Lamin A/C (LMNA) Gene-Related Emery–Dreifuss Muscular Dystrophy Presenting with Junctional Rhythm and Ventricular Arrhythmias in Monozygotic Twins

INTRODUCTION

Emery–Dreifuss muscular dystrophy (EDMD) is a genetically heterogeneous neuromuscular disorder characterized by contractures, progressive muscle weakness, and early cardiac involvement. Cardiac manifestations, more so than skeletal muscle disease, are the principal determinants of prognosis and survival.^[1] Among EDMD subtypes, the lamin A/C gene (LMNA)-related disease is notable for early atrial cardiomyopathy, conduction system disease, and malignant ventricular arrhythmias that frequently occur before the onset of overt cardiomyopathy.^[2,3]

LMNA encodes lamins A and C, nuclear envelope proteins that play critical roles in nuclear stability, gene expression, and mechanotransduction. Pathogenic variants in LMNA disrupt these functions, predisposing patients to arrhythmic complications, myocardial fibrosis, and sudden cardiac death, often independent of the left ventricular systolic dysfunction.^[2,3] Recent clinical criteria and guideline updates underscore the need for early risk stratification and appropriate device therapy in patients with LMNA cardiomyopathy and electrical instability.^[4,5]

CASE REPORT

A 28-year-old man, one of the monozygotic twins born out of a second-degree consanguineous marriage, presented following a single episode of syncope preceded by palpitations. The episode was sudden in onset, lasted approximately 30 s, and resolved spontaneously. There was no seizure activity or postictal confusion, and no family history of sudden cardiac death.

Both twins had a history of insidious onset, slowly progressive muscle weakness, first noticed at approximately 9 years of age, when the patient was unable to compete physically with peers. The weakness predominantly involved limb-girdle musculature associated with wasting of arm and calf muscles.

On arrival, the patient was hemodynamically stable. Heart rate was 52 beats/min, blood pressure was 110/70 mmHg, respiratory rate 16 breaths/min and oxygen was 98% on room air.

Both twins demonstrated prominent wasting of humeroperoneal muscle groups with additional involvement of scapular and pelvic girdle muscles. There was contracture of the right tendoachilles in both twins. Power was 3/5 in all four limbs. Deep tendon reflexes were absent, and B/L plantar reflexes were mute. These features were suggestive of primary muscular dystrophy [Figure 1].

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Figure 1: Clinical photographs demonstrating severe wasting of humeroperoneal muscle groups in monozygotic twins.

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Cardiovascular examination was unremarkable. Jugular venous pressure was normal. Heart sounds were normal with no murmurs, gallops or rubs. Peripheral pulses were palpable and symmetrical. There were no signs of congestive heart failure.

Resting 12-lead electrocardiography demonstrated a junctional rhythm with absent P waves and a narrow QRS complex [Figure 2a]. Twenty-four-hour Holter monitoring revealed multiple runs of nonsustained ventricular tachycardia (NSVT) with frequent ventricular ectopy [Figure 2b]. Transthoracic echocardiography showed normal chamber dimensions with preserved biventricular size and function. Cardiac magnetic resonance imaging demonstrated extensive subendocardial late gadolinium enhancement involving the inferolateral, anterolateral, apical lateral, and inferior left ventricular segments, consistent with myocardial fibrosis [Figure 2c].

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Figure 2: Electrocardiographic and cardiac magnetic resonance findings in the symptomatic twin. (a) resting 12 lead electrocardiography demonstrating junctional rhythm of symptomatic twin; (b) Twenty 4 h Holter monitoring demonstrating runs of nonsustained ventricular tachycardia of symptomatic twin; (c) cardiac magnetic resonance images showing subendocardial late gadolinium enhancement involving the inferolateral and inferior left ventricular segments.

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Genetic testing

Whole-exome sequencing identified a pathogenic autosomal-dominant variant in the LMNA gene (c.746 G>A; p.Arg249Gln), confirming EDMD2. Based on the genetic findings in the symptomatic twin, targeted cardiac evaluation of the previously asymptomatic twin was undertaken, which revealed a junctional rhythm on electrocardiography and episodes of NSVT on Holter monitoring [Figure 3].

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Figure 3: Electrocardiographic findings in the asymptomatic twin. (a) Resting 12 lead electrocardiography in the asymptomatic twin demonstrating junctional rhythm; (b) Twenty 4 h Ambulatory Holter monitoring in the asymptomatic twin demonstrating nonsustained ventricular tachycardia.

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Management

Given multiple high-risk features, including syncope, NSVT, junctional rhythm, myocardial fibrosis, and LMNA mutation, both patients were planned for implantable cardioverterdefibrillator (ICD) implantation. Intraoperative electrograms demonstrated markedly attenuated atrial signals consistent with advanced atrial cardiomyopathy. Consequently, both patients underwent successful single-chamber ICD implantation. The index patient received the device for secondary prevention, while his twin underwent primary prevention ICD implantation as shown in Figure 4.

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Figure 4: Fluoroscopic images showing single-chamber implantable cardioverter-defibrillator implantation in twins. (a) Twin 1 (secondary prevention); (b) Twin 2 (primary prevention).

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DISCUSSION

EDMD comprises genetically distinct entities with overlapping skeletal muscle involvement but differing cardiac phenotypes. X-linked EDMD (EDMD1), caused by mutations in the EMD gene, is typically characterized by early contractures and progressive atrioventricular conduction disease, often requiring pacing, whereas malignant ventricular arrhythmias are less frequent.^[1,6] Autosomal-dominant EDMD (EDMD2), resulting from LMNA mutations, is associated with a particularly high burden of arrhythmic complications, including diffuse atrial cardiomyopathy, ventricular myocardial fibrosis, ventricular tachyarrhythmias, and sudden cardiac death, which may occur before the development of significant left ventricular systolic dysfunction.^[2,3]

Atrial involvement in EDMD2 often presents with atrial arrhythmias, progressive atrioventricular conduction disease, junctional rhythm, or atrial standstill due to extensive atrial myocardial fibrosis.^[1,2,6] This early electrical instability contrasts with other muscular dystrophies, in which arrhythmias typically occur in the setting of advanced structural cardiomyopathy.^[7]

Cardiovascular magnetic resonance (CMR) plays a crucial role in risk stratification in LMNA cardiomyopathy. The presence and extent of late gadolinium enhancement have been shown to independently predict ventricular arrhythmias and adverse outcomes, even in patients with preserved systolic function.^[8] These findings have been integrated into recent clinical recommendations emphasizing early ICD consideration in patients with LMNA pathogenic variants and high-risk electrical features.^[9,10]

Consensus guidance from the American College of Cardiology/American Heart Association and other international bodies supports ICD implantation in LMNA mutation carriers who have NSVT, syncope, significant myocardial fibrosis on CMR, or additional risk factors for sudden cardiac death.^[9] Notably, pacing alone does not prevent sudden death in this population and may delay appropriate defibrillator therapy.^[10]

The concordant electrical and arrhythmic phenotype observed in these monozygotic twins underscores the high penetrance of LMNA-related disease and highlights the importance of systematic family screening and early intervention.

CONCLUSION

LMNA-related EDMD is a uniquely arrhythmogenic disorder in which electrical instability often precedes overt cardiomyopathy. Junctional rhythm and NSVT in young patients with muscular dystrophy should prompt urgent evaluation for LMNA disease and consideration of early ICD implantation to prevent sudden cardiac death.