Risk stratification in laminopathies and Emery Dreifuss muscular dystrophy

Abstract

Laminopathies are genetic disorders due to gene mutation encoding for proteins of the nuclear envelope. Patients are at risk of conduction defect, arrhythmia, sudden death and heart failure. The authors summarize predictive factors for cardiac events reported in the literature in this group of disease.

Introduction

Laminopathies are genetic disorders due to gene mutation encoding for proteins of the nuclear envelope that include emerin and lamins. Emery Dreifuss muscular dystrophy (EDMD) is a neuromuscular disorder, reported in 1966 by Emery and Dreifuss,¹ characterized by peripheral skeletal muscular weakness, joint contractures and cardiac conduction disorders.² Clinical spectrum is large in laminopathy, ranging from skeletal muscle failure to heart disease. Heart involvement is crucial to search since cardiolaminopathy affects prognosis, due to risk of conduction defect, ventricular arrhythmia and heart failure. Predictive factors for significant cardiac events are essential to know in clinical practice.

Laminopathies

Laminopathies are due to LMNA mutations, leading to a wide spectrum of diseases that may include dilated cardiomyopathy with conduction defect,³ neuropathy, limb girdle muscular dystrophy type IB (LGMD1B),⁴ congenial form of muscular dystrophy,⁵ EDMD, lipodystrophy type Dunnigan, mandibulo-acral dysplasia and Hutchinson-Gilford progeria syndrome.

LMNA gene is located on chromosome 1q21 and encodes lamins A and C that are A-type lamins. Lamines A and C are nuclear intermediate filaments proteins, forming a meshwork (the nuclear lamina) within the inner nuclear membrane. Lamines A and C provide a mechanical stabilization of the nucleus and act as a scaffold for nuclear factors. In 1999, Bonne et al.⁶ reported the first LMNA mutation gene in a group of patients with autosomal dominant EDMD. LMNA mutation was found to be present in 8% of patients with dilated cardiomyopathy. A subset of clinical parameters has been shown to be predictive for LMNA mutations in dilated cardiomyopathy: supraventricular arrhythmia, conduction defects, presence of skeletal muscle failure and moderate cardiomyopathy.

In patients with lamins A/C mutation, cardiac involvement may include atrio-ventricular conduction and sinus node disorders. Conduction system disease seems to appear earlier, reaching 18% in patients <10 years whereas cardiomyopathy seems to occur later, reaching 60% in older patients (>50 years).⁷ Other cardiac phenotypes have been reported to be associated with LMNA mutations. 4% of patients with arythmogenic right ventricular cardiomyopathy and without desmosomal gene mutations carried LMNA mutations.⁸ Apical left ventricular aneurysm associated with ventricular rhythm impairment has been reported in two members of family carrying LMNA mutations.⁹ In a recent study, LMNA, TTN and MYBPC3 genes were found to be the most prevalent genes disease associated with left ventricular noncompaction. ¹⁰

Emery Dreifuss muscular dystrophy

Emery Dreifuss muscular dystrophy is the most known muscular dystrophy among laminopathies. We distinguish:

1. An X linked form related to mutation in EMD gene. In 1994, Bione et al.¹¹ identified the gene. The EMD gene is located on chromosome Xq28 and encodes emerin, a protein of the inner nuclear membrane. Emerin is involved in gene expression regulation, chromatin architecture and cell signaling.

2. Au autosomal dominant form related to mutation in LMNA gene⁶

3. An autosomal recessive form which seems to be rare¹²

4. Recently, FHL1 dysregulation has been reported to be associated with EDMD¹³ Heart involvement includes arrhythmia,

conduction defects and dilated cardiomyopathy. Heart disease is characterized by progressive replacement of myocardium by adipose and fibrosis tissue that begins in atria and affects progressively atrio-ventricular node and ventricles. Symptoms may occur early, with conduction defects and cardiac disease become usual in the third decade. Bradycardia, complete atrio-ventricular block, atrial paralysis can occur in EDMD as well as supraventricular and ventricular arrhythmia.⁷ Sudden cardiac death (SCD) may be the initial manifestation of disease.¹⁴

Risk stratification

Patients with EDMD and laminopathies are at risk of SCD. Ventricular arrhythmia and sudden death may occur despite pacemaker implantation.⁷ The risk for ventricular arrhythmia was reported to reach 18% in a study that included 269 LMNA mutation carriers (median follow up 43 months).¹⁵ In a study that included 122 LMNA mutation carriers (follow up 7 years), the cumulative atrio-ventricular (AV) block events were 57±5%, atrial arrhythmia 63±5% and ventricular arrhythmia 34±5%.¹⁶ In the study by Meune et al.,¹⁷ 42% of patients with LMNA mutation carrying an implantable cardioverter-defibrillator (ICD) received appropriate shock in relation with arrhythmia. Prophylactic implantation of an implantable cardioverter defibrillator (ICD) need to be considered and discussed in LMNA mutations patient’s with conduction system disorders.

Some parameters merged from the literature for risk stratification. In the study by Pasotti et al.,¹⁸ the following parameters were found to be predictive factors for heart failure or death: NYHA III or IV, conduction system disorder, clinical manifestation of LMNA deficiency, left ventricular ejection fraction (LVEF) <35%, left ventricular end diastolic volume >180 mL and history of competitive sport. In multivariate analysis, NYHA III or IV and history of competitive sport were predictive factors for congestive heart failure or SCD or death.¹⁸ In the study by Van Rijsingen et al.,¹⁵ risk factors for ventricular arrhythmia were: male gender, non-sustained ventricular tachycardia, LVEF<45% and non-missense mutation. Recently, Kumar et al.¹⁶ reported the following parameters as predictive factors for cardiac events: male gender, LVEF≤50% and non-missense mutations.

Conclusions

Patients with EDMD and laminopathies are at risk for cardiac morbidity ad mortality due to rhythmic events and dilated cardiomyopathy. Risk stratification relies on genetic, electrocardiogram (EKG), EKG Holter findings as well as LVEF value and exercise testing. Cardiac magnetic resonance imaging and electrophysiological studies may provide additional prognostic value and require more future research in this field.

Funding Statement

Funding: none.