Lmna-Related Dilated Cardiomyopathy

Watchlist

(log in to enable)

Retrieved

2021-01-18

Source

Gene_reviews

Trials

—

Genes

—

Drugs

—

Interested in hearing about new therapies?

Summary

Clinical characteristics.

LMNA-related dilated cardiomyopathy (DCM) is caused by pathogenic variants in LMNA and is characterized by left ventricular enlargement and/or reduced systolic function preceded or accompanied by significant conduction system disease and/or arrhythmias. LMNA-related DCM usually presents in early to mid-adulthood with symptomatic conduction system disease or arrhythmias, or with symptomatic DCM including heart failure or embolus from a left ventricular mural thrombus. Sudden cardiac death can occur, and in some instances is the presenting manifestation; sudden cardiac death may occur with minimal or no systolic dysfunction.

Diagnosis/testing.

LMNA sequence analysis identifies pathogenic variants in most individuals with LMNA-related DCM. Conduction system disease is detected by a 12-lead electrocardiogram (ECG); arrhythmias are detected by an ECG, 24-hour rhythm recording, or event monitor. Left ventricular enlargement is diagnosed with cardiac imaging; reduced systolic function is assessed by two-dimensional echocardiography, angiography, radioisotope scanning, or magnetic resonance imaging.

Management.

Treatment of manifestations: Chronic atrial fibrillation is treated initially with attempts to restore normal sinus rhythm, anticoagulation, and rate control. Symptomatic supraventricular arrhythmias are usually treated with pharmacologic therapy or ablation; symptomatic bradyarrhythmias or significant heart block is treated with an electronic pacemaker. Symptomatic ventricular arrhythmias, ventricular tachycardia, ventricular fibrillation, and resuscitated sudden cardiac death are treated with an implantable cardiac defibrillator (ICD) and drug therapy as needed. Because risk for sudden cardiac death in LMNA-related DCM accompanies heart block and bradyarrhythmias, ICD use (rather than just pacemaker use) has been recommended for all indications. Treatment of symptomatic DCM, including heart failure, is pharmacologic with ACE inhibitors, beta blockers, and/or anti-aldosterone agents. Progressive deterioration in left ventricular function is treated with an ICD, and some experts recommend anticoagulation. Cardiac transplantation or other advanced therapies may be considered for refractory disease in persons receiving comprehensive care from cardiovascular disease experts.

Surveillance: Individuals with an LMNA pathogenic variant who are found to have any ECG abnormality should undergo a cardiovascular evaluation for disease progression at least annually. Asymptomatic individuals with a pathogenic LMNA variant should undergo cardiovascular evaluation (medical history, physical examination, echocardiogram, and ECG) every one to two years and/or whenever new symptoms arise. In families with a known LMNA pathogenic variant, at-risk individuals for whom genetic testing is not possible may be offered yearly cardiovascular screening. At onset of new symptoms an immediate evaluation for evidence of DCM and/or conduction system disease is indicated regardless of genetic status.

Evaluation of relatives at risk: To facilitate prompt diagnosis, targeted LMNA genetic testing when the family-specific pathogenic variant is known; otherwise routine surveillance with cardiovascular screening tests.

Pregnancy management: Pregnancy is contraindicated in women with DCM. Pregnant women with DCM should be followed by a high-risk obstetrician. At-risk women with unknown genetic status should undergo a cardiovascular evaluation and be offered genetic counseling, ideally prior to pregnancy.

Genetic counseling.

LMNA-related DCM is inherited in an autosomal dominant manner. Some individuals diagnosed with LMNA-related DCM have an affected parent; the proportion of cases caused by a de novo pathogenic variant is unknown. Each child of an individual with LMNA-related DCM has a 50% chance of inheriting the parent's pathogenic variant. Prenatal diagnosis for LMNA-related DCM is technically possible when the pathogenic variant in the family is known.

Diagnosis

Suggestive Findings

LMNA-related dilated cardiomyopathy (DCM) should be suspected in individuals with a clinical diagnosis of idiopathic DCM (etiology not attributed to coronary artery disease, structural heart disease, or other conditions that may cause DCM; see Dilated Cardiomyopathy Overview), almost always in the setting of conduction system disease and/or supraventricular or ventricular arrhythmias.

The diagnosis of DCM is based on the principal findings of left ventricular enlargement and/or reduced systolic function (other causes of which have been excluded):

Left ventricular enlargement is most commonly identified with two-dimensional echocardiography, optimally assessed by a height- and gender-based approach [Vasan et al 1997]. Other testing modalities include cardiac magnetic resonance imaging (MRI) or computed tomography (CT).
Reduced systolic function is usually described as a reduction in left ventricular ejection fraction, which can be measured by two-dimensional echocardiography, angiography, radioisotope scanning, or MRI of left ventricular function. An ejection fraction of less than 50% is considered systolic dysfunction.

Note: LMNA-related DCM is almost always associated with conduction system disease and/or arrhythmias that commonly occur prior to the development of heart failure symptoms. Clinicians should also be aware that in some cases the conduction system disease precedes any evidence of DCM (see Clinical Description).

Establishing the Diagnosis

The diagnosis of LMNA-related DCM is established in a proband with idiopathic DCM, systolic dysfunction, or left ventricular enlargement of unknown cause by the identification of a heterozygous pathogenic variant in LMNA on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Because of the genetic heterogeneity of DCM, single-gene testing is not recommended for a proband.

Instead, the most common molecular testing approach for DCM in the US is use of a multigene panel that includes LMNA and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if a multigene panel that includes LMNA fails to confirm a diagnosis in an individual with suspected LMNA-related DCM. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in LMNA-Related Dilated Cardiomyopathy

Gene ¹	Test Method	Proportion of Probands with a Pathogenic Variant ² Detectable by This Method
LMNA	Sequence analysis ³	>99% ⁴
LMNA	Gene-targeted deletion/duplication analysis ⁵	Unknown ⁶

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Almost all pathogenic variants identified to date have been missense, nonsense, or splice-site variants.
5.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
6.: No data on detection rate of gene-targeted deletion/duplication analysis are available. Duplication/deletion analysis may increase testing sensitivity: two reports have identified LMNA-related DCM resulting from deletions [van Tintelen et al 2007b, Gupta et al 2010].

Clinical Characteristics

Clinical Description

LMNA-related dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and/or reduced systolic function frequently accompanied by significant conduction system disease.

Age of onset. While LMNA-related DCM usually presents in adulthood either with conduction system disease commonly accompanied by arrhythmias or with symptomatic DCM (including heart failure or embolus from a left ventricular mural thrombus), it may also be present in asymptomatic individuals: DCM, conduction system disease, or arrhythmia may be discovered during a medical evaluation conducted for another reason (e.g., a routine preoperative ECG) or clinical screening of at-risk relatives.

Presenting signs, timing, and progression. Family studies suggest that conduction system disease commonly precedes the development of DCM by a few years to a decade or more. In a study involving 64 individuals with an LMNA pathogenic variant, the median time differential from ECG abnormalities to observed left ventricular dysfunction was seven years [Brodt et al 2013].

Conduction system involvement usually starts with disease of the sinus node and/or atrioventricular node that can manifest as sinus bradycardia, sinus node arrest with junctional rhythms, or heart block (commonly first-degree heart block that progresses to second- and third-degree block). The following are also common:
- Symptomatic bradyarrhythmias requiring cardiac pacemakers
- Supraventricular arrhythmias including atrial flutter, atrial fibrillation, supraventricular tachycardia, and the sick sinus syndrome (i.e., tachycardia-bradycardia syndrome)
- Ventricular arrhythmias including frequent premature ventricular contractions (PVCs), ventricular tachycardia, and ventricular fibrillation
Sudden cardiac death may occur with progressive disease. Although more malignant, life-threatening arrhythmias may occur with longstanding and usually previously symptomatic DCM, sudden cardiac death can also be the presenting manifestation of LMNA-related DCM.
Variable DCM. Only mild to moderate left ventricular dilatation despite progressive disease has been noted by some investigators. Therefore, LMNA-related DCM may be an appropriate diagnosis in those with an LMNA pathogenic variant who have clinical conduction system disease and/or arrhythmia prior to the left ventricular enlargement or with minimal or no systolic dysfunction.
Skeletal muscle disorder. Occasionally, individuals with LMNA-related cardiomyopathy also manifest signs or symptoms of skeletal myopathy, which may be associated with elevated serum creatine kinase (CK) concentration.

Large prospective longitudinal studies to define the range of natural history of individuals with LMNA pathogenic variants have not yet been published.

Click here (pdf) for clinical descriptions of the cardiovascular manifestations of LMNA-related DCM.

Genotype-Phenotype Correlations

No specific genotype-phenotype correlations have been established for LMNA-related DCM.

A few studies focusing on pathogenic variant type suggest a correlation between splice site variants and increased risk for sudden cardiac death [Pasotti et al 2008] and between non-missense variants (indel, truncating, splice site) and risk for malignant ventricular arrhythmias.

Penetrance

LMNA-related DCM demonstrates age-related penetrance with onset in the third and fourth decades, so that by the seventh decade penetrance is considered greater than 90%-95%.

Prevalence

A population-based estimate of the prevalence of DCM of unknown cause is not available. A review has suggested that the frequency of DCM is equal to the established frequency of hypertrophic cardiomyopathy (1:500) or greater [Hershberger et al 2013].

The frequency of LMNA-related DCM in persons with DCM of unknown cause (also referred to as idiopathic dilated cardiomyopathy [IDC]) ranges from 5% to 10% of familial DCM and 2% to 5% of non-familial DCM [Arbustini et al 2002, Kärkkäinen et al 2006, Parks et al 2008, Perrot et al 2009].

Differential Diagnosis

The differential diagnosis of LMNA-related dilated cardiomyopathy (DCM) relates to the general phenotype of DCM of unknown cause. Current evidence indicates that idiopathic DCM (i.e., DCM of unknown cause) may be familial (and therefore possibly genetic) in 20%-50% of cases [Burkett & Hershberger 2005].

With a clear pattern of familial disease, a genetic cause of DCM may be established (see Dilated Cardiomyopathy Overview). LMNA-related cardiomyopathy may be the most common known cause of familial DCM with prominent conduction system disease (see Prevalence).

In those in whom gene testing fails to identify a pathogenic variant in LMNA or another gene associated with DCM, physical examination to evaluate for extra-cardiac features (especially neuromuscular issues) or additional study of the cardiovascular findings may lead to a diagnosis of other disorders causing DCM and conduction system disease (CSD):

DES-related myopathy. While isolated DCM has been reported with pathogenic variants in DES [Li et al 1999], DES-related myopathy is characterized by DCM with conduction and neuromuscular disease involving desmin protein aggregates in cardiomyocytes and skeletal muscle cells. A clinical evaluation with focus on neuromuscular disease accompanied by molecular genetic testing is required to diagnose DES-related myopathy. Van Spaendonck-Zwarts et al [2011] reported that DES pathogenic variants in the 2B domain correlate with isolated neurologic involvement whereas head and tail domain pathogenic variants correlate with an isolated cardiac phenotype. Some individuals with DES pathogenic variants can present with mild conduction system disease [Taylor et al 2007].
Limb-girdle muscular dystrophy (LGMD type 1D). Collectively describing a group of disorders involving varying degrees and forms of skeletal muscle disease with or without cardiac involvement, LGMD can be caused by pathogenic variants in several genes. A splice site variant in DES was reported in a family with DCM, CSD, and proximal muscle involvement, constituting the LGMD1D subtype. A clinical evaluation with focus on neuromuscular disease accompanied by molecular genetic testing are required to diagnose LGMD1D. Inheritance is autosomal dominant.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death. While involvement of LMNA pathogenic variants is reported in some cases (see Genetically Related Disorders), most cases of ARVD/C are caused by rare variants encoding desmosomal proteins (see ARVD/C). A molecular evaluation along with a clinical evaluation focusing on cardiovascular findings [Marcus et al 2010] is usually required to diagnose ARVD/C.
Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of joint contractures that begin in early childhood; slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles; and cardiac involvement that may manifest as palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure. Age of onset, severity, and progression of muscle and cardiac involvement demonstrate both inter- and intrafamilial variability. Clinical variability ranges from early onset with severe presentation in childhood to late onset with slow progression in adulthood. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. Cardiac involvement usually occurs after the second decade. The three genes in which pathogenic variants are known to cause EDMD are EMD (encoding emerin) and FHL1 (encoding FHL1), which cause X-linked EDMD (XL-EDMD); and LMNA (encoding lamin A and C), which causes autosomal dominant EDMD (AD-EDMD) and autosomal recessive EDMD (AR-EDMD). A clinical evaluation with focus on neuromuscular disease and molecular analysis is required to diagnose Emery-Dreifuss muscular dystrophy.

Management

Guidelines for the clinical management of individuals with LMNA-related DCM have been published [Hershberger et al 2009].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with LMNA-related DCM, the following evaluations are recommended.

Comprehensive cardiovascular evaluation

Evaluation for conduction system disease and arrhythmia:
- Personal and family history of presyncope, syncope, resuscitated sudden cardiac death, palpitations, and other symptoms of arrhythmia
- Follow up of abnormalities with additional testing as indicated (e.g., 24-hour monitoring or event monitors)
- Referral to a cardiologist or electrophysiologist for any indication of symptomatic disease
- Indicated in some patients: invasive electrophysiologic evaluation for conduction system disease
Evaluation for left ventricular dysfunction and DCM:
- Family history for cardiomyopathy of any type, personal history of shortness of breath, dyspnea on exertion, paroxysmal nocturnal dyspnea, chest pain
- Assessment of left ventricular function (most commonly by two-dimensional echocardiography) to determine left ventricular dimension and function. Alternatively, MRI provides similar data, and radionuclide ventriculography provides a measure of the ejection fraction.

Measurement of serum CK concentration to evaluate for skeletal myopathy

In some affected individuals elevated serum CK concentrations with or without a skeletal muscle myopathy similar to Emery-Dreifuss muscular dystrophy or limb-girdle muscular dystrophy is observed.
If CK levels are elevated, an evaluation for skeletal muscle weakness, including neuromuscular evaluation, may be necessary.

History and physical examination for signs and symptoms of skeletal myopathy. If there is evidence of myopathy, refer to a neuromuscular disease specialist for evaluation.

Other. Consultation with a clinical geneticist and/or genetic counselor is recommended.

Treatment of Manifestations

For the general approach to managing DCM, see Dilated Cardiomyopathy Overview, Management.

The Pasotti et al [2008] report (see details) provides the most longitudinal data on LMNA-related DCM: 94 individuals with an LMNA pathogenic variant were followed for a median of 57 months (range: 36-107 months). In the report of Brodt et al, the progression from first observed conduction system disease to the onset of ventricular dysfunction in a subset of 64 individuals with LMNA variants was a median of seven years [Brodt et al 2013]. Additional reports of large prospective longitudinal natural history studies of LMNA-related DCM are not yet available.

The Heart Failure Society of America and Heart Rhythm Society (in conjunction with the European Heart Rhythm Association) have commissioned guideline documents for the management of genetic cardiomyopathies that included specific mention of LMNA-related DCM [Hershberger et al 2009, Ackerman et al 2011]. Elements of the guidelines include the following:

Because of the complexity of treatment interventions in LMNA-related DCM in symptomatic and asymptomatic individuals, referral to centers with special expertise in cardiovascular genetic medicine should be considered.
Consider therapy based on cardiac phenotype (i.e., DCM or arrhythmia).
With an established arrhythmia or known risk of arrhythmia, consider ICD implantation before the ejection fraction falls below 35%. Note that this recommendation was developed in the Heart Failure Society guidelines in large part because of the risk for lethal arrhythmias in persons with an LMNA pathogenic variant who have systolic function well above a left ventricular ejection fraction of 35%, the usual measure of systolic dysfunction below which ICDs are indicated in most US guidelines.

The management of LMNA-related DCM is focused on treatment of conduction system disease, arrhythmia, and DCM.

Cardiac conduction system disease and arrhythmias

Chronic atrial fibrillation unresponsive to cardioversion is treated with anticoagulants and agents for ventricular rate control.
Other symptomatic supraventricular arrhythmias are treated with pharmacologic agents, and at times are augmented with electrophysiologic intervention (e.g., atrial or atrioventricular node ablations).
Symptomatic bradyarrhythmias or asymptomatic but significant heart block is treated with an implantable electronic pacemaker. However, when a device is to be implanted, use of an implantable cardiac defibrillator (ICD) rather than an electronic pacemaker has been advocated and should be strongly considered, as the risk of mortality from sudden cardiac death usually accompanies supraventricular arrhythmias and conduction system disease. Sudden cardiac death presumably results from lethal tachyarrhythmias despite the presence of a pacemaker to treat bradyarrhythmias [van Berlo et al 2005, Meune et al 2006], and for this reason use of an ICD has been advocated for LMNA-related cardiomyopathy with significant conduction system disease and/or arrhythmia regardless of the left ventricular ejection fraction [Hershberger et al 2009].
Symptomatic ventricular arrhythmias, ventricular tachycardia, ventricular fibrillation, and resuscitated sudden cardiac death are treated with an ICD and drug therapy as needed.
When DCM is present and the left ventricular ejection fraction is less than 35%, an ICD should be implanted following the usual guidelines [Yancy et al 2013].

LMNA-related DCM

Treatment of symptomatic DCM, including heart failure, is pharmacologic with ACE inhibitors, beta blockers, diuretics, and other conventional approaches, as summarized in Yancy et al [2013] (full text).
With progressive deterioration in left ventricular function (left ventricular ejection fraction <30%) while still in sinus rhythm, some experts recommend full anticoagulation to prevent the development of left ventricular mural thrombus and embolic events including stroke.
Cardiac transplantation or other advanced therapies should be considered with progressive DCM, advancing heart failure, and otherwise refractory disease in persons receiving comprehensive cardiovascular care from experts in the field [Yancy et al 2013].

Prevention of Secondary Complications

Whether conventional medical therapy (e.g., ACE inhibitors, beta blockers) is able to ameliorate or prevent DCM or heart failure in LMNA-related DCM has not been formally tested and is therefore unknown.

Implantable cardiac defibrillators or pacemakers are highly effective in preventing sudden cardiac death.

Surveillance

Screening and identification of DCM before the onset of symptoms enables the initiation of medical therapy that may delay disease progression.

Individuals with an LMNA pathogenic variant who are found to have any ECG abnormality should undergo a cardiovascular evaluation for disease progression at least annually [Brodt et al 2013]. This should include, minimally, an ECG, 24- or 48-hour rhythm monitoring, and measurement of ventricular function.
Asymptomatic individuals with a pathogenic LMNA variant should undergo cardiovascular evaluation (medical history, physical examination, echocardiogram, and ECG) every one to two years and/or whenever new symptoms arise.

Agents/Circumstances to Avoid

Drugs (e.g., beta blockers, calcium channel blockers, others) that exacerbate heart block, if present, should be avoided in LMNA-related DCM unless an electronic pacemaker is in place.

Evaluation of Relatives at Risk

When the LMNA pathogenic variant has been identified in a family, molecular genetic testing can be offered to relatives at risk in order to facilitate prompt diagnosis, surveillance, and treatment in those in whom the LMNA pathogenic variant has been detected.

If molecular genetic testing is not possible, the first-degree relatives of a proband with LMNA-related DCM should be evaluated annually by medical history, physical examination, echocardiogram, and ECG to determine if any have detectable DCM and/or conduction system disease.

Note: Because the age of onset is variable and penetrance is reduced, a normal baseline echocardiogram and ECG in a first-degree relative who has not undergone molecular genetic testing does not rule out LMNA-related DCM in that individual, and the recommendations set forth in Surveillance should be followed.

Any abnormal cardiovascular test results in a relative of a proband with a known LMNA pathogenic variant should be followed up with a full cardiovascular assessment to evaluate for any acquired causes of disease (e.g., coronary artery disease). Results on screening tests that do not meet criteria for DCM but do show some abnormality (e.g., left ventricular enlargement but normal function; decreased ejection fraction but normal-sized left ventricle) may reflect variable expression of LMNA-related DCM in that relative. Targeted genetic testing to clarify the diagnosis as well as close surveillance (e.g., cardiovascular testing every 1-2 years) for progression of cardiovascular disease is recommended for such individuals.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy is contraindicated in women with DCM because of the significantly increased mortality with pregnancy in DCM. Women with DCM who become pregnant should be followed by a high-risk obstetrician. At-risk women with unknown genetic status should undergo a cardiovascular evaluation and be offered genetic counseling prior to pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.