sudden cardiac death and exercise stress testing, as physical exercise can be proarrhythmo- investiga- and attention further require also patients These genic. entific statement on the management of cardiac disease in disease in of cardiac on the management entific statement disease. patients with neuromuscular Cardiac screening and monitoring be screened with Patients with a neuromuscular disease should even if they are ECG and echocardiography at time of diagnosis of disease (i.e., asymptomatic. Patients with certain types [Barth syndrome, tonic dystrophy, mitochondrial myopathy should also have Friedreich ataxia], myofibrillar myopathy) because of the higher ambulatory ECG monitoring at diagnosis risk of arrhythmia and sudden cardiac death. - on a variety of neuromuscular dis vides background information is cardiac involvement, including X-linked orders in which there dystrophies (Duchenne, Becker and and recessive muscular - muscular dystrophy, myotonic dys Emery–Dreifuss), limb–girdle and myofibrillar myopathy. The trophy, congenital myopathy - cardiac manifestations, including cardio statement highlights - unique to each neuromuscular dis myopathy and arrhythmia, summarized in Box 1. Recommendations ease listed, which are therapies medical follow-up, evaluation, cardiac initial on focus to ranging from lifestyle modifications and other therapies cardioverter–defibrillator implantation. VOLUME 190 VOLUME | - Of note, Of note, 2 DECEMBER 3, 2018 | CMAJ Patients with this condi- 6 X-linked Emery–Dreifuss muscu- 1 More specifically, electrocardiography can can More specifically, electrocardiography 3,4 and to severe left ventricular systolic dysfunction dysfunction systolic ventricular left severe to and In X-linked and autosomal dominant forms of Emery– In X-linked and autosomal dominant forms 5 - admission, electrocardiogra before this current A few months Emery–Dreifuss muscular dystrophy is characterized by characterized by Emery–Dreifuss muscular dystrophy is

Twelve-lead electrocardiogram during hospital admission showing a 3:2 Mobitz Figure 2: Twelve-lead electrocardiogram during hospital admission showing a 3:2 Mobitz type I second-degree atrioventricular block, with a heart rate of 57 beats/min. Emery–Dreifuss muscular dystrophy is a rare inherited form of of dystrophy is a rare inherited form Emery–Dreifuss muscular - that can be inherited in an X-linked, autoso muscular dystrophy rarely, an autosomal recessive pattern. mal dominant or, more combined prevalence of the X-linked and Data suggest that the - forms of Emery–Dreifuss muscular dystro autosomal dominant autosomal recessive phy is 0.1–0.4 cases per 100 000, with the subtype being extremely rare. Discussion years 4 next current admission. of 23%) on this (ejection fraction block. Dur- atrioventricular showed a new first-degree phy (ECG) includ- captured rhythms admission, telemetry ing this hospital type I) second-degree (Mobitz bradycardia and a ing sinus asymptomatic remained He 2). (Figure block atrioventricular for therefore, there was no indication throughout all episodes; pacemaker insertion. lar dystrophy is caused by a mutation in the EMD gene producing lar dystrophy is caused by a mutation in the emerin and the FHL1 gene producing FHL1 protein, whereas the are caused by a muta- autosomal dominant and recessive forms tion in the LMNA gene producing lamin A/C proteins. show bradycardia from both sinoatrial or atrioventricular ori atrioventricular or sinoatrial both from bradycardia show gins, as well as tachyarrhythmia from atrial or ventricular atrial or ventricular gins, as well as tachyarrhythmia from origins. although genetic testing was never done in this patient, his in this patient, his although genetic testing was never done muscular dys- biopsy confirmed emerin-positive Emery–Dreifuss one of the other trophy, which suggests his mutation affected protein products. tendons and cervi- early-onset contractures of elbows, Achilles and atrophy in a cal spine, with progressive muscle weakness is estimated humeroperoneal distribution. Cardiac involvement mani- condition, the with patients of 90% than more in occur to and variable dilated festing as a variety of conduction defects cardiomyopathy. Dreifuss muscular dystrophy, there is a high rate of atrial fibrilla- Dreifuss muscular dystrophy, there is a high tion and flutter, and atrial standstill, which increases the risk of thromboembolic events and stroke. PRACTICE E1416 ade andmineralocorticoidantagonistarerecommendedinthesetting An ACEinhibitororangiotensinreceptorblocker,β Management ofcardiacinvolvement myopathy Mitochondrial dystrophy muscular Limb–girdle dystrophy Myotonic Myofibrillar myopathy *This list includes specificdiseases associated withincreased riskofsudden cardiac death. 1B–E, LGMD2B–I =limb–girdle musculardystrophy types2B–I,VT=ventricular tachycardia. DM2 =myotonic dystrophy 2,ECG =electrocardiography, musculardystrophy, EDMD=Emery–Dreifuss EP=electrophysiology, LGMD1B–E =limb–girdle musculardystrophy types Note: +=at riskfor suddencardiac death, –=not at riskfor suddencardiac death, AFib=atrial fibrillation, AT =atrial tachycardia, AV =atrioventricular, DM1=myotonic dystrophy 1, dystrophy Muscular Neuromuscular disease arrhythmia), riskof suddencardiac death andrecommended follow-up Box 1:Neuromuscular diseases* andtheircorresponding clinical presentation, cardiac manifestations (cardiomyopathy and Barth and LGMD2B–I LGMD1B–E DM2 DM1 Duchenne Dreifuss Emery– Becker ataxia Friedreich restriction since birth and growth muscle weakness proximal skeletal Neutropenia, and shouldergirdles weakness ofpelvic Proximal muscle myotonia distal limb)and (facial, neckand Muscle weakness myotonia distal limb)and (facial, neckand Muscle weakness respiratory failure progressing to weakness Proximal muscle atrophy weakness and humeroperoneal cervical spine)plus tendons, elbows and Contractures (Achilles less severe course but later onset and Similar to Duchenne, diabetes dysfunction and scoliosis, sensory Ataxia, spasticity, proximal muscles involving distal and muscle weakness Slowly progressive presentation Clinical CMAJ | DECEMBER 3,2018 -adrenergic block- hypertrophic Dilated, Dilated Rare hypertrophic Dilated, Dilated (common) Dilated (rare) Hypertrophic hypertrophic Dilated, Cardiomyopathy | VOLUME 190 mended evenifpatientsstillhavepreservedleftventricularfunction. including DuchenneandBecker,someofthesetherapiesarerecom- of reducedejectionfraction.Insomeformsmusculardystrophy, VT AV AT, block, VT Rare flutter, VT AFib, atrial flutter, AFib, VT AV atrial block, VT AFib, VT AV AT, block, flutter, AT AFib, atrial Arrhythmia 8 | ISSUE 48 + (LGMD1B) Sudden death + + + – – – – • • • • • • • • • • • • • • • • • ECG andechocardiography ECG andechocardiography young patients withDM1 Serial exercise stress testing in an EPstudy AV blockshouldbeconsidered for > 240ms,QRS duration >120msor dizziness, syncope, PR interval Patients withpalpitations, in asymptomatic patients plus echocardiography 2–4yr every ECG andambulatory ECG 1yr every in autosomal recessive EDMD ECG andambulatory ECG 1yr every recessive EDMD autosomal dominantandX-linked ambulatory ECG 1yrin every ECG, echocardiography and Ambulatory ECG 1–3yr every asymptomatic patients if there are cardiac findingsin 1yrinpatientsevery aged >10yror 2 yrinpatients aged < 10 yrand ECG andechocardiography every asymptomatic boys ambulatory ECG 1yrin every ECG, echocardiography and 1 yrinasymptomatic infants 6 moplusambulatory ECG every additional investigations Symptoms shouldprompt 1 yrifcardiac findingsare present in asymptomatic LGMD1B orevery ECG andambulatory ECG 2yr every 1 yrifcardiac findingsare present dystrophy except LGMD1B) orevery all typesoflimb–girdle muscular 2 yrinasymptomatic patients (for patients Ambulatory ECG insymptomatic 1 yrinasymptomatic patients ECG andechocardiography every ambulatory ECG monitoring Symptoms shouldprompt asymptomatic patients Ambulatory ECG 1–4yrin every 1 yrinasymptomatic patients ECG andechocardiography every Follow-up

every every every 8 PRACTICE

E1417 ISSUE 48 ISSUE | Feingold B, Mahle W, Auerbach S, et al. Management of cardiac involvement involvement Management of cardiac S, et al. B, Mahle W, Auerbach Feingold statement from the associated with neuromuscular diseases: a scientific American Heart Association. Circulation 2017;136:e200-31. transplantation after cardiac et al. Clinical outcomes S, Brown R, Wu RS, Gupta 2010;29:432-38. in muscular dystrophy patients. J Heart Lung Transplant in Becker’s muscular dys- Finsterer J, Bittner R, Grimm M. Cardiac involvement before apparent skeletal trophy, necessitating heart transplantation, 6 years muscle involvement. Neuromuscul Disord 1999;9:598-600. Anselme F, Moubarak G, Savoure A, et al. Implantable cardioverter-defibrillatorsAnselme F, Moubarak G, Savoure A, et al. Implantable disorders. Heart Rhythm in lamin A/C mutation carriers with cardiac conduction 2013;10:1492-8. Theodorn A, Rodrigues M, Roxburgh R, et al. Prevalence of muscular dystro- of muscular Prevalence et al. M, Roxburgh R, A, Rodrigues Theodorn review. Neuroepidemiology 2014;43:259-68. phies: a systemic literature Emery-Dreifuss muscular dystrophy. Handb Clin Puckelwartz M, McNally E. Neurol 2011;101:155-66. - fibrillation/flut atrial of relevance Clinical al. et L, Merlini M, Gallina G, Boriani and heart failure in Emery-Dreifuss muscular ter, stroke, pacemaker implant, study. Stroke 2003;34:901-8. dystrophy: a long-term longitudinal assessment of Draminska A, Kuch-Wocial A, Szulc M, et al. Echocardiographic with Emery-Dreifuss mus- left ventricular morphology and function in patients cular dystrophy. Int J Cardiol 2005;102:207-10. involvement of cardiac Management et al. L, T, Oukerraj R, Elhouari Bouhouch in neuromuscular diseases. Open Cardiovasc Med J 2008;2:93-6. Card Electro- Rajdev A, Groh W. Arrhythmias in the muscular dystrophies. physiol Clin 2015;7:303-8.

8. 9. 1. 2. 3. 4. 5. 6. 7. 10. designContributors: Both authors were involved in the conception and manuscript, which bothof the manuscript. Whitney Faiella drafted the of the version to beauthors revised. Both authors gave final approval of the work. published and agreed to be accountable for all aspects Correspondence to: Whitney Faiella, [email protected] References can be life-threatening. This case stresses the importance of of importance the stresses case This life-threatening. be can follow-up and regular annual by a cardiologist early evaluation neuromuscu - in patients with absence of symptoms despite the ACE Medical therapies including lar disease. inhibitor, β-blocker to optimize should be initiated antagonist and mineralocorticoid a of insertion and of arrhythmia detection Early function. cardiac can be life-saving, as sudden cardiac pacemaker or defibrillator the first presenting cardiac feature in this death can often be patient population. VOLUME 190 VOLUME |

8 DECEMBER 3, 2018 | 9,10 CMAJ Cardiac involvement in patients with neuromuscular disor- Cardiac involvement Because of the high risk of sudden cardiac death in patients in patients cardiac death sudden high risk of of the Because Competing interests: None declared. This article has been peer reviewed. The authors have obtained patient consent. II HealthAffiliations: Department of Medicine (Faiella), Queen Elizabeth NS; Division of Cardiol- Sciences Centre, Dalhousie University, Halifax, Hos- Regional John Saint Centre, Heart Brunswick New (Bessoudo), ogy pital, Saint John, NB ders can result in end-stage heart failure. The use of ventricular The use of ventricular ders can result in end-stage heart failure. has not been well assist devices and cardiac transplantation associated musculo- studied, since these patients often have making them skeletal weakness or restrictive lung disease, some case reports poor surgical candidates. There have been patients whose cardio- on successful cardiac transplantation in their skeletal mus- myopathy has progressed more rapidly than a potential option for cle weakness, suggesting that this may be select patients with neuromuscular disease. with neuromuscular disease, the AHA statement includes spe- AHA statement includes disease, the with neuromuscular of implant- to the placement relating cific recommendations implantable Placement of an able cardioverter–defibrillators. with left in patients is recommended cardioverter–defibrillator of 35% and an ejection fraction systolic dysfunction ventricular - of this criteria, placement should be con or less. In the absence with a neuromuscular disease in which sidered in patients includes This feature. predominant a be may arrhythmia dystrophies; muscular Emery–Dreifuss and Becker Duchenne, limb–girdle and ataxia; Friedreich 1; type dystrophy myotonic - type 1B. In Emery–Dreifuss muscular dys muscular dystrophy do who patients in considered be should implantation trophy, - if they have additional high-risk fea not meet the usual criteria an ejection tachycardia, ventricular tures, such as nonsustained 45%, male sex and lamin A/C mutation. fraction of less than

Conclusion for several years, the Despite known dilated cardiomyopathy - epi until asymptomatic largely remained case this in patient a presentation that sodes of sustained ventricular tachycardia,