Cardiac features of Emery–Dreifuss muscular dystrophy caused by lamin A/C gene mutations

Tommaso Sannaa,*, Antonio Dello Russoa, Daniela Toniolob, Michal Vytopilb, Gemma Pelargonioa, Giuseppe De Martinoa, Enzo Riccic, Gabriella Silvestric, Vincenzo Gigliod, Loredana Messanoa, Elisabetta Zacharae and Fulvio Belloccia

a Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy
b Institute of molecular genetics, CNR, Pavia, Italy
c Institute of Neurology, Catholic University of the Sacred Heart, Rome, Italy
d Centre for neuromuscular disease UILDM, Rome, Italy
e San Camillo Hospital, Rome, Italy

* Address for correspondence: Tommaso Sanna, Institute of Cardiology, Catholic University of the Sacred Heart, L.go A. Gemelli, 8, 00168 Rome, Italy. Tel: +39-339-8065840; fax: +39-06-3055535
E-mail address: tommaso.sanna{at}rm.unicatt.it

Received 19 April 2003; revised 30 August 2003; accepted 18 September 2003

Abstract

Aims Retrospective studies have identified a mutation in the lamin A/C (LMNA) gene in patients selected on the basis of a phenotype characterized by dilated cardiomyopathy, atrioventricular conduction disturbances and sudden death. However, the features of cardiac abnormalities in patients with an initial diagnosis of Emery–Dreifuss muscular dystrophy (EDMD) are poorly known. Aim of the present study was to investigate the spectrum of cardiac disease in patients with an initial diagnosis of EDMD caused by a mutation in the LMNA gene.

Methods and results Ten consecutive patients with EDMD and a LMNA gene mutation were evaluated with structured medical interview, physical examination, ECG, echocardiogram and 24-h Holter monitoring. Electrophysiological testing and cardiac catheterization were performed if a class 1 or 2 American Heart Association guidelines indication was present. Cardiac disease was found in eight of 10 patients and consisted in the variable combination of supraventricular arrhythmias, disorders of atrioventricular conduction, ventricular arrhythmias, dilated cardiomyopathy, non-dilated cardiomyopathy, restrictive cardiomyopathy and sudden death despite pacemaker implant.

Conclusions Cardiac disease is common in patients with an initial diagnosis of EDMD caused by a mutation in the LMNA gene and consists of arrhythmias, disorders of atrioventricular conduction, cardiomyopathies and sudden death despite pacemaker implant.

Key Words: Muscular dystrophy • Lamin A/C • Cardiac disease • Arrhythmia • Cardiomyopathy • Sudden death

1. Introduction

Emery–Dreifuss muscular dystrophy (EDMD) is a genetic disorder characterized by early onset contractures of the elbows, Achilles tendons and post-cervical muscles with progressive muscle wasting and weakness. EDMD wasfirst described as an X-linked disease caused by mutations in the gene encoding the nuclear protein emerin on chromosome Xq28.1–3More recently it has been found that EDMD can also be an autosomal disorder caused by mutations in the gene encoding the nuclear proteins lamin A and lamin C (LMNA) on chromosome 1q21.2-q21.3.4Cardiac abnormalities have been described in both variants of the disease. Variable combinations of atrial and ventricular arrhythmias, disorders of atrioventricular conduction, dilated cardiomyopathy and sudden death have been reported.5–12Moreover, mutations in the LMNA gene have been retrospectively found in series of patients selected on the basis of a specific cardiac phenotype of dominant dilated cardiomyopathy with conduction system disease but without EDMD,13–15,32,33in a large kindred with a high prevalence of sudden death, conduction system and myocardial disease and a low prevalence of EDMD,16in a single family with dilated cardiomyopathy and variable skeletal muscle involvement,17and in patients with familial or even sporadic dilated cardiomyopathy with variable arrhythmias and skeletal muscle involvement.18However, the heterogeneous spectrum, the prevalence of different phenotypes and the course of cardiac disease in the whole population of patients affected by EDMD are still incompletely defined and deserve further investigations. The aim of our research was to add information about the spectrum and the course of cardiac disease in EDMD caused by LMNA gene mutations through the analysis of a series of consecutive and unrelated patients followed at our institutions.

2. Methods

2.1. Patient selection
Study protocol was approved by the ethical board of our institution. After informed consent, 10 consecutive unrelated patients followed at the Centre for Neuromuscular Diseases (Uildm, Section of Rome) with early onset contractures of the elbows, Achilles tendons and post cervical muscles, progressive muscular wasting and weakness fulfilling standard diagnostic criteria for EDMD19and a mutation in the LMNA gene, were enrolled in the study.

2.2. Genetic analysis
A mutation in the emerin gene had been previously ruled out in all patients by immunohistochemistry on muscle tissue or DNA analysis.20A peripheral venous blood sample was obtained, DNA was extracted from circulating leukocytes using standard methods and exons and exon-intron junctions of the LMNA gene were amplified with polymerase chain reaction as described.8,21The polymerase chain reaction products were analysed by denaturing high performance liquid chromatography and fragments showing an altered migration were directly sequenced. All new mutations were searched in the DNAs of 50 unrelated, unaffected individuals (100 chromosomes) to exclude that they corresponded to common polymorphisms. Cases were defined as sporadic or familial on the basis of a parental history of EDMD or, when available, parental LMNA gene analysis. The 10 patients enrolled in the study (nine males, one female) showed mutations of the LMNA gene respectively in exon 1 (patients A, B, C), exon 4 (patients D, E, F), exon 6 (patient G), exon 7 (patient H) and exon 9 (patients L, M), as summarized in Table 1; the genetic characterization has been previously reported.8,21The mutations studied were localized throughout the protein, in the first coiled coil or in the central portion of the rod domain and in the tail. Of note, patient A carried a low penetrance mutation and patient E, homozygous for the mutation C664T causing the amino acid change H222Y, was affected by an autosomal recessive form of the disease, as discussed elsewhere in detail.8


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Table 1 LMNA gene mutations in the study population

 
2.3. Cardiac evaluation
Patients with mutations in the LMNA gene were evaluated at baseline and every 6 months thereafter with structured medical interview, physical examination, functional capacity assessment, 12 lead-ECG, echocardiogram and 24-h Holter monitoring. Electrophysiological testing and cardiac catheterization were performed if a class 1 or 2 American Heart Association guidelines22,23indication was present at baseline or at follow-up. Echocardiographic studies were performed according to the recommendations of the American Society of Echocardiography24with a commercially available echocardiograph (SONOS 5500, Agilent, Andover, Massachussetts) equipped with a 2 to 4MHz phased-array probe. Twenty-four hour Holter recordings were performed using 3-channels real-time tape recorders (Diagnostic Monitoring, Irvine, CA, USA) monitoring the bipolar leads CM2, CM5 and modified aVF. Holter tapes were analysed using the Oxford Medilog Excel 2.0 (Abingdon, UK). Cardiac invasive electrophysiologic studies were performed with patients in the unsedated fasting state after withdrawal of all antiarrhythmic drugs for more than four half-lives. Programmed atrial stimulation was performed at not less than two constant basic cycle lengths with up to three extrastimuli down to chamber refractoriness or 200ms. Programmed ventricular stimulation was performed at not less than two constant basic cycle lengths, from two ventricular sites (right ventricular apex and right ventricular outflow tract) with up to three extrastimuli down to chamber refractoriness or 200ms and using long-short sequences. Age at first evidence of muscle manifestations and age at first evidence of cardiovascular disease were retrospectively assessed on the basis of all available data (caring physician records, UILDM records, and personal documents).

2.4. Statistics
Statistical analysis was performed with Statistics for Windows software package Rel. 4.0, Statsoft Inc. Normal distribution of explored variables was assessed with K-S, Lillefors and Shapiro–Wilk W test. All variables showed a normal distribution and were expressed as mean±standard deviation (median, range).

3. Results

3.1. Age at first evidence of muscular and cardiac disease
Age of patients included in the present study was 25.6±12.1 years (median 21, range 12–48). Age at first evidence of muscle involvement was 3.4±1.9 years (median 2.5, range 2–7). Objective signs of cardiac disease were found in eight out of 10 patients (patients A, C, D, F, G, H, L, M) and are summarized in Table 2. Age at first evidence of cardiac disease was 18.3±9.7 years (median 15.5, range 9–41); muscle disease preceded the first evidence of cardiac disease by 14.6±9.0 years (median 13, range 7–35), as summarized in Table 3.


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Table 2 Cardiac abnormalities in study population at baselinea

 

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Table 3 Age at first evidence of muscular and cardiac disease in study population

 
3.2. Baseline evaluation
3.2.1. Functional capacity
Functional capacity was limited in all patients to a variable extent because of mild to severe muscle phenotype. Four patients were wheelchair bound by age 5, 8, 10 and 17 years (respectively patients E, F, C, M).

3.2.2. ECG findings
ECG was abnormal in eight out of 10 patients (A, C, D, F, G, H, L, M). Three patients showed atrial fibrillation (A, F, H), one patient showed absence of atrial activity with slow junctional rhythm (patient M) and five patients exhibited disorders of atrioventricular and/or intraventricular conduction: Patients A and F left anterior fascicular hemiblock (LAH); patient D, first degree atrioventricular block (1st AVB)+right bundle branch block (RBBB)+LAFH; patient G: incomplete RBBB; patient L: 1st AVB+RBBB.

3.2.3. Echocardiographic findings
Echocardiogram was abnormal in four out of 10 patients (A, F, H, M). In detail, three patients showed A wave absence at pulsed wave Doppler of mitral inflow, because atrial fibrillation (A, F) and atrial standstill (M) were present. One patient (F) presented a mild reduction of left ventricular ejection fraction with normal left ventricular end-diastolic volume. One patient (M) presented a mild left ventricular dilation with normal systolic function. One patient (H) exhibited right ventricular enlargement, moderate tricuspid regurgitation and a restrictive filling pattern of left ventricle at pulsed wave Doppler of mitral inflow with normal left ventricular systolic function; in this patient a restrictive cardiomyopathy had been previously confirmed at cardiac catheterization. Cardiac diameters, volumes, wall thickness, systolic and diastolic function, continuous wave, pulsed wave and colour Doppler findings normalized for age and body weight were within reference limits in five patients (B, C, D, E, G, L).

3.2.4. Holter monitoring findings
Holter monitoring was abnormal in seven out of 10 patients (A, C, D, F, H, L, M). Two patients presented atrial arrhythmias only (H, C), five patients showed both atrial and ventricular arrhythmias (A, D, F, L, M), four of whom in association with atrioventricular conduction disturbances (D, F, L, M).

3.2.4.1. Atrial arrhythmias
Three patients showed permanent atrial fibrillation (A, F, H), one with slow ventricular response (F), two paroxysmal atypical atrial flutter (D, L), three atrial tachycardia (C, D, L), one frequent premature atrial complexes (C) and one had no evidence of electrical activity of the atria with slow junctional rhythm (M).

3.2.4.2. Ventricular arrhythmias
Five patients showed non-sustained ventricular tachycardia (A, D, F, L, M).

3.2.4.3. Atrioventricular conduction disturbances
First degree atrioventricular block was found in two patients (D, L) and second degree type 2 atrioventricular block in one (D).

3.2.5. Results of electrophysiological study
A class 1 or 2 indication for electrophysiological study was present in six patients (A, C, D, F, L, M).

3.2.5.1. Sinus node function assessment
Two patients showed mild prolongation of corrected sinus node recovery time (cSNRT) (D, L). Two patientshad permanent atrial fibrillation (A, F). One patient (M) showed atrial standstill, defined as the failure to record any electrical activity and to capture the atria through multisite atrial pacing as previously described.25–27Sinus node function was normal in one patient (C).

3.2.5.2. Atrioventricular node function assessment
Two patients (A, C) showed normal values of atrioventricular Wenckebach cycle length, AH and HV intervals. Wenckebach cycle length was at the upper limits of our laboratory normal reference values in one patient (L) and was mildly abnormal in another (D). One patient (L) showed a mild prolongation of both AH and HV intervals and four patients showed isolated prolongation of HV interval, one in association with atrial standstill (M), one in association with atrial fibrillation (F) and the others in association with prolonged cSNRT (D, L).

3.2.5.3. Programmed atrial stimulation
Atrial tachycardia was inducible in three patients (C, D, L) and atypical atrial flutter in one patient (D). Programmed atrial stimulation could not be performed in three patients because of atrial fibrillation (A, F) and atrial standstill (M).

3.2.5.4. Programmed ventricular stimulation
Unsustained polymorphic ventricular tachycardia (9 beats) was induced in one patient (M).

3.2.6. Device implantation
A pacemaker was implanted in three patients (D, F, M) on the basis of clinical and electrophysiological findings according to American Heart Association guidelines.28One patient had previously received a pacemaker for symptomatic slow ventricular response atrial fibrillation (patient H). No patient had conventional indications for automatic implantable cardioverter defibrillator (ICD).

3.2.7. Cardiac catheterization
One patient (patient H) had undergone cardiac catheterization and endomyocardial biopsy before our evaluation because of suspected restrictive cardiomyopathy which was confirmed at haemodynamic study. Endomyocardial biopsy had been inconclusive. No new indications for cardiac catheterization were found in study population.

3.2.8. Drug therapy
Drug therapy at baseline has been reported in Table 2. In detail, patient A was treated with beta-blockers and anticoagulants for atrial fibrillation. Patients C and L were treated with class Ic antiarrhythmic drugs prescribed by the caring physician for the prevention of recurrences of supraventricular arrhythmias. Patients F and M were treated with anticoagulants respectively because of atrial fibrillation and atrial paralysis. Patient H was treated with enalapril, carvedilol, furosemide and acenocumarol for right sided heart failure and atrial fibrillation. All the other patients (B, D, E, G) were untreated.

3.3. Follow-up
Disease progression was observed in five patients after a median follow-up of 29 months (range 23–37) from baseline evaluation (Table 4). One patient (patient H), who received a pacemaker for slow ventricular response atrial fibrillation at age 41, died suddenly and unexpectedly at age 48. Four patients (patients A, F, L, M) developed variable degrees of left ventricular contractile dysfunction. Left ventricular ejection fraction decreased from 65% to 30% in patient A, from 40% to 19% in patient F, from 55% to 45% in patient L and from 50% to 35% in patient M. Interestingly, patients A, F and L exhibited left ventricular systolic dysfunction in the absence of left ventricular dilation at the time of last follow-up. Patient F, who developed severe heart failure and showed unsustained ventricular tachycardia at 24-h Holter monitoring, received a biventricular upgrade of his pacemaker with clinical benefit at the time of last contact. All patients who presented atrial fibrillation at baseline showed cardiac disease progression at follow-up. No other associations with findings at baseline and clinical course have been found.


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Table 4 Disease progression at follow-upa

 
4. Discussion

Most previous studies on cardiac abnormalities in patients with LMNA gene mutations have been based on the retrospective analysis of series of patients selected on the basis of a specific cardiac phenotype (Table 5). These studies led to the relevant finding that LMNA gene mutation can cause autosomal dominant dilated cardiomyopathy with conduction system disease without EDMD phenotype,13–15,32,33sudden death, conduction system and myocardial disease with a low prevalence of EDMD phenotype,16dilated cardiomyopathy with variable skeletal muscle involvement17and familial or sporadic dilated cardiomyopathy with variable arrhythmias and skeletal involvement.18However, information about the prevalence of these cardiac abnormalities in patients with LMNA gene mutation selected on the basis of an initial diagnosis of EDMD are limited.10–12In our consecutive series of patients with LMNA gene mutation selected on the basis of a muscular phenotype of EDMD, we observed supraventricular arrhythmias (atrial premature contractions, atrial tachycardia, atypical atrial flutter, atrial fibrillation and the uncommon condition of atrial paralysis), disorders of atrioventricular conduction (any degree of atrioventricular block), ventricular arrhythmias (ventricular premature beats, unsustained ventricular tachycardia), impairment of left ventricular systolic function in the absence of left ventricular dilation (non-dilated cardiomyopathy), dilated cardiomyopathy, restrictive cardiomyopathy and sudden death despite pacemaker implant. At one extreme of the spectrum one patient died of sudden death. Sudden death in patient with LMNA gene mutation has been extensively investigated, and evidence of sudden death in pacemaker recipients is increasingly recognized as an intriguing problem,29,30which moves the focus of clinical research from detection of early markers of conduction disease progression (often unpredictable in the single patient), to other causes of cardiac arrest. Unfortunately, at present time any hypothesis on the mechanism of sudden death in these patients is entirely speculative and non-cardiac sudden death, pacemaker failure, electromechanical dissociation or ventricular arrhythmias are all possible and deserve furtherinvestigations. The hypothesis of sudden death as aconsequence of ventricular arrhythmias should beassessed with the highest priority, as in this case ICD implantation could be tested as a strategy to reduce the number of fatalities. At the other extreme of the spectrum, no signs of cardiac disease were found in two patients (patients B and E) with LMNA gene mutation in exon 1 (Del GAG 334-336) and exon 4 (C644T) even after 13 and 43 years of skeletal muscle disease duration, respectively: however, we cannot exclude a future onset of cardiac disease in patient B, as the time lag between onset of muscular disease and cardiac disease has ranged in our study from 7 to 35 years. The absence of cardiac impairment in patient E, affected by an autosomal recessive form of the disease, generates the hypothesis that a milder cardiac involvement might be a characteristic of recessive mutations. Four patients with moderate to severe muscular phenotype developed a significant reduction of left ventricular contractile performance over a relatively short term follow-up. Three out of four of these patients developed a significant reduction of left ventricular systolic function in the absence of left ventricular dilation. One of these patients was actually on treatment with propafenone that could have caused or have contributed to the reduction of left ventricular systolic function. However, in the other two patients, left ventricular dysfunction in the absence of left ventricular dilation could still represent a novel, distinct phenotype associated to LMNA gene mutation (non-dilated cardiomyopathy). The possibility that suchphenotype may just represent the early phase of dilated cardiomyopathy is obviously entirely possible. Only a longer follow-up will resolve this issue. Reasons for different clinical phenotypes and their severity in patients with LMNA gene mutation (exclusively muscular, exclusively cardiac, variable combination of muscular and cardiac phenotypes) are still speculative. A model has been recently proposed31according to which damage of many nuclei is requested to compromise function of multi-nucleated skeletal muscle myocytes, while nuclear damage in mono-nucleated adult cardiac myocytes is rapidly cumulative and determines a faster progression of conduction tissue and contractile cells dysfunction. Yet, it is difficult to reconcile this model with the observation in our study that muscular abnormalities almost always preceded cardiac abnormalities. LMNA gene mutation has also been supposed to cause cellular fragility, particularly evident in tissues subjected to mechanical stress (heart and muscle), but this hypothesis needs confirmation.31Domain specific phenotype has also been proposed as an explanation for phenotype variability. Fatkin et al. studied 11 families with autosomal dominant cardiomyopathy and conduction-system disease. Five different novel missense mutations of LMNA gene were identified in five of these families.13Four were missense mutation in the rod domain of LMNA gene (Arg60Gly and Leu85Arg in exon 1, Asn195Lys and Glu203Gly in exon 3), while the other was a missense mutation of the lamin C tail domain (Arg571Ser in exon 10). In their series, mutations in the rod domain of lamins A and C gene were not associated to any clinical or laboratory sign of EDMD while mutation in the lamin C tail domain was associated to normal clinical findings but mildly elevated serum levels of creatine kinase, suggesting subclinical skeletal muscular disease. Authors formulated the hypothesis that missense mutations in the tail region of lamins A and C cause EDMD while rod mutations cause isolated myocardial disease. This has not been confirmed in our series as coexistence of EDMD and cardiac disease has been observed also with mutations in the rod domain of LMNA gene. Moreover, cardiac phenotype and cardiac disease severity in our series were not related to the domain involved, thus confuting the hypothesis of a domain-specific phenotype.


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Table 5 Published mutations in the LMNA gene in series of patients selected on the basis of pre-specified cardiac abnormalitiesa

 
4.1. Study limitations
Even though maximal care was taken to analyse all available data, age of onset of cardiac disease has been determined retrospectively and a delay in initial detection cannot be excluded. A causal association between LMNA gene mutation and the described spectrum of cardiac disease cannot be supported by our study design.

5. Conclusions

Cardiac abnormalities in patients with an initial diagnosis of muscular dystrophy caused by LMNA gene mutation are represented by supraventricular arrhythmias (atrial premature contractions, atrial tachycardia, atypical atrial flutter, atrial fibrillation and the uncommon condition of atrial paralysis), disorders of atrioventricular conduction (any degree of atrioventricular block), ventriculararrhythmias (ventricular premature beats, unsustained ventricular tachycardia), non-dilated cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy and sudden death despite pacemaker implant. The time interval between onset of muscular manifestations of disease and first evidence of cardiac disease is usually long, so that serial assessment of cardiac status is strongly advised after diagnosis.

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