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European Journal of Heart Failure 2003 5(6):821-825; doi:10.1016/S1388-9842(03)00149-1
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© 2003 European Society of Cardiology

Apical left ventricular aneurysm without atrio-ventricular block due to a lamin A/C gene mutation

Jean-François Forissiera,h, Gisèle Bonneb,c, Christiane Bouchierc,d, Laetitia Duboscq-Bidotc,d, Pascale Richardc,e, Claudine Wisnewskib,c, Sylvain Briaultf, Claude Morainef, Olivier Dubourga, Ketty Schwartzb,c and Michel Komajdac,d,g,*

a Service de Cardiologie, Hôpital Ambroise Paré Boulogne-Billancourt, France
b Inserm U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière Paris, France
c IFR 14 Cœur, Muscles et Vaisseaux, Groupe Hospitalier Pitié-Salpêtrière Paris, France
d Laboratoire Génétique et Insuffisance Cardiaque, Association Claude Bernard/Université Paris VI, Groupe Hospitalier Pitié-Salpêtrière Paris, France
e Service de Biochimie B, Groupe Hospitalier Pitié-Salpêtrière Paris, France
f Service de Génétique, Hôpital Bretonneau Tours, France
g Service de Cardiologie, Groupe Hospitalier Pitié-Salpêtrière Paris, France
h Centre cardiologique Arago Perpignan, France

* Corresponding author. Present address: Laboratoire Génétique et Insuffisance Cardiaque, Pavillon Rambuteau, Groupe Hospitalier Pitié-Salpêtrière-47 bd de l'Hôpital, Paris cedex 13, 75651, France. Tel.: +33-1-42-17-68-10; fax: +33-1-42-17-68-00 E-mail address: michel.komajda{at}psl.ap-hop-paris.fr


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Mutations in LMNA gene encoding two ubiquitously expressed nuclear proteins, lamins A and C, give rise to up to 7 different pathologies affecting specific tissues. Three of these disorders affect cardiac and/or skeletal muscles with atrio-ventricular conduction disturbances, dilated cardiomyopathy and sudden cardiac death as common features.

Results: A new LMNA mutation (1621C>T, R541C) was found in two members of a French family with a history of ventricular rhythm disturbances and an uncommon form of systolic left ventricle dysfunction. The two patients: the proband and his daughter, were affected and exhibited an atypical form of dilated cardiomyopathy with an unexplained left ventricle aneurysm revealed by ventricular rhythm disturbances without atrio-ventricular block.

Conclusion: This finding reinforces the highly variable phenotypic expression of LMNA mutation and emphasizes the fact that LMNA mutations can be associated with different cardiac phenotypes.

Key Words: Left ventricular aneurysm • Dilated cardiomyopathy • Atrio-ventricular block • Lamin A/C gene

Received April 3, 2003; Revised June 11, 2003; Accepted July 17, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The LMNA gene encodes two nuclear envelope proteins, lamins A and C that were first implicated in the autosomal dominant form of Emery–Dreifuss muscular dystrophy (AD-EDMD) [1]. The wide variability of the phenotypes of LMNA mutations is now well recognized, since up to seven disorders are now reported to be caused by LMNA mutations. Three of these disorders affect striated muscles, cardiac and/or skeletal, i.e. AD-EDMD, limb-girdle muscular dystrophy associated with cardiac conduction disease (LGMD1B) and dilated cardiomyopathy with conduction system disease (DCM-CD) [2–4]. The Dunningan type of partial lipodystrophy is specific to the adipose tissue [5], whereas the mandibuloacral dysplasia associated both adipose and bone tissue defects [6] and axonal neuropathy affect specifically the peripheral nerves [7]. Finally, LMNA mutations were recently reported in Hutchinson–Gilford progeria syndrome characterized by premature aging [8,9]. Whereas mandibuloacral dysplasia and axonal neuropathy are recessive disorders of geographical founder origin, the five other disorders are autosomal dominant disorders, although homozygous LMNA mutation was reported in a patient with Emery–Dreifuss muscular dystrophy [10]. Atrio-ventricular block (AV block), myocardial dysfunction and sudden death represent the usual cardiac manifestations in laminopathies affecting striated muscles, i.e. AD-EDMD, DCM-CD, LGMD1B. The family we report here exhibits an atypical phenotype with unexplained apical Left ventricle (LV) aneurysm revealed by ventricular arrhythmias and at a later stage systolic dysfunction without AV block. Faced with this systolic myocardial dysfunction we analysed the lamin A/C gene for mutations.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Subjects
After informed consent was obtained under the guidelines of the Ethical Committee of Pitié-Salpêtrière Hospital, all genotyped subjects underwent neurological and cardiovascular examination including 12-Lead ECG, echocardiography (M-mode, 2D and Doppler) and creatine kinase level measurement at the time of genotyping. Subjects II-1 and III-1 underwent neuromuscular investigations including electromyography. Subject II-1 underwent cardiac catheterisation, including ventriculography and coronary angiography, before heart transplantation. The investigation conforms to the principles outlined in the Declaration of Helsinki.

2.2. Genetic analysis
Screening for mutations in the lamin A/C gene (LMNA) was carried out by the single strand conformation polymorphism method followed by sequencing on DNA extracted from the peripheral blood as described elsewhere [11]. The presence of the mutation was controlled on a second blood sample by direct sequencing and restriction fragment length polymorphism analysis.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
We report here a French family with no history of congestive heart failure or sudden death (Fig. 1). Two subjects II-1 and III-1 were clinically affected and exhibited a history or an atypical form of dilated cardiomyopathy (DCM). The clinical and echocardiographic characteristics of these patients are shown in Table 1.


Figure 1
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  		Fig. 1 Pedigree of family Q. Filled symbols indicate patients, clear symbols indicate unaffected family members and symbols with a question mark indicate individuals with unknown DMC status. The presence (CT) or the absence (CC) of the LMNA mutation is indicated for family members for whom a DNA sample was available for screening.

 


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  		Table 1 Phenotype of the two affected subjects with the R541C LMNA mutation

 
Subject II-1 is a 49-year-old man. His medical history began with a ventricular tachycardia when he was 22-years old. Due to refractory episodes of ventricular tachycardia, an apical aneurismectomy was performed at the age of 33 years and an automatic implantable defibrillator was implanted 6 years later. He was finally transplanted at 44-years old. His coronary arteries were normal before heart transplantation and the ECG showed a left bundle branch block without AV conduction disturbance.

When he was 26-years old, a first cardiac catheterisation was performed. The ventriculography showed an apical dyskinesia with subnormal LVEF (53%). Just before transplantation, LV was dilated and hypokinetic with a LVEF=30% and despite the aneurismectomy, showed a large remaining apical aneurysm (Fig. 2). His neurological examination has always been normal and his most recent (in 2001) creatine kinase plasma determination level was 97 IU/l.


Figure 2
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  		Fig. 2 Panels A and B are left ventricle diastolic and systolic views, respectively, on angiography (Patient II-1). Arrows indicate the apical LV aneurysm.

 
Subject III-1 is the 29-year-old daughter of subject II-1. Her disease was revealed by ventricular premature contractions (VPC) during a pregnancy when she was 20-years old. Basal ECG showed multiple VPCs without AV conduction disturbance and ECG monitoring showed a sinusal rhythm with multiple VPCs and 2 episodes of non-sustained ventricular tachycardia without AV conduction disturbance at the age of 25 years.

Under beta-blocker therapy, she remained asymptomatic and ECG monitoring showed a reduction in the number of VPCs and no episode of ventricular tachycardia. The latest echocardiography at the age of 29 showed a slight dilated left ventricle with apical dyskinesia. LVEF was estimated by radionucleide imaging at 33%. At the beginning of the disease the first echocardiographic examination had shown a normal left ventricle with mild apical hypokinesia. Neurological examination was normal and creatine kinase plasma level was slightly elevated (169 IU/l).

Subject II-2 is subject's III-1 mother. Her clinical examination, ECG and echocardiography were normal and she was clinically unaffected. Subject IV-1 is the 4-year-old son of subject III-1. He is asymptomatic and his clinical examination, ECG and echocardiography were normal. Thus, he was considered as unaffected. The other family members had normal clinical examination, ECG and echocardiography. Thus, they were considered as unaffected.

Genetic analysis of the DNA of the index case (subject II-1) was carried out using single strand conformation polymorphism (SSCP) and sequencing methods. An abnormal SSCP conformer was found for the exon 10 PCR fragment of the patient. Further sequencing of this exon 10 revealed a 1621C>T transition that changed an arginine in a cysteine at position 541 (R541C). This mutation was then searched for in other family members and was identified in patient III-1 and was absent in other family members as well as in 100 unrelated control subjects (Fig. 1). Presence of identical intronic silent polymorphisms both in the index case (II-1) and his father (I-1) indicates that the father was definitively the biological parent. Therefore, the absence of the mutation in the two parents (I-1 and I-2) who do not have any cardiac disorders and the presence of the mutation in both the propositus and his daughter, who both present the same cardiac disease, show clearly the 1621C>T transition affecting a CpG site is a de novo mutation arising at the second generation of this family.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
We report here, what is to our knowledge the first description of a mutation affecting the gene encoding the lamin A/C in a family with an unusual form of dilated cardiomyopathy without atrio-ventricular conduction disturbance or neurological disease.

The cardiac phenotype of the two affected members is particularly interesting: first, the disease was revealed early (22 years in the father and 20 years in the daughter) by a LV apical aneurysm and ventricular rhythm disturbances without initial ventricular dilatation and systolic dysfunction. Usually clinically affected members of a family with a LMNA mutation exhibit at middle age a dilated cardiomyopathy with mild to moderate impairment of LV contraction and heart failure symptoms [3,4,12]. Moreover, apical aneurysm has never so far been related to a lamin A/C mutation. Reported usual causes of apical LV aneurysm and pseudoaneurysm are myocardial infarction [13,14], infective myopericarditis [15], Chagas’ disease [16], and rarely hypertrophic cardiomyopathy [17]. Secondly, the two affected subjects had severe ventricular rhythm disturbances: the father was hospitalised because of a sustained ventricular tachycardia at the age of 22 years, his daughter had salves of non-sustained ventricular tachycardia at the age of 25 years. Interestingly, no sinus node dysfunction or AV conduction disturbance was observed, which is in contrast to previously reported lamin A/C mutation families where AV block usually occurs with or without supraventricular or ventricular rhythm disturbance in approximately 87% of 39 affected subjects [4] and often reveals the cardiac disease before LV dilatation [3].

Thus, the lamin A/C mutation described here results in a particular form of DCM without skeletal muscle involvement. Isolated cardiac forms have been previously described [3,4,12,18,19] but the DCM phenotype was always classic with LV dysfunction and was always associated with AV block [20]. Here myocardial dysfunction occurred at a later stage and apical aneurysm was the initial presentation with ventricular arrhythmia but without AV block.

The mutation identified here, R541C, is the third mutation reported so far in the exon 10 of the LMNA gene. This R541C mutation is localised in an exon 10 region that is common to both lamins A and C and thus affects the two proteins. Another mutation, R541H, was reported (unpublished) in a 20-years-old woman, whose mother had difficulties with the mobilisation of her neck and died suddenly. Proband's phenotype was different than that of our family, because the young woman exhibited auricular and ventricular extrasystols, without AV block and LV aneurysm, and was wheelchair-bound suggesting a Emery–Dreifuss muscular dystrophy.

The other exon 10 mutation reported, R571S, is localized in a region of exon 10 that encodes only lamin C tail, modifying, therefore, only this isoform [4]. This R571S mutation was reported in a family with a relatively mild phenotype of DCM-CD without muscle involvement with a low prevalence of atrial fibrillation and dilated cardiomyopathy and no sudden death [4].

Thus, the three LMNA mutations identified so far in the exon 10 lead to three distinct phenotypes: an atypical dilated cardiomyopathy with LV aneurysm (R541C), AD-EDMD (R541H)(unpublished) and DCM-CD (R571S) [4]. This strongly underlines the wide heterogeneity of phenotypes for mutations affecting the same exon of LMNA gene. Moreover, LMNA mutations were reported to lead to different phenotypes (DCM-CD and/or AD-EDMD, LGMD1B) within the same family [3,12]. This suggests the role of modifier genes and/or exogenous factors.

The R541C mutation affects Ig-like structure of the C-terminal domain of Lamin A/C: buried side chain of arginine 541 participates in the stabilisation of the beta sandwich through hydrophobic contacts with the core of the domain [21]. Such interactions are disrupted by its mutation to cysteine (R541C) or histidine (R541H), and should lead to a destabilisation of the domain structure. Further analyses of consequences of the R541C mutation in skin fibroblasts of the index case (II-1) are in progress and will certainly give some clues regarding the pathogenic effect of this mutation on the nuclear envelope structure.

The present LMNA mutation arose de novo in the family; since the mutation was detected in the two affected family members (II-1 and III-1), but was absent in the DNA of the index case parents (individual I-1 and I-2, Fig. 1), who were both unaffected. De novo mutations are frequent in the LMNA gene and were previously reported in a family with AD-EDMD [1,11], suggesting that LMNA mutations might be searched for in sporadic cases of DCM-CD, but also in sporadic cases of atypical dilated cardiomyopathy and/or unexplained apical left ventricular aneurysm.

In conclusion, Lamin A/C gene mutation seems to be a new cause of apical left ventricle aneurysm without atrio-ventricular block and should be screened systematically in familial atypical dilated cardiomyopathy and/or unexplained apical left ventricular aneurysm. This finding emphasizes the fact that lamin A/C gene mutations are associated with various cardiac phenotypes.


   Acknowledgements
 
We thank Dr Luc Maillard for providing medical evaluation of patient II-1. G.B. is supported by grants from the Human Frontiers Science Program (grant #RGP0057/2001-M101 and by the European Union Fifth Framework Program (Grant Myo-Cluster Euromen contract #QLG1-1999-00870).


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

  1. Bonne G., Di Barletta M.R., Varnous S., et al. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery–Dreifuss muscular dystrophy. Nature Genet (1999) 21:285–288.[CrossRef][Web of Science][Medline]
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  5. Shackleton S., Lloyd D.J., Jackson S.N., et al. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nature Genet (2000) 24:153–156.[CrossRef][Web of Science][Medline]
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  7. De Sandre-Giovannoli A., Chaouch M., Kozlov S., et al. Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot- Marie-Tooth Disorder Type 2) and mouse. Am J Hum Genet (2002) 70:726–736.[CrossRef][Web of Science][Medline]
  8. De Sandre-Giovannoli A, Bernard R, Cau P et al. Lamin A truncation in Hutchinson-Gilford progeria. Science. 2003.
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