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European Journal of Heart Failure 2006 8(5):484-493; doi:10.1016/j.ejheart.2005.11.004
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© 2005 European Society of Cardiology

Genetic and phenotypic analysis of dilated cardiomyopathy with conduction system disease: Demand for strategies in the management of presymptomatic lamin A/C mutant carriers

Andreas Perrota,*, Holger H. Siguschb, Herbert Nägelec, Janine Genscheld, Hans Lehmkuhle, Roland Hetzere, Christian Geiera, Veronica Leon Pereza, Dirk Reinhardb, Rainer Dietza, Karl Josef Osterziela and Hartmut H.-J. Schmidtd

a Charité- Universitätsmedizin Berlin/Kardiologie am Campus Buch and Virchow-Klinikum, und Max-Delbrück-Centrum für Molekulare Medizin Wiltbergstr. 50, 13125 Berlin, Germany
b Universitätsklinikum der Friedrich-Schiller-Universität Jena Klinik für Innere Medizin I, Kardiologie, Erlanger Allee 101, 07740 Jena, Germany
c Krankenhaus Reinbeck Hamburger Str. 41, 21465 Hamburg, Germany
d Charité- Universitätsmedizin Berlin/Gastroenterologie Hepatologie & Endokrinologie, Campus Mitte, Schumannstr. 20/21, 10117 Berlin, Germany
e Deutsches Herzzentrum Berlin/Herz-und Gefässchirurgie Augustenburger Platz 1, 13353 Berlin, Germany

* Corresponding author. Tel.: +49 30 9417 2508; fax: +49 30 9417 2279. E-mail address: perrot{at}fvk-berlin.de (A. Perrot)


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: One-third of cases of dilated cardiomyopathy (DCM) is of familial aetiology. Several genes have been reported to cause the autosomal dominant form of DCM.

Aims: To analyze the lamin A/C gene (LMNA) in 31 unrelated patients with DCM and conduction system disease (CSD).

Methods: Patients and family members underwent physical examination, ECG/Holter-ECG, echocardiography, and selective coronary angiography. Genetic analysis of all coding exons of LMNA was performed using PCR and sequencing.

Results: Three different LMNA mutations (Arg377His, c.1397delA, c.424_425ins21nt) were identified in three families with autosomal dominant disease comprised of 39 individuals. 21 individuals were mutation carriers, of whom 12 were symptomatic. We observed a progressive and age-dependent form of DCM with CSD and arrhythmias. First, the patients developed a moderate left ventricular dilatation without symptoms. Later, systolic function declined progressively and the patients became symptomatic resulting in a high mortality due to sudden death and heart failure.

Conclusions: Genetic screening leads to the identification of symptomatic and asymptomatic mutant carriers. The latter at a young age should be regarded as "presymptomatic" because of the age-dependent disease manifestation. New guidelines are required for the management of these individuals.

Key Words: Lamin A/C • LMNA • Mutation • Familial dilated cardiomyopathy • DCM • Conduction system disease

Received February 14, 2005; Revised July 29, 2005; Accepted November 8, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by ventricular dilatation and impaired systolic function. The incidence of DCM is 7/100,000 per year and the prevalence is 37/100,000 [1,2]. DCM is a leading cause of heart failure and the most frequent indication for heart transplantation in young patients [3]. Most patients die from pump failure or sudden cardiac death.

Although familial DCM was reported for the first time by Whitfield et al. in 1961 [4], the incidence of the familial aetiology was only recently examined systematically [5]. Systematic examination of relatives revealed that more than 25% of DCM cases are of familial aetiology [6-8]. The mode of inheritance in most families seems to be autosomal dominant [6] but autosomal recessive, X-linked mitochondrial transmissions have also been reported [5].

Several genes have been reported to cause the autosomal dominant form of DCM (see review J. G. Seidman and C. Seidman [9]). One of the most frequent disease genes is the LMNA gene encoding for the two differentially spliced proteins lamin A and C of the intermediate filaments which localize at the nucleoplasmic surface of the inner nuclear membrane as a meshwork structure [10]. It has been proposed that the lamins are important for nuclear envelope assembly and structure and therefore play a role in mitosis and nuclear integrity [10]. In 1999, the first mutations in the rod domain within LMNA were described as the cause of DCM and conduction system disease by Fatkin et al. [11], suggesting that this special phenotype is associated with genetic variants in LMNA. Other studies have described this phenotype caused by LMNA mutations in more detail [12-16]. A meta-analysis from van Berlo et al. [17] suggested that cardiomyopathy due to LMNA mutations portends a high risk of sudden death. They showed that cardiac dysrhythmias were reported in 92% of patients after the age of 30 years. In addition to DCM, LMNA mutations can cause a variety of other familial diseases like lipodystrophy, limb-girdle muscular dystrophy, and Emery-Dreifuss muscular dystrophy (see reviews [18,19]).

We analyzed the lamin A/C gene in 31 unrelated patients with DCM and conduction defects/arrhythmias and identified three LMNA mutations in three families with autosomal dominant disease. Here we report a comprehensive analysis of the corresponding phenotype in these pedigrees.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Phenotypic characterization
A cohort of 31 unrelated patients with idiopathic DCM and conduction disease/arrhythmias was included in the study. After identification of the three mutations, the family members of the three respective DCM patients were examined (families A, B and C). All individuals were evaluated by medical history, physical examination, echocardiography, 12-lead electrocardiogram (ECG) and, in some cases, by Holter ECG in a blinded fashion (i.e. without knowing the genotype). Left ventricular ejection fraction was determined by the area-length method [20]. Coronary artery disease as a cause of the decreased left ventricular function was excluded by selective coronary angiography in the DCM patients. Echocardiographic evaluation was performed according to guidelines of the American Society of Echocardiography [21]. Left ventricular dilatation was defined as left ventricular end-diastolic diameter (LVEDD) >117% of the predicted value for age and body surface area [22,23]. Reduced systolic left ventricular function was defined as ejection fraction (EF) <45% and/or fractional shortening (FS) <25% [24]. All investigations were performed as part of this study. None of the family members contacted refused to participate in the study.

The diagnosis of dilated cardiomyopathy was based on the criteria suggested by Mestroni et al. [24], who proposed diagnostic guidelines especially for the study of familial DCM. The clinical findings were rated as major and minor criteria. Major criteria were left ventricular dilatation and reduced systolic function. Minor criteria were unexplained supraventricular or ventricular arrhythmias, left ventricular dilatation >112%, left ventricular ejection fraction <50% or fractional shortening <28%, unexplained conduction disease, unexplained sudden death or stroke, or segmental wall motion abnormalities.

The assessment of the clinical status was performed in a blinded fashion without knowledge of the genotype, as follows: affected (presence of both major criteria, or left ventricular dilatation and one minor criterion, or three minor citeria), uncertain (presence of one or two minor criteria), and unaffected (individuals with no cardiac anomalies).

Neuromuscular examination was performed in family B because the mutation Arg377His has been shown to result in muscular dystrophy.

Clinical examinations were performed and blood samples were drawn after obtaining informed consent in accordance with the guidelines of the institutional review boards at the respective hospitals. The study protocol was in accordance with the Helsinki Declaration.

2.2. Genetic characterization
Genomic DNA was isolated from whole EDTA blood using standard protocols. All exons of LMNA and the promoter region were amplified using the modified primers and PCR conditions published by Fatkin et al. [11] and were sequenced in the 31 DCM patients and the family members of families A, B, and C. DNA sequencing of the amplified exons was performed by cycle sequencing using fluorescent dye terminators (Applied Biosystems, Darmstadt, Germany). An ABI 310 automatic sequencer (Applied Biosystems, Darmstadt, Germany) was used for analysis. Sequencing was performed in both directions in two independent runs. Two mutations were also confirmed by establishing RFLP assay and/or separation by electrophoresis.

Control samples were obtained from 120 healthy volunteers, who were matched for sex and ethnic origin to the study population. In order to check for the 3 different mutations, the controls were sequenced in exon 6. PCR fragments from exon 8 were digested with the restriction enzyme Mfe I and from exon 2 simply separated by electrophoresis.

The c.1397delA mutation generates a loss of a Mfe I restriction site within the amplified fragment of exon 8. Briefly, for amplification we used the primers forward 5'-TCAATTGCAGGCAGGCAGAG-3'and reverse 5'-GCTCCCATCGACACCCAAGG-3'. In the absence of the c.1397delA mutation, there is a restriction site for Mfe I (CAATTG) resulting in DNA fragments of 114 and 145 bp after digestion and subsequent agarose electrophoresis (see Fig. 3B). There is an undigested 259 bp fragment detectable in the presence of the mutation.

The c.424_425ins21nt mutation is detectable using the amplification of exon 2 (forward primer 5'-GACACTCCTTCTCTTAAATCTAC-3', reverse primer 5'-CCTAGGTAGAAGAGTGAGTGTAC-3'). Amplifying the wild-type sequence results in a PCR fragment of 268 bp. In the presence of the c.424_425ins21nt mutation, a larger fragment of 289bp is present on the electrophoresis gel of 2% agarose (see Fig. 1D).


Figure 1
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  		Fig. 1 DNA sequencing electropherograms demonstrating heterozygosity for the three detected LMNA mutations. (A) The deletion of an adenine (1397delA) at codon 466 is indicated by the presence of overlapping wild-type sequence and mutated sequence shifted 1 bp leftward. (B) The missense mutation in codon 377 is shown by two overlapping peaks. (C) The in-frame insertion of 21 bp at codon 142 is demonstrated by the presence of overlapping wild-type sequence and mutated sequence shifted 21 bp leftward. (D) Amplifying the wild-type sequence of exon 2 results in a PCR fragment of 268 bp. In the presence of the c.424_425ins21nt mutation, a larger fragment of 289 bp is found on the electrophoresis gel.

 

   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Genetic characterization of LMNA
We detected three different mutations in the LMNA gene (one novel and two known) in three patients by sequencing the whole coding region. The families of the three patients showed an autosomal dominant inheritance of DCM. All three mutations were heterozygous as shown in the sequencing electropherograms (see Fig. 1A-C). The mutations were distributed over the gene in exons 2, 6, and 8 affecting various protein domains (see Fig. 2). The mutation type was different in the three genetic variants: we identified one deletion, one missense mutation, and one insertion.


Figure 2
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  		Fig. 2 Localisation of the detected mutations. The upper panel shows the genomic organization of the LMNA gene. Exons 11 and part of exon 12 encode for lamin A while the alternatively spliced part of exon 10 encodes for the lamin C isoform. The lower panel shows the domain structure of the lamin A/C protein with the function of these domains. The protein consists of a globular head domain, a central alpha-helical coiled-coil dimerization domain, and a globular tail domain. LAP2P — lamin-associated protein 2P-isoform.

 
In family A we identified a known deletion of adenine located at codon 466 (nucleotide position 1397 according to the cDNA sequence, accession numbers M13451 [GenBank] and M13452 [GenBank] ) in exon 8 (c.1397delA). The mutation is predicted to lead to a frameshift with a premature stop codon at codon 479 resulting in a truncated protein.

In family B we detected a known missense mutation guanine to adenine in exon 6 (c.1129G >A) leading to an amino acid exchange of arginine to histidine at codon 377 (Arg377His).

In family C we identified a novel in-frame insertion of 21 nucleotides at position 425 in exon 2 (c.424_425ins21nt). This mutation is predicted to result in an insertion of seven new amino acids (KDLDALL) but no frameshift in the open reading frame.

None of the three described mutations was present in 240 alleles from unrelated control subjects without DCM and of German origin.

Detailed clinical characteristics of all individuals carrying the LMNA mutation are presented in Table 1.


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  		Table 1 Clinical characteristics of individuals from families A, B, and C carrying LMNA mutations

 
3.2. Clinical characterization of family A
Family history of the index patient with the c.1397delA mutation was very informative and resulted in the identification of 12 additional mutant carriers within this three-generation pedigree (see Fig. 3). Six of them presented with the clinical phenotype of DCM. The severity of symptomatic heart disease was variable in the affected members (Table 1). In general, disease onset was notable in adolescence with sinus or atrioventricular node dysfunction. Conduction defects, such as supraventricular tachy-arrythmias, first- to third-degree atrioventricular (AV) block, sinus bradycardia, and/or sinus tachycardia, were observed. Severe systolic dysfunction and moderate dilatation of the left atria and ventricles occurred in advanced age. The end stage of the disease was congestive heart failure (CHF).


Figure 3
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  		Fig. 3 Pedigree of family A and mutation detection. (A) Pedigree of family A. Squares indicate males; circles, females. Open symbols represent unaffected subjects; solid symbols, affected individuals; shaded symbols, individuals with uncertain disease status; and slanted bars, deceased individuals. Plus symbols represent the presence of a LMNA mutation, and minus symbols the absence of the respective mutation in this individual. Arrow indicates the index patient. (B) In the presence of the c.1397delA mutation, there is an undigested 259 bp DNA fragment detectable. In the absence of the mutation, there is a restriction site for Mfe I resulting in fragments of 114 and 145 bp after digestion.

 
Individual II-2 died at the age of 50 years due to refractory heart failure. DCM was diagnosed at the age of 43 years when the patient suffered from a probably embolic apoplectic insult. The patient presented with NYHA III and suffered mostly from repeated sustained ventricular tachycardias of about 200/min. He was treated with implantation of an automated cardioverter/defibrillator (AICD). Myocardial function rapidly declined and the patient died before a heart donor was available.

His 33-year-old son (individual III-1) was negative for the mutation and asymptomatic. Electrocardiogram (ECG) and echocardiography were normal aside from a very mild global LV-hypokinesia.

Individual III-2, his 28-year-old son, had dizziness and dyspnoea on moderate exertion (NYHA II). The left ventricle was of borderline size but systolic function was clearly reduced.

Individual II-3 (50 years of age) was asymptomatic. She had normal LV size and function. On ECG the only abnormality was a first-degree AV block.

At the age of 47 years, individual II-4 developed global congestive heart failure. After medical recompensation she had dyspnoea on exertion (NYHA II). Early in the course of the disease she developed first-degree AV block and later bradyarrhythmic atrial fibrillation.

Individual II-6, index patient of the family, became symptomatic at the age of 48 years because of a sustained ventricular tachycardia, with 220/min. Therefore, an AICD was implanted which recorded repeated episodes of ventricular tachycardias and ventricular fibrillations. Dyspnoea was present after moderate exertion (NYHA II). Despite regular AICD function, the patient died of irreversible ventricular fibrillation at the age of 51 years.

The 21-year-old son (individual III-4) was asymptomatic and ECG and echocardiography revealed unremarkable results. His other children, the mutation carriers III-6 (18 years), III-7 (15 years), III-8 (14 years), and III-10 (8 years), were asymptomatic and presented with normal ECG.

Individual II-9 developed dyspnoea on moderate exertion and presyncopal episodes at the age of 39 years. The first hospitalisation was due to ventricular fibrillation; after successful resuscitation, he showed LV-dilatation with impaired systolic function. At the age of 43 years, an AICD was implanted because of recurrent sustained ventricular tachycardias. He died 3 years later of heart failure.

His 23-year-old son (individual III-11) was asymptomatic and had only mild systolic LV-dysfunction with normal LV-dimensions. Individual III-12, his 15-year-old son, was negative for the mutation and asymptomatic. The only finding was a sinus tachycardia.

Individual II-11 had ventricular tachycardias at the age of 30 years. Five years later, a DDD pacemaker was implanted because of symptomatic bradycardias. There was a mild LV-dilatation and a global hypokinesia on angiography. He died suddenly at the age of 36 years, most likely due to a malignant tachy-arrhythmia. No material was available for genetic testing.

Individual II-13 became symptomatic with a reversible paresis of the left leg and was diagnosed NYHA class II. Diagnostic work-up found a severely dilated left ventricle with globally reduced systolic function. An AICD was implanted 1 year later because of non-sustained ventricular tachycardias. He had a heart transplant at the age of 39 years.

Individual II-15 had complained of palpitations and dizziness since she was 23 years old. Repeated echocardiographic evaluations showed borderline LV-size and mild global hypokinesia. ECG showed a first-degree AV block and, on Holter ECG, non-sustained supraventricular tachycardias were recorded.

The other family members, individuals II-1, II-5, II-7, II-8, II-10, II-12, II-14, III-3, III-5, III-9, III-13, and III-14 (all negative for the mutation), were asymptomatic and revealed normal cardiac findings.

The clinically affected individuals II-2, II-6, II-9, II-11 and II-13 underwent selective coronary angiography and left ventricular angiography. Coronary artery disease was clearly excluded in these cases.

3.3. Clinical characterization of family B
In family B we identified the mutation Arg377His in five individuals (II-1, II-3, III-3, IV-1, IV-2). The four-generation pedigree is presented in Fig. 4.


Figure 4
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  		Fig. 4 Pedigree of families B and C. Symbols as in Fig. 3.

 
Individual I-2 died at the age of 60 years of refractory heart failure. Her clinically unaffected husband (individual I-1) died of cancer at the age of 85 years.

Their son, individual II-3, had DCM diagnosed by echocardiography. He received a dual chamber pacemaker because of a third-degree AV block at the age of 58 years. His sister (individual II-1) had DCM and also had a pacemaker.

Individual III-3 (index patient of family B) was diagnosed with DCM at the age of 40 years. He received a dual chamber pacemaker because of a third-degree AV block at the same age. About 6 months after pacemaker implantation he developed permanent atrial fibrillation. The patient underwent endomyocardial biopsy during the initial evaluation of his heart disease. Histological evaluation (Gerhard Mall, Darmstadt, Germany) showed a dramatic loss of myocytes and pronounced active interstitial fibrosis (see Fig. 5). The remaining myocytes were hypertrophied (mean myocyte diameter 35 µm; reference ≤16 µm). His wife (III-2) was clinically unaffected.


Figure 5
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  		Fig. 5 Photomicrographs showing histology obtained from left ventricular endomyocardial biopsy specimen of the index patient of family B (individual III-3). (A) HE staining (400x magnification) of left ventricular myocardium showing hypertrophy of myocytes, a significant loss of myofibrils, and excessive interstitial fibrosis. (B) Immunohistology using a primary antibody to detect MHC class II molecules expressing cells. The content of these cells - most likely fibroblasts - is increased indicating active interstitial fibrosis.

 
The index patient's brother (III-1) and his two sons, individuals IV-1 and IV-2 (11 and 7 years old), were all asymptomatic. There were no abnormalities on ECG.

Individuals III-3, IV-1, and VI-2 did not show any evidence of skeletal muscle involvement by clinical neurological evaluation. There were no pathologic findings on physical evaluation for quadriceps muscle myopathy.

3.4. Clinical characterization of family C
In family C we identified the 21 nucleotide insertion mutation at position 424 in 2 family members (II-2 and III-2). The three-generation pedigree is shown in Fig. 4.

Individual III-2 developed ventricular and supraventricular premature beats and first-degree AV block at the age of 10 years. His LV function was slightly impaired at that time. At the age of 19 years, an AICD was implanted because of ventricular tachycardias. Echocardiography showed a LVEDD of 59 mm, a LVESD of 37 mm and an impaired LV function (FS=20%). Despite medical treatment, symptoms in this patient quickly worsened. Therefore, he was accepted onto the waiting list for heart transplantation at the age of 21 years. The heart transplantation was successfully performed 1 year later.

The index patient II-2, his mother, developed palpitations during pregnancy at the age of 22 years. An AICD was implanted at the age of 34 years because of AV block and syncope. She developed dyspnoea at the age of 40 years; DCM was diagnosed 3 years later. LV angiography showed an impaired LV function with an EF of 33%. Several episodes of global cardiac decompensation ensued. She underwent successful heart transplantation at the age of 44 years.

Three family members died at a young age due to DCM but there was no clinical data or material for genetic analysis available for these individuals. Individual I-2 died at the age of 28 years, individual II-3 at the age of 32 years, and individual III-1 at the age of 24 years.

3.5. Clinical phenotype of the families in summary
We have examined 39 family members of whom 21 were mutation carriers. Twelve of these mutation carriers were symptomatic, showing DCM with a variable degree of LV dilatation and function as well as cardiac rhythm disturbances. This group had a mean age of 49.9±12.4 years; the majority were males (66%). In general, the patients showed a mild to moderate LV dilatation with a mean LVEDD of 59.3±7.5 mm. LV function was clearly diminished with a mean EF of 33.4±10.5% and a mean FS of 18.8±5.0%. All patients showed conduction disease with either AV and left bundle branch block or atrial fibrillation. 58% of them presented with ventricular arrhythmias (mostly ventricular tachycardia and fibrillation). Both types of arrhythmias lead to sudden cardiac death/reanimation as well as to pacemaker/AICD implantation. At later ages, the patients showed a severe form of DCM leading to CHF. If they did not undergo heart transplantation (which was successfully performed in three individuals), we observed a high rate of cardiac death due to heart failure at an age of around 50 years.

Taking into account the nine mutation carriers without DCM phenotype (seven with status "unaffected" and two with "uncertain" status), a clear age dependent penetrance was observed. The disease penetrance for all individuals with mutations was 57% (12/21) while for individuals aged ≥35 years the penetrance was 91% (10/11). All nine mutation carriers without DCM were under the age of 25 years (except for one individual).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The previously reported LMNA mutations associated with conduction-system disease and/or dilated cardiomyopathy are scattered throughout the gene usually resulting in severe changes in the secondary protein structure. This in turn may lead to dyslocalization and functional loss of both lamin A and lamin C within the nucleus [11]. Interestingly, individual mutations may cause both peripheral muscle dystrophy and cardiomyopathy [10,25]. The reason why one patient may present solely with one organ involvement and the other may present with both manifestations is still unknown. However, this clearly implicates the existence of modifying factors in determining the LMNA-associated phenotype.

Various hypotheses have been proposed to explain the role of these nuclear proteins in the pathogenesis of cardiomyopathy. Lamin A/C-deficient mice rapidly develop DCM. Affected cardiomyocytes display altered nuclear architecture and gene expression including detachment of desmin filaments disrupting the interaction between the nuclear surface and the cytoskeletal desmin network [26]. These findings were also present in cardiac muscle from LMNA mutant carriers presenting with cardiomyopathy [27,28]. Studies in lamin A/C-deficient mouse embryo fibroblasts support the hypothesis that under mechanical strain affected cells develop increased nuclear deformation, defective mechanotransduction, and impaired viability [29]. It was suggested that impaired nuclear mechanics and resulting secondary alterations in gene expression may cause striated muscle damage [30].

We report here on three families carrying different mutations in LMNA, one novel and two previously reported. We consider the detected genetic alterations as disease causing mutations for the following reasons. First, LMNA is a proven disease gene for DCM as demonstrated in various patient studies and animal models. Additionally, there is a clear cosegregation of the respective mutation with the disease phenotype in the three examined families: all clinically affected relatives carried a LMNA mutation. Both the deletion and insertion mutations were predicted to lead to severe changes in the protein sequence implying functional importance. Finally, neither of the identified mutations was present in 240 control alleles.

The c.1397delA mutation was previously reported by us in one patient with DCM from family A [31]. The missense mutation Arg377His was described as disease causing in a small family with DCM/conduction disease and mild muscular dystrophy [12]. Further, a family carrying this mutation with DCM/conduction disease and a specific quadriceps restricted myopathy has been published [32]. The neuromuscular phenotype could not be found in family B whereas the cardiac manifestation was quite similar as described by Taylor et al. [12] and Charniot et al. [32].

All mutation carriers developed symptoms of heart failure in their third decade of life, but they did not develop peripheral muscle or neurological disease. In addition, none of the studied subjects presented with dyslipemia, insulin resistance, or acanthosis nigricans. Thus, we did not observe any overlap with other known laminopathies in these families.

We observed a severe and progressive form of DCM with conduction defects in the three families. At the beginning, the phenotype was characterized by mild to moderate dilatation but later on by worsening of symptoms and severe systolic dysfunction leading to the indication for heart transplantation and a high mortality due to sudden death and CHF. Further, the patients were characterized by conduction defects and arrhythmias leading to pacemaker or AICD implantation in 7 of 12 patients. The three families showed a close connection between CHF and malignant conduction disease and/or ventricular tachy-arrhythmias. Beside drug treatment for heart failure, awareness and early detection of the type of arrhythmia is necessary for adequate therapy.

Obviously, LMNA mutations are the most frequent cause of familial DCM as shown by the high number of identified mutations worldwide [10,12]. Our study and others [12-16] have shown that individuals with LMNA mutations clearly have a worse prognosis than other DCM subjects. The cardiac phenotype seems to be similar for all LMNA mutations. The course of the disease is progressive. The observed age related penetrance is similar to other genetic heart muscle diseases such as hypertrophic cardiomyopathy (see review [9]). Beginning in the third decade of life, all LMNA mutation carriers from the three families reported by us developed a steadily decreasing myocardial function. Thus, every asymptomatic LMNA mutant carrier should be considered as "presymptomatic". In addition, nearly all LMNA mutations were associated with conduction disease such as sinus bradycardia and AV block indicating that this is a highly specific manifestation of mutations in this gene [17]. We would recommend frequent Holter monitoring in mutant carriers to document bradycardias and/or ventricular tachy-arrhythmias as early as possible. Currently, there are no guidelines for prophylactic implantation of AICDs or pacemakers in asymptomatic mutant carriers. However, there is a need for prospective trials with respect to anti-arrhythmic drug and device therapy in persons carrying LMNA mutations. Only then can evidence-based strategies for clinical management be developed.

In conclusion, information about the genotype in an individual from a DCM family could be very useful for the clinician, especially when dealing with healthy relatives, who are dubious about their risk of developing DCM and cardiac rhythm disturbances. However, predictions about the disease course in individual patients based on their genotype remains difficult, although there are a lot more clinical and genetic data available about DCM caused by LMNA mutations than by mutations in any other DCM disease gene. Therefore, we hope that the increasing use of LMNA screening and increasing knowledge about genotype-phenotype correlations will lead to better genetic counseling and improved clinical management of DCM patients and their relatives in the future.


   Acknowledgements
 
We thank the families for their cooperation in this study. This study was supported by a grant-in-aid from Charité- Universitätsmedizin Berlin and the Deutsche Stiftung für Herzforschung. We are indebted to Gerhard Mall, Darmstadt/Germany, for histological evaluation of endomyocardial biopsy specimen and generation of photomicrographs of the index patient of family B.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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D. V. Moller, T. T. Pham, F. Gustafsson, P. Hedley, M. K. Ersboll, H. Bundgaard, C. B. Andersen, C. Torp-Pedersen, L. Kober, and M. Christiansen
The role of Lamin A/C mutations in Danish patients with idiopathic dilated cardiomyopathy
Eur J Heart Fail, November 1, 2009; 11(11): 1031 - 1035.
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