REVIEW ARTICLE

Cardiac Involvement in Emery-Dreifuss and Related Management Strategies

Shuai Wang,1 MD and Daoquan Peng,1 MD

Summary Emery-Dreifuss muscular dystrophy (EDMD) is a group of hereditary muscular dystrophy syndrome caused by deficiency of genes encoding proteins. Patients having EDMD show the triad of muscle dystrophy, joint contracture, and cardiac disease. In almost all patients, cardiac involvement is prevalent and is the most severe aspect of EDMD. Cardiac disease is predominantly shown by conduction defects, atrial fibrillation/flutter, and atrial standstill. Sudden death and because of left ventricular dysfunction are important causes of mortality, particularly in those patients that have the LMNA . Medical treatment of EDMD is limited to addressing symptoms and ambulation support; moreover, pacemaker implantation is neces- sary when there are severe conduction defects and bradycardia occurs. Note that automated defibrillation de- vices may be considered for those patients who have a high risk of sudden death, rate, or rhythm control. Also, anticoagulation should be initiated in those patients who have atrial fibrillation/flutter. Thus, for optimal man- agement, a multidisciplinary approach is required. (Int Heart J 2019; 60: 12-18) Key words: disease,

n the 1960s, two neurologists, Emery and Dreifuss, Inheritance and Genes of EDMD identified a unique group of hereditary muscle-joint- I cardio syndrome.1) Compared with Duchenne and Although there is a defining group of clinical find- Becker muscular dystrophy (DMD and BMD), the clinical ings, the proteins and underlying gene defects responsible course for its treatment is benign.2-4) The syndrome was for EDMD are different. Among the affected families, dif- named as Emery-Dreifuss muscular dystrophy (EDMD), ferent inheritance patterns have been observed (Table). which is characterized by the following triad. First, a EDMD was first recognized as a different form of muscu- gradual progressive wasting and weakness in the scapulo- lar dystrophy from DMD/BMD in a family that had an X- humeroperoneal muscles, for which symptoms in most linked recessive inheritance pattern.7,8) Defects in EMD cases can appear in early childhood (< 15 years); how- (alternately known as STA), which encode nuclear enve- ever, the progress in muscle wasting is slow with loss of lope protein , were identified to be the cause of ambulation being reported only for exceptional cases. Sec- disease (EDMD1).9) ond, early contractures of elbows, achilles tendons, and Similarly, another inheritance type of EDMD is post-cervical muscles is observed. Third, cardiac involve- autosomal dominant (AD-EDMD). Although AD-EDMD’s ment, which usually becomes evident when affected indi- prevalence is unknown, it appears to be more common viduals reach the second or third decade of life, is pre- compared to X-linked EDMD (X-EDMD).10) For autoso- dominantly seen in the form of atrial mal dominant EDMD (EDMD2), mutation in LMNA is (conduction disturbance, atrial fibrillation/flutter, and atrial the most common cause.1) LMNA encodes A and standstill); moreover, it is occasionally companied by left C, both of which are components of nuclear envelope and ventricular systolic dysfunction (Figure 1).5) Although a located in the lamina. Moreover, autosomal recessive in- skeletal muscle disease such as EDMD is relatively be- heritance of LMNA has been described (EDMD3).11) Actu- nign compared to other muscular dystrophies, the cardiac ally, in addition to EDMD, in LMNA have been involvement can be severe and is the most serious and im- associated with various phenotypes, including limb-girdle portant aspect of EDMD.6) muscular dystrophy type 1B, autosomal recessive axonal neuropathy (CMT2B), and Hutchinson-Gilford syndrome. Furthermore, for (DCM), LMNA is being listed as one of the most common

From the 1Department of Cardiovascular Medicine, Second Xiangya Hospital of Central South University, Changsha, P.R. China. This work is funded by National Natural Science Foundation of China (Number: 81600359). Address for correspondence: Daoquan Peng, MD, Department of Cardiovascular Medicine, Second Xiangya Hospital of Central South University, 139 Ren- min Middle Road, Changsha, Hunan, 410011, P.R. China. E-mail: [email protected] Received for publication October 29, 2017. Revised and accepted December 27, 2017. Released in advance online on J-STAGE December 5, 2018. doi: 10.1536/ihj.17-604 All rights reserved by the International Heart Journal Association. 12 IntHeartJ January 2019 CARDIAC MANAGEMENT IN EDMD 13

Figure 1. Clinical presentation and management strategy for EDMD.

Table. Genes and Inheritance for EDMD

Type of Proportion of EDMD Gene Protein Location of protein Inheritance pattern EDMD attributed to this gene EDM (STA) Emerin Inner nuclear membrane (ubiquitously expressed) X-linked recessive EDMD1 ~61% of X-linked EDMD intercalated disc () LMNA Lamins A/C Inner nuclear membrane (ubiquitously expressed) Autosomal dominant EDMD2 ~45% of AD-EDMD Autosomal recessive EDMD3 unknown for AR-EDMD SYNE1 Nesprin-1 Nuclear envelope (ubiquitously expressed) Autosomal dominant EDMD4 Rare STNE2 Nesprin-2 Nuclear envelope (ubiquitously expressed) Autosomal dominant EDMD5 Rare FHL1 FHL1A Sarcomere I-band and Z-line, costamere (pre- X-linked recessive EDMD6 ~10% of X-linked EDMD dominant in skeletal muscle and intermediate level in the heart) FHL1B Shuttling between the nucleus and the cytoplas- ma (brain, skeletal muscle, cardiac muscle) FHL1C Nuclear (testis, skeletal muscle and cardiac mus- cle) TMEM43 LUMA Nuclear envelope Autosomal dominant EDMD7 Rare causative genes.12,13) Between the clinical phenotype and Pathogenesis type or localization of mutations within the gene, there has been no clear correlation. Moreover, in the clinical ex- LMNA and EMD are the two most common mutant pression of LMNA mutations, inter- and intra-familial vari- genes that have been identified in EDMD. Lamins A/C ability exist, ranging from patients expressing EDMD’s and emerin are the nuclear membrane proteins and com- full clinical picture to those characterized by only cardiac ponents of a proteinaceous meshwork (the nuclear lam- involvement. This suggests that modifier genes may also ina), which plays an important role for maintaining the ar- be involved during the course of EDMD. chitecture and serves as a scaffold for various other nu- Less common causative genes of EDMD are SYNE1, clear factors involved in DNA replication, chromatin or- which encodes nesprin-1 (autosomal dominant EDMD4), ganization, and transcription.6) Muscle biopsies for both and SYNE2, which encodes nesprin-2 (autosomal domi- affected X-EDMD and AD-EDMD patients revealed that nant EMD5).1,14) Moreover, mutations in TMEM43 and myonuclei display an aberrant nuclear architecture, break- FHL1 have been reported to be responsible for EDMD down of fragile nuclear membrane, and chromatin reor- myopathy1,14) (EDMD7) and 10% of X-EDMD (EDMD ganization.18,19) In addition to specific localization at the 6).15-17) Except for FHL1, all these genes encode linkers of inner nuclear membrane, in heart, and cultured rat cardio- nucleoskeleton and complex of the inner nu- myopathy, emerin was found to localize on the interca- clear membrane. lated disc, which may account for characteristic conduc- tion defects in EDMD.20) However, although mouse mod- els have been created and several working hypotheses have been developed,12,21) the pathogenic processes by IntHeartJ 14 WANG, ET AL January 2019

Figure 2. Replacement of atrial myocardium by fibrosis and adipose tissue is the major pathological changes in EDMD, which can eventually affect atrialventricular node and ventricle. which mutations in genes encoding nuclear envelope pro- usually is less evident after the third decade.20) The normal teins cause striated muscle abnormalities in EDMD re- myocardium is gradually replaced by the fibrous and adi- main unclear. pose tissue. It is a process that usually starts in the atria, often involves the atrioventricular node, and eventually af- fects the ventricles (Figure 2).23,24) Therefore, patients with Noncardiac Findings EDMD may have atrial , conduction abnor- Typically, occurs during adoles- malities, progressive dilation, and systolic failure. The se- cence and leads to the onset of EDMD symptoms. The af- verity of cardiac involvement does not correspond to the fected skeletal muscles follow a scapulohumeroperoneal progression of muscular weakness. In patients who only distribution with the serum creatine kinase (CK) levels be- have a mild skeletal muscle disorder, many suffer severe ing elevated in the affected family members.20) Compared conduction defects and require implantation of pacemak- with other muscular dystrophy, skeletal muscle involve- ers. Note that severe dilated cardiomyopathy has been re- ment of EDMD is benign. Moreover, muscle weakness ported for either EMD or LMNA mutation carriers. More- has a mild to moderate tendency to progress over years over, sudden death can even happen for a few of them, for a majority of X-EDMD patients.20) Severe disease which is probably attributable to malignant ventricular ar- course leading to loss of ambulation has only been re- rhythmia because it could not be prevented by implanta- ported for exceptional cases. Patients having AD-EDMD tion of pacemakers.25,26) Therefore, it is recommended that are prone to have a more severe disease course. During a patients diagnosed with EDMD should be referred for car- long-term longitudinal study that included 53 AD-EDMD diology evaluation.27) patients, 17% of them had markedly elevated serum CK Arrhythmia: In EDMD, conduction disturbances are the and lost the ability to walk unsupported early in life.22) predominant cardiac involvement. The initial cardiac result Joint contracture is another common presentation after is often accidental identification of a prolonged PR inter- muscle weakness. Flexion contractures of elbows, shorten- val and reduced amplitude of P wave in the ECG (Figure ing of achilles tendon and tightening of spinal extensor 3). Furthermore, various degrees of heart block may oc- muscle lead to a lordotic stance, a waddling gait, and ab- cur.1,28) sence of the deep tendon reflexes for the affected adults.5) Longitudinal studies related to EDMD suggested that atrial fibrillation and flutter, which can occur at various stages of EDMD, are the most frequent cardiac inci- Cardiac Involvement dents.23) A prolonged P-wave duration and increased P- In EDMD, cardiac involvement is quite common and wave dispersion (measures differences between the short- IntHeartJ January 2019 CARDIAC MANAGEMENT IN EDMD 15

Figure 3. Electrocardiogram (ECG) from a patient with EDMD. It shows bradycardia, junctional escape, and reduced amplitude of P wave in the ECG (red arrow). est and longest P-wave durations recorded from differen- a minority of patients having EDMD, which is different tial leads) can serve as a marker to identify the risk of from other X-linked muscular dystrophy such as DMD/ paroxysmal atrial fibrillation.29) BMD.22) In longitudinal studies reported by Boriani, et al., In EDMD, electrical silence of atrium is typically ob- heart failure requiring transplantation only occurred for 1 served, which is noticed by the P wave’s absence and the of 18 patients, whereas asymptomatic left ventricular dys- junctional or ventricular escape rhythm in the surface function occurred only for 3 patients.31) To date, although ECG. However, to verify true atrial silence, additional > 200 different EMD mutations have been reported, only electrophysiological examination is required because sinus a few of them have been reported to be associated with node dysfunction shares the same trace in the surface DCM.25) ECG. Although patients who develop third-degree heart Sudden death: In EDMD, cardiac involvement is unpre- blocks or atrial standstills are prone to suffer from symp- dictable and can be possibly life threatening, present with toms such as fatigue and , it is better tolerated by arrhythmias, and heart block-causing syncope or sudden EDMD, which may be a result of patients adapting to a death. For X-EDMD, syncope and sudden death may be slower rhythm and significant decreased physical activity the first symptom in rare cases.32) Sudden death in X- compared to their peers.30) EDMD is primarily caused by complete heart block and In EDMD patients who require a pacemaker for sig- can be possibly averted by pacemaker implantation. In nificant bradycardia, introduction of the dual-chamber longitudinal studies, no case of sudden death was ob- (DDD) pacing mode is practically limited because a served at long-term follow-up after pacemaker implanta- chronic AF is developed. In a longitudinal study, 18 pa- tion.33) However, pooled clinical data demonstrated that tients with genetically confirmed X-linked or autosomal patients carrying mutation in LMNA gene had an unex- dominant EDMD were followed for a period ranging from pected high risk of premature sudden death. This risk was 1 to 30 years. It was found that pacemakers were required not related to heart failure and seems to have been caused by 10 of 18 patients (56%). In 11 of 18 patients (61%), by lathy ventricular tachyarrhythmia because it cannot be atrial fibrillation/flutter developed, with atrial standstill prevented by pacemaker therapy.34,35) It is unclear which subsequently occurring for 5 of 11 (45%) cases.31) During clinical factors predicted the increased risk of sudden another retrospective study, 75% of those who received a death. In a European cohort study, nonsustained ventricu- DDD pacemaker had the mode changed to VVI. This was lar tachycardia, left ventricular ejection fraction of < 45%, requested 3-7 years after the first procedure because of male sex, and non-missense mutations were identified to the development of chronic AF.30) be risk factors for malignant ventricular arrhythmias.36) In the presence of either atrial standstill or atrial fib- Although female carriers of EMD mutation are not rillation/flutter, there is risk of cerebral thromboembolism affected by musculoskeletal manifestation,33) they are at because of emboli of cardiac origin. Note that a stroke risk of cardiac arrhythmia37-39) and sudden death.24) Sys- can be the first clinical manifestation of EDMD in young temic studies on the natural history of cardiac involvement adults and can be disabling. Therefore, for antithrom- in EMD mutation carriers are not available; however, it boembolic prophylaxis, administration of anticoagulants is seems appropriate to consider continuous ECG surveil- probably required in EDMD patients affected by atrial fib- lance. rillation/flutter or standstill.31) Cardiomyopathy and heart failure: While atrial cardio- Diagnosis myopathy is the predominant cardiac effect, heart failure because of dilated cardiomyopathy (DCM) occurs only in EDMD-related diagnosis is based on a clinical trial IntHeartJ 16 WANG, ET AL January 2019 of joint contractures, proximal muscle weakness, and car- flutter, there is a risk of cerebral thromboembolism be- diac involvement. For this diagnosis, some tests could be cause of emboli of cardiac origin. Strokes can be the first pursued. Electrocardiography and echocardiography can clinical manifestation of EDMD in young adults and can help detect rhythm abnormalities or cardiomyopathy. Note be disabling; therefore, administration of anticoagulants that CK levels may be elevated and computed tomography for antithromboembolic prophylaxis is probably required can reveal the muscle involved. in EDMD patients affected by atrial fibrillation/flutter or Usage of cardiac magnetic resonance (CMR) to standstill.31) ACEIs, angiotensin receptor blocker (ARBs), evaluate patients with EDMD is limited because of the and mineralocorticoid receptor antagonist are the corner- frequent requirement for pacemaker implantation. More- stone of neurohormonal modulation in heart failure and over, although histological study confirmed that wide- were shown to be effective for reduction of cardiovascular spread atrial fibrosis underlies EDMD’s pathogenesis, a mortality in patients with heart failure and reduced LV study that included 8 patients with AD-EDMD demon- function. Although there is a lack of evidence in this spe- strated absence of significant replacement fibrosis by late- cial circumstance, it may be reasonable to prescribe gadolinium enhanced (LGR) CMR.40) This is different neurohormonal therapy to EDMD patients who have LV from other muscular dystrophy such as DMD/BMD, in dysfunction. In those who do not have pacemaker, use of which CMR is recommended for mutation carriers to de- beta-adernergic receptor blockers should be very cautious tect myocardial fibrosis, which is also an early sign of because of the concern of conduction defect and bradycar- myocardial injury even before systolic dysfunction oc- dia. curs.41,42) Such differences may imply different pathogene- sis of cardiac involvement in EDMD. Moreover, although Future Consideration and Unanswered Questions LGE-CME is generally used for ventricular imaging, it is not being widely employed for atrial imaging because of Cardiac diseases are a major cause of morbidity and technical challenges faced in achieving adequate image mortality in patients with EDMD. Currently, there is no resolution in thin-walled atriums.43) cure and treatment strategy is largely based on addressing Emerin and A/C are ubiquitously expressed at symptoms. Furthermore, EDMD is defined by a group of the nuclear membrane and can be assayed using exfolia- clinical manifestation. Although now it is known that it tive buccal cells, skin biopsy, or blood samples rather than could be caused by mutations in a group of genes encod- muscle biopsy.44) Consider that ~90% of EMD mutations ing nuclear envelope proteins, the mechanism and the result in the complete absence of proteins by immunohis- genotype-phenotype relationship is unclear. Moreover, at tochemical staining, immunocytochemistry may be infor- present, there is only limited clinical data available from mative if defects are found in emerin.45) However, im- several longitudinal studies because it was not until 1960s munochemistry has not been proven to be useful for es- that EDMD was separated from DMD/BMD and was rec- tablishing a diagnosis with defects in lamin A/C because ognized to be a unique syndrome. Because of its relatively of the isoform’s redundancy.46) Thus, to establish the ge- lower incidence, maintaining the global database collected netic diagnosis of EDMD, next-generation sequencing and from multiple registry center is important for us to better gene panels are commonly used. understand EDMD and answer related questions. Further- more, a multidisciplinary team, including a neurologist, a cardiologist, and an orthopedic spine surgeon is required Management Strategies for better management. At present, there is no cure for any of the subtypes of EDMD. All patients diagnosed with EDMD should be referred to cardiologists for a careful cardiological evalu- Disclosures ation. Treatment strategy is largely based on addressing these symptoms. For patients with muscular dystrophy, Conflicts of interest: None declared. gentle aerobic exercise combined with supervised sub- maximal strength training program as well as assistive de- References vices that are adapted to the patient’s deficiencies should be prescribed to preserve mobility and function.28,47,48) For 1. Pillers DA, Von Bergen NH. Emery-Dreifuss muscular dystro- certain patients, tendon release and corrective spinal sur- phy: a test case for precision medicine. Appl Clin Genet 2016; gery may be considered to assist mobility and optimize 9: 27-32. 1) 2. Kimura K, Morita H, Nakamura A, Takenaka K, Daimon M. quality of life. 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