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European Journal of Heart Failure 2006 8(3):249-256; doi:10.1016/j.ejheart.2005.08.007
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© 2005 European Society of Cardiology

Severe dilated cardiomyopathy and quadriceps myopathy due to lamin A/C gene mutation: A phenotypic study

Jean-Christophe Charniota,*, Michel Desnosb, Khaled Zerhounia, Dominique Bonnefont-Rousselotc, Jean-Paul Albertinia, Jeffrey Zaketto Salamad, Guillaume Basseze, Michel Komajdaf and Jean-Yves Artigoua

a Service de Cardiologie, Avicenne Hospital, Paris XIII University Bobigny, France
b Service de Cardiologie, European Georges Pompidou Hospital, Paris V University Paris, France
c Laboratoire de Biochimie, Pitié-Salpétrière Hospital, Paris VI University Paris, France
d Service de Neurologie, Avicenne Hospital, Paris XIII University Bobigny, France
e Service d'anatomo-pathologie, Henri Mondor Hospital Creteil, France
f Laboratoire Génétique et Insuffisance Cardiaque, Association Claude-Bernard/Paris VI University, Pitié-Salpêtrière Hospital Paris, France

* Corresponding author. E-mail address: jean-christophe.charniot{at}avc.ap-hop-paris.fr (J.-C. Charniot)


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 5. Limitation of this...
 References
 
This study reports a family affected by a new phenotype associated with dilated cardiomyopathy and quadriceps myopathy.

Methods: 29 family members underwent a physical and neurological examination, including an electromyogram and biopsy of muscle abnormalities. A cardiac examination was performed in all subjects.

Results: The family pedigree (n=72) demonstrated that transmission was autosomal dominant. Eleven subjects had cardiac involvement, only four had quadriceps muscle involvement. Cardiac impairment preceded neurological involvement. The mean age for neurological involvement was 44±0.8 years (range 43–45) and cardiac involvement was 37±7.9 years (range: 24–45). Cardiac involvement consisted of: hypokinetic dilated cardiomyopathy (64%); atrial fibrillation (100%); ventricular arrhythmias (64%); impaired conduction with bundle branch or complete atrio ventricular block (73%). Four patients required pacemakers and anti arrhythmic therapies. Four patients died: two of refractory heart failure and two of sudden death; two patients were resuscitated following cardiac arrest. Three patients required a prophylactic implantable cardiac defibrillator (ICD). Muscle morphological abnormalities were characterized by a variable number of fibers with rimmed vacuoles. The quadriceps deteriorated progressively without impairment of other muscles. Genotypic study showed a lamin A/C gene mutation.

Conclusions: This family was affected by a new phenotype composed of an autosomal dominant severe dilated cardiomyopathy with conduction defects or arrhythmias and quadriceps myopathy. Cardiac abnormalities preceded neuromuscular disorders and defined the prognosis of this disease.

Key Words: Arrhythmia • Myopathy • Genetics • Cardiomyopathy • Phenotype

Received November 30, 2004; Revised July 1, 2005; Accepted August 16, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 5. Limitation of this...
 References
 
Dilated cardiomyopathy (DCM) is a disorder characterized by impaired systolic function and dilation of either the left, or both ventricles, it represents a final common pathway of a heterogeneous group of inherited and acquired disorders [1,2].

Cardiac involvement is well documented in several different forms of muscular dystrophy, including Duchenne and Becker type muscular dystrophy, autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2) and myotonic dystrophy [3-9]. Limb girdle muscular dystrophy (LGMD) is a heterogeneous disorder with a limb girdle distribution of weakness and variable inheritance [10,11]. Recent reports have described cardiac involvement, but this appears to be rare [5,10-12]. Neuromuscular disorders precede cardiac abnormalities in all forms of muscular dystrophy.

In this report, we describe a large family with a new disease phenotype observed for the first time in a French family, which manifests as DCM with conduction defects and quadriceps muscle myopathy.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 5. Limitation of this...
 References
 
The family history was obtained by interviewing the different members of the family. No consanguinity due to marriage was found. All subjects gave written consent to participate in the study.

2.1. Neurological status
All patients were examined in our hospital by a neurologist (J.S.) who conducted complete neuro muscular examinations. A standardized protocol was used to determine age and symptoms at onset, disease duration, and clinical features. When muscle weakness and/or amyotrophy were present, electromyograms (EMG) of leg and arm muscles were obtained. For patients with EMG abnormalities (especially chronic denervation), a biopsy of the abnormal skeletal muscle was taken under local anaesthesia. Muscle samples were frozen in isopentane, cooled in liquid nitrogen, for conventional histochemical studies : 10 µm transverse sections were stained for hematoxylin and eosin, modified Gomori trichrome, periodic acid-Schiff (PAS), Sudan black, Congo red and reacted for NADH dehydrogenase, and Cytochrome-c oxydase [13]. Frozen sections from all biopsies were immunostained using a sensitive avidin-biotin peroxidase technique (Dab kit, Nexes IHC staining module, Ventana Medical Systems, Tucson, AZ), with the following primary antibodies desmin (Dako, dilution 1:30), P-B crystallin (Novocastra, 1:100), ubiquitin (Dako, 1:100), dystrophin (Tebu, 1:2), sarcoglycans (Novocastra), (P 1:20, β - {gamma} 1:100 and {delta} 1:25) laminin P2 and emerin (Novocastra, 1:20), CD8 (Dako, 1:20). Skeletal muscle sections were also incubated with ATPase at PH 10,3 : 9,4; 4,6 : 4,32 to identify structural changes in different muscle fiber types.

Blood tests were performed, including CK activity, C reactive protein, and fibrinogen.

2.2. Cardiac status
Detailed clinical information was obtained from each subject including family history, age of presentation, symptoms of heart failure (NYHA class), physical examination, 12-lead electrocardiogram (ECG), two dimensional and M-mode echocardiography and colour flow Doppler using an ATL 5000 apparatus with systematic recording of the tracings. All usual parameters were assessed, with evaluation of systolic (EDD; LVEF) and diastolic dysfunction (JCC).

For all patients, Holter monitoring was obtained using an Elatec recorder (Ela Medical, Le Plessis-Robinson, France). Patients with dilated cardiomyopathy (DCM) underwent coronary angiography with left ventriculography and a gamma-radionuclide angiography.

Myocardial biopsies were performed in patients with DCM in the right ventricle if patients gave consent.

The diagnosis of DCM was based on the presence of the following two criteria:

- LVEF <45% and/or a shortening fraction <25%, as assessed by echocardiography, isotopic angiography or contrast ventriculography.
- LV diameter >117% calculated according to Henry's formula [2].

For the three patients who died before the study, a meticulous study of the medical records was performed and for one patient myocardial samples from autopsy were re-examined.

2.3. Lamin A/C mutation analysis
Genomic DNA was extracted from blood samples using a standard procedure. A systematic PCR-Single Stand Conformation Polymorphism (SSCP) sequencing analysis was performed as previously described [14]. Control DNA samples were analyzed from 200 unrelated matched control subjects.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 5. Limitation of this...
 References
 
This family comprised 72 members, of these, 29 adults from five generations were studied. Healthy minors were not included. The pattern of inheritance was autosomal dominant (Fig. 1). Affected individuals were found in a least three generations, males and females were equally affected, and male-to-male transmission was present. Among the 29 subjects studied, 11 (including 5 females) were diagnosed as having cardiac involvement, which was associated with bilateral quadriceps muscle impairment in four subjects. The clinical characteristics of these 11 subjects are shown in Table 1.


Figure 1
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  		Fig. 1 The pedigree of five generations of a family was interpreted as being transmitted by autosomal dominant inheritance. Symbols : circles : females; squares : males; /: dead ; all black : cardiac and muscle involvement; left half black: cardiac involvement; right half black : muscle involvement; upper left quarter black : suspected cardiac involvement; upper right quarter black: suspected muscle involvement. Arrow indicates the proband.

 


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  		Table 1 Clinical characteristics of the 11 family members with cardiac involvement and/or skeletal myopathy

 
The first apparent cardiac abnormalities were arrhythmias and progressive conduction disorders with dilated cardiomyopathy. Average age at onset of cardiac symptoms was 37±7.9 years (47 years for the first generation, 42.5±2.5 years for the second and 27.3±2.5 years for the third generation). Cardiac involvement always preceded neuro muscular impairment. Cardiac involvement consisted of hypokinetic DCM in 7/11 (64%) patients (LVEDD=63±5 mm range : 57-70), in whom LVEF was only mildly reduced (45,1%); and three of whom had signs of cardiac decompensation NYHA class II for one patient and class IV for two (Table 2). Seven patients had normal coronary arteries, as assessed by coronary arteriography (n=6) or autopsy (n=1). All patients had AF and 7/11 (64%) patients had ventricular arrhythmias. These latter seven patients had ventricular extrasystoles of Lown III (100%) and paroxysmal VT (n=6; 84%) or torsade de pointes (n=1; 16%; Fig. 2). Conduction abnormalities were detected in 8/11 (73%) patients with complete RBBB (n=1) or LBBB (n=4) in addition to complete AVB in three (33.3%) patients (Table 1).


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  		Table 2 Summary of the clinical evolution of the 11 family members with cardiac involvement and/or skeletal myopathy

 


Figure 2
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  		Fig. 2 Patient II.3 ECG tracing of 29 October 1989: episode of torsade de pointes.

 
Pacemakers were implanted in three individuals because of symptomatic complete AV block and for torsade de pointes in one patient (Table 2). Two patients died of refractory heart failure at 45 and 78 years, and two of sudden cardiac death, at 49 and 51 years, respectively; one went into cardiac arrest but was resuscitated (patient II.3, torsade de pointes). All patients who had a pacemaker, subsequently received a prophylactic implantable cardiac defibrillator (ICD). One patient (patient II-4) had a cardiac arrest due to ventricular fibrillation 4 months after implantation, which was treated by a shock delivered by the ICD (Fig. 3). The ECG of a first cousin of the proband (patient II.9), taken in 1970, one year before death (at the age of 45 years), shows a permanent AF with complete LBBB and polymorphic paroxysmal VT with microvoltage (Fig. 4). This ECG shows the same characteristics as the proband's ECG, 6 months before his death.


Figure 3
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  		Fig. 3 Patient II.4. Ventricular fibrillation treated by ICD shock (august 2001).

 


Figure 4
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  		Fig. 4 Patient II.9. ECG tracing of 11 May 1970 : AF and polymorphic VT.

 
Cardiac biopsies were performed on the proband and hematoxylin/eosin staining showed myocyte hypertrophy and nuclear dystrophy and also an encircling fibrosis. Quantification of fibrosis by morphometric analysis on post mortem heart from the proband showed extensive fibrosis of the left ventricle (25%) and mild fibrosis of the right ventricle (11%) (Fig. 5).


Figure 5
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  		Fig. 5 Morphological muscle abnormalities of the proband include a variable number of fibers with rimmed vacuoles (A). Occasional fibers display cytoplasmic inclusion seen in trichrome section in B. Mitochondrial abnormalities were present in all biopsies with ragged red fibers (C) or cytochrome c oxidase (negative fibers (D). Desmine (E) and P –B Crystallin (F) immunolocalizations show increased expression in numerous fibers on adjacent sections with focally granular and subsarcolemmal deposits. (A) Hematoxylin-eosinx100 (B-C). Modified Gomori trichromex40. (D) Cytochrome c oxydase histoenzymologyx10. (E-F) Immunohistochemical studies for desmin (E) and P -B Crystallin (F)x40. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

 
The average age at onset of neuro muscular involvement was 43,7±0,8 years (45 years in the first generation and 43.5±0.5 years in the second generation). No member of the third generation has yet been affected. All subjects with neuromuscular symptoms had cardiac abnormalities (Table 1). Affected subjects experienced difficulties in walking, with a loss of quadriceps skeletal muscle in both legs. Neurological examination detected bilateral and symmetrical deficit of the quadriceps muscles with amyotrophy. EMG recorded polyphasic tracings in the left and right quadriceps muscles showed no signs suggestive of peripheral neuropathy. All clinically affected patients had normal serum CK levels and no inflammatory syndrome. Muscle morphological abnormalities included a variable number of fibers with rimmed vacuoles (Fig. 5). ATPase staining showed the presence of all types of fibers, with a slight predominance of type II fibers, atrophy was not related to any fiber type and no signs of denervation were noted. Biopsies did not show filamentous inclusions. All patients with neurological impairment showed the same histological characteristics. These results show that the muscular disease in this family is a new unrelated phenotype characterized by a quadriceps-restricted myopathy. During follow-up, the bilateral and symmetrical motor deficits of the quadriceps, deteriorated progressively, without involvement of other muscles. No sensorineural hearing-loss was detected.

The genotypic study showed a missense mutation in exon 6 that changes the arginine 377 to histidine, the functional consequence of this mutation is associated with a disorganisation of the lamine [15].


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
5. Limitation of this...
 References
 
For a long time, familial cases of DCM have been underestimated and it is currently thought, based on prospective studies, that genetic inheritance is involved in approximately 25-30% of cases [16,17]. Although different modes of transmission have been observed, the most common is autosomal dominant inheritance as in the family reported here [18].

We report a new phenotype of quadriceps myopathy with cardiac involvement: i) life threatening conduction disturbances are described in a few neuromuscular dystrophies including myotonic dystrophy and a genetically heterogeneous variant including myofibrillar myopathies, EDMD, LGMD [4,11,19,20]; ii) LMNA-mutations have been reported in autosomal dominant [20,21] EDMD, autosomal dominant LGMD [22,23], sensory and motor axonal neuropathy Charcot-Marie-Tooth type 2 [24] and familial partial lipodystrophy, which is characterised by the development of abnormal patterns of adipose tissue distribution [25,26].

EDMD is characterised by early contractures of the Achilles tendons, elbows, and post cervical muscles, slow progressive wasting and weakness with a predominantly humero-peroneal distribution and cardiomyopathy with conduction defects [9]. Genotypic study has shown an autosomal dominant inheritance due to lamin A/C gene mutation [20]. In contrast to EDMD, the affected individuals in our study presented only with progressive quadriceps impairment without involvement of other muscles. Early contraction of elbows and Achilles tendons was absent in our patients.

Two forms of LGMD with autosomal dominant inheritance have been identified. One form, called Bethlem myopathy, has an early, often congenital onset and is characterised by proximal or generalized muscle weakness, joint contractures but cardiac signs and symptoms are absent [21]. The other form constitutes a heterogeneous group of disorders with later onset and a slow progressive course [11,12]. The diagnostic criteria for LGMD are a slowly progressive symmetrical proximal weakness with onset in the lower limbs, gradual involvement of the upper limbs, normal to mildly raised serum creatinine kinase (CK) activity, myopathic changes on electromyography (EMG) and muscle biopsies with normal dystrophin analysis [11-27]. Cardiac abnormalities, which were found in more than half of the patients, included arrhythmias and atrioventricular conduction disturbance with sudden death. Genetic localization of autosomal dominant LGMD was on chromosome 1q 11-21 [27]. By contrast to LGMD, the clinical features of our family show that cardiac involvement preceded neuro-muscular disease in all affected patients, cardiac involvement may occur at any age or may even be present at the very onset, and that only the quadriceps muscle was affected.

Neurological manifestations in the family with limbs girdle muscular dystrophy as described by Graham, differ in our family on cardiological manifestations that consist in predominant left ventricular hypertrophy [28].

Myofibrillary myopathies are a heterogeneous group of skeletal muscle diseases, of sporadic or hereditary origin, associated with cardiomyopathy. In a study by Chuckow et al. eight patients with myofibrillary myopathies were evaluated [29]. One patient was from a family with autosomal dominant cardiomyopathy. In five patients, the myopathy was sporadic. The pattern of muscle weakness was predominantly distal with legs more severely affected than arms. Cardiac involvement preceded peripheral muscle involvement by a mean of 12 years (range : 3-20 years). Cardiomyopathy was evident in 5 patients (arrhythmias or heart failure for 1 patient). Six patients had cardiac involvement with high-degree syncopal conduction disorders requiring insertion of a pacemaker. Peripheral muscle involvement responsible for a clinically detectable motor deficit started distally at a mean age of 28 years and progressed, with the involvement becoming more-and-more proximal, affecting the respiratory and/or facial muscles. In our family, only the quadriceps is impaired and not the distal skeletal muscles [29].

Therefore, we conclude that the patients in our family are suffering from a new disease entity in which cardiac involvement predominates the clinical picture: two distinct phenotypes were identified: cardiac involvement with or without quadriceps myopathy.

Based on this study:

  1. 1) this specific phenotype, characterized by an early atrial fibrillation preceding DCM and quadriceps skeletal myopathy, requires monitoring, therapeutic intervention and screening for LMNA mutation. These results are similar to Sebillon et al. who found that LMNA should be screened only in DCM with conduction defects and/or skeletal myopathy and also in DCM with early atrial fibrillation preceding or coexisting with DCM [30].
  2. patients had a poor prognosis. The natural history of lamin A/C gene mutation in subjects with dilated cardiomyopathy is severe: event-free survival at the age of 45 years is 31% [31]. Cardiac abnormalities affect prognosis. For these patients, the use of ICDs is recommended.


   5. Limitation of this study
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 5. Limitation of this...
References
 
Cardiac disease presentation is progressively earlier from generation 1 to generation 3 (from 27 to 47 years). Perhaps, this is due to more thorough and earlier screening of the third generation.


   Acknowledgements
 
This study would not have been possible without the invaluable assistance of patients. The authors gratefully acknowledge the assistance of Dr J.R. Hazard, Dr V.E. Mouton and Ph. Bouvet.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 5. Limitation of this...
 References
 

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