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European Journal of Heart Failure 2006 8(5):477-483; doi:10.1016/j.ejheart.2005.11.003
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© 2005 European Society of Cardiology

Desmin accumulation restrictive cardiomyopathy and atrioventricular block associated with desmin gene defects

Eloisa Arbustinia,*, Michele Pasottib, Andrea Pilottoa, Carlo Pellegrinic, Maurizia Grassoa, Stefano Previtalid, Alessandra Repettob, Ornella Bellinia, Gaetano Azane, Manuela Scaffinoa, Carlo Campanab, Giovanni Piccolof, Mario Viganòc and Luigi Tavazzib

a Molecular Diagnostic Laboratory, I.R.C.C.S. Policlinico San Matteo Pavia, Italy
b Cardiology, I.R.C.C.S. Policlinico San Matteo Pavia, Italy
c Cardiac Surgery, I.R.C.C.S. Policlinico San Matteo Pavia, Italy
d Neurology, I.R.C.C.S. Istituto San Raffaele Milano, Italy
e Neuropathology, I.R.C.C.S. Istituto Auxologico Italiano Piancavallo, Italy
f Neurology, I.R.C.C.S. Casimiro Mondino Pavia, Italy

* Corresponding author. Diagnostica Molecolare, Area Trapiantologica, Viale Forlanini 16, 27100 Pavia, Italy. Tel.: +39 0382 503829; fax: +39 0382 525866. Email address: e.arbustini{at}smatteo.pv.it


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Primary desminopathies are caused by desmin gene [DES (MIM*125660)] mutations. The clinical spectrum includes pure myopathies, cardiomuscular diseases and cardiomyopathies. Patients with restrictive cardiomyopathy (RCM) plus atrioventricular block (AVB) due to DES defects are frequently unrecognized unless desmin accumulation is specifically investigated in endomyocardial biopsy (EMB) by ultrastructural study.

Aims: To describe a cardiological phenotype characterized by RCM plus AVB due to desmin accumulation caused by DES defects.

Methods and results: Desmin accumulation was diagnosed by means of ultrastructural and immunocytochemical studies of EMB in four unrelated probands with RCM and AVB. Candidate genes [DES and {alpha}B-crystallin (CRYAB)] were screened using sequence analysis. Four DES gene mutations were identified: three new (R16C, T453I and a 10 bp deletion at the exon—intron boundary of exon 3 disrupting the donor splice site) and one known (R406W). The disease was autosomal dominant in two families, recessive in one and associated with a de novo mutation in one. The mutations cosegregated with phenotype in all patients. CRYAB gene screening was negative.

Conclusions: A cardiac phenotype characterized by RCM and AVB caused by desmin accumulation is associated with DES mutations. Although the mutations affected different domains, the cardiac phenotype was identical.

Key Words: Desmin • Restrictive cardiomyopathy • Atrioventricular block

Received July 23, 2005; Accepted November 3, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Restrictive cardiomyopathy (RCM) is a rare familial or sporadic disease characterized by impaired diastolic ventricular filling with atrial dilation, increased systemic and pulmonary venous pressure, and heart failure [1]. The diseases causing RCM include desmin-related myopathies [DRMs (MIM601419)] that share intracytoplasmic desmin accumulation and consist of primary desminopathies caused by mutations of the desmin gene [DES (MIM*125660)]and PB-crystallinopathies caused by mutations of the PB-crystallin gene [CRYAB (MIM+123590)]. The clinical phenotypes of primary desminopathies range from pure myopathies [2-10] and cardiomuscular diseases [2,3,6,10-18] to pure cardiac phenotypes [19-21], which include dilated cardiomyopathy (DCM) [20,21] and desmin accumulation RCM associated with atrioventricular block (AVB) [19,22].

Desmin is a 53-kDa intermediate filament of myocardial, skeletal and smooth muscle that reciprocally connects myofibrils and anchors them to the sarcolemma, thus stabilizing the sarcomeres [23]. Twenty-five DES (Chr 2q35) mutations have so far been identified in 46 families [10,12,17,21] (Fig. 1). The majority of cases reported to date reached the clinical attention for generalized myopathy. When first reaching clinical attention for cardiomyopathy and/or AVB without myopathy, patients are frequently unrecognized as affected by desmin accumulation unless they develop myopathy and undergo skeletal muscle biopsy (SMB), or desmin accumulation is specifically investigated in endomyocardial biopsy (EMB) by ultrastructural study or immunoelectron microscopy [19,22].


Figure 1
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  		Fig. 1 The figure shows the pedigrees, chromatograms of the mutated and corresponding wild type sequences, the pathological patterns of desmin accumulation and the alignments showing the conservation of the mutated residues. In the pedigrees, filled symbols indicate patients, open symbols non-affected subjects and dots in open symbols proven carriers of the DES gene defect. Diagonal lines indicate death. The probands are indicated by arrows. For family D, the chromatogram corresponding to the proband sequence shows the homozygous C>T and the chromatogram of one of the three healthy carriers shows the heterozygous mutation. (a) Light microscopy immunochemistry of the skeletal muscle biopsy of patient A-III:1 showing desmin-immunoreactive material. (b) Specific immunostaining of desmin with anti-desmin antibodies in the cardiac muscle (b) and in the skeletal muscle (b1) of the patient B-II:3: note the specific pattern of immunostain in the skeletal muscle (b1) and the non-specific, although intense, pattern in the myocardial sample (b); (c) cardiac electron micrograph showing cardiomyocyte desmin accumulation of moderate severity; (d) cardiac myocytes showing severe amount of accumulated desmin. The bottom cartoon summarizes known and novel DES mutations identified to date.

 
We have identified three novel and one known DES mutations in four unrelated probands with RCM plus AVB caused by desmin accumulation.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients and families
All of the studies were approved by our Institutional Ethical Committee. RCM was diagnosed using the WHO criteria [24]. Informed and consenting relatives underwent clinical-genetic screening including a physical examination, electrocardiogram and 2D-Doppler echocardiography, serum creatine phosphokinase (sCPK) measurements, myological evaluation and genetic analysis. None of the patients or relatives had cataract.

Nine of the 19 members of the 4 families were affected. Eight were clinically diagnosed as having RCM plus AVB; the ninth is the son of proband A (A-III:1) who has mild distal myopathy and early diastolic dysfunction (Fig. 1). For two of the nine patients, both deceased, medical reports and autopsy samples made available: both had RCM plus AVB, treated with pacemaker implantation. Table 1 shows the clinical data from the seven patients who underwent evaluation.


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  		Table 1 Clinical data for probands and affected relatives

 
2.2. Histological analysis
Heart samples obtained at EMB (A-II:2; B-I:2, B-II:2, B-II:3; C-II:3; D-II:3) or transplantation (B-I:2, B-II:3), and skeletal muscle samples obtained at SMB (A-III:1 and D-II:3) or transplantation (B-I:2 and B-II:3) were processed for light and electron microscopy as previously reported [21]. Light and electron immunochemistry was performed using anti-desmin antibodies (1:100) (Dako, Denmark).

2.2.1. Control endomyocardial biopsy samples
To assess the specificity of desmin immunostain on light microscopy study, we investigated 50 EMBs from patients without DES mutations (excluded by direct sequencing of the gene in the molecular genetic screening of familial cardiomyopathies), both DCM (n=39), and RCM without AVB (n=11) and absence of granulo-filamentous material at the ultrastructural study.

2.3. Mutation analysis
The molecular genetic analysis included DES and CRYAB screening. Polymerase chain reaction was performed in a final volume of 50 µl containing 10 ng of genomic DNA isolated from peripheral blood by standard procedures [3]. The polymerase chain reaction products were sequenced using an ABI PRISM 3100 Genetic Analyzer and the ABI PRISM Big Dye Terminator Cycle Sequencing Kit (Applied Biosystems, Foster City, CA). The 4 mutations were not found in 112 healthy subjects, in 39 probands with familial autosomal dominant DCM and in 11 patients with sporadic (n=7) and familial (n=4) RCM without AVB and in a prior series of idiopathic DCM [25].


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Family screening
Nine of the 19 members of the 4 families were clinically and genetically affected; the remaining 10 are healthy and do not carry the mutation (Table 1). One of the relatives of family B died from heart failure due to RCM with AVB, treated with pacemaker implantation, when he was 15 years old, before the family was brought to our attention.

3.2. Immunochemistry and ultrastructural results (Fig. 1)
The myocardial and muscle samples showed identical deposits of electron-dense, amorphous material positively immunostained by anti-desmin antibodies (Fig. 1). In the myocardial tissue, desmin accumulation was distributed throughout the myocytes. The skeletal muscle deposition was mostly concentrated in the subsarcolemmal spaces (Figs. 1a,b1 and 2b). All of the cardiac myocytes showed variably severe desmin accumulation ranging from mild (Fig. 2a) and very severe amounts (Fig. 1d); the vessel smooth muscle cells did not show desmin deposits.


Figure 2
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  		Fig. 2 (a) Immunoelectron micrograph showing specific immunostaining with anti-desmin antibodies of desmin deposits in the myocardium (patient B-II:3). (b) shows the typical subsarcolemmal localization of desmin accumulation in the skeletal muscle of the same patient.

 
Light microscopy immunohistochemistry of EMB samples did not provide specific findings, sufficient to support or exclude, by themselves, the pathological diagnosis of desmin accumulation.

3.3. Molecular genetic results (Fig. 1)
DES sequencing documented four DES mutations in the four unrelated probands and affected relatives: heterozygous R406W (family A), a 10 bp deletion at the exon-intron boundary of exon 3 disrupting the donor splice site (family B) and de novo T453I in proband C (alternative paternity was excluded by microsatellite analysis). The proband in family D carried the novel homozygous R16C mutation that was heterozygous in the unaffected parents and older brother. Denaturing high-performance liquid chromatography analysis of amplicons containing exons 1, 3, 6 and 8 in normal controls excluded the four changes in healthy controls. The mutations were also absent in 50 control index patients, the 39 with familial DCM and the 11 patients with RCM without AVB.

3.4. Genotype-phenotype correlation
Our four probands and three of their affected living relatives shared the common clinical phenotype of RCM plus AVB that characterized the onset and evolution of the disease. Only two patients showed clinical evidence of myopathy: the son of proband A at disease onset and the proband of family D 7 years after heart transplantation (HTx). The penetrance was 100% in all mutated family members. Two of our four mutations were in the carboxy-terminal part of the rod domain, one in the tail and one in the first conserved P-helical subdomain. Despite this allelic heterogeneity, the cardiac phenotype was identical. The only difference was the variable age of onset of the cardiomyopathy (17-48 years).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Our data demonstrate that the desminopathies caused by DES defects include a distinct subgroup of cardiac phenotypes characterized by RCM and AVB and absence of myopathy. The absence of clinical and biochemical signs of myopathy may not help cardiologists to suspect a desmin-related RCM, but, once the most common cause of RCM (cardiac amyloidosis) is excluded and the restrictive phenotype shows the typical combination with the AVB, desmin accumulation should be investigated.

The gold standard for the diagnosis of desmin accumulation in patients with RCM plus AVB is the ultrastructural study of EMB [22]. In the restless myocardium sampled with the bioptome (that generates typical artifactious contraction bands), desmin accumulation may be difficult to be recognized with the light microscopy study. The accumulated desmin distributes irregularly throughout the sarcoplasms, and typical patterns of subsarcolemmal accumulation similar to those seen in the light microscopy study of skeletal muscle biopsies are not detectable (Fig. 1b versus 1b1 and Fig. 2a versus b). There is only one report, among genotyped cases, describing myocardial desmin accumulation on light microscopy immunohistochemistry without electron microscopy study in a patient with sporadic DCM associated with DES I451M defect [21]. Our control series documents that light microscopy immunohistochemical study with anti-desmin antibodies on EMB samples is not sufficient, by itself, to provide a definite diagnosis of desmin accumulation (Fig. 1). It may raise suspicions, but the diagnosis is provided by the ultrastructural identification of granulo-filamentous material that immunoreacts with anti-desmin antibodies. In contrast, the light microscopy pattern of desmin accumulation in skeletal muscle is typical: either as subsarcolemmal accumulation (Figs. 1b1 and 2b) or definite increased immunostain of single muscle fibers that contrast with the normally stained adjacent fibers (Fig. 1a) [26]. This is one of the reasons why desmin accumulation diagnosis is more likely to escape detection when only conventional light microscopy study of EMB is performed, as clearly shown in case #4 reported by Dagvadorj et al.: this 18-year-old patient underwent both left and right EMB that only showed fibrosis and myocyte hypertrophy on light microscopy. The EMB diagnosis of desmin accumulation was missed. Five years later, the patient underwent SMB, and both immunohistochemical and electron microscopy study correctly identified desmin accumulation [17].

Family study may contribute to the diagnosis: the majority of DES-related disorders with desmin accumulation are familial autosomal dominant; a minority are recessive or caused by de novo mutations [3,10,12,17,21]. Proven recessive forms have been reported by Goldfarb et al. (double heterozygosity A360P plus N393I), in our series (R16C) and in one proband described by Munoz-Marmol et al. (21 bp del, R173_E179del). In this latter family, however, the father of the proband was not available for investigation and the authors could not exclude a hemizygosity condition [11]. A further recessive form is reported by Olivè et al. in one un-genotyped patient with symmetric hypertrophic cardiomyopathy diagnosed at the age of 12 years and still well at the age of 47 [10].

4.1. Genotype-phenotype correlations
The broader myological experience suggests that different mutations lead to distinct clinical phenotypes [3,10,12,17,21]. However, our four probands carrying mutations affecting different domains, all had RCM plus AVB due to identical myocardial desmin accumulation. Although the mechanisms of disease in carriers of different mutations are probably different, the histopathological and cardiac phenotypes are similar.

The known R406W mutation identified in family A has previously been found in nine unrelated patients with sporadic cardioskeletal DES disease [3,10,14,17]. This mutated residue is located at the C-terminal of the desmin core domain (2B segment) that is critically relevant for filament assembly [27], absolutely conserved and harbours the intermediate filament consensus motif YRKLLEGEE [28] involved in dimer-dimer interactions [29]. The substitution prevents filament assembly and the cytoplasm network in transfected SW13 (vim-) cells [14]. In family B, the novel 10 bp deletion at the exon-intron boundary of exon 3 disrupts the donor splice site of exon 3, which has also been reported to be disrupted by two other mutations (IVS3+1G>A; IVS3+3A>G), while others disrupt the acceptor site (IVS2–1G>A; IVS2–2A>T) [12]. All splicing mutations cause an exon 3 deletion predicting a mutant desmin lacking 32 amino acids from the 1B segment of the alpha helical rod and the accumulation of desmin-positive material [13]. The novel T453I mutation identified in family C joins the two previously reported mutations in the "tail domain", which is part of the 9-amino acid motif that is highly conserved among type III intermediate filaments and whose major function is desmin interaction with other cytoskeletal proteins [12]. Finally, the novel R16C mutation of our family D was associated with a recessive phenotype: the three heterozygous carriers of the family were not affected. Double heterozygosity (A360P, N391I) and homozygous deletion of seven amino acids (R173_E179del) have so far been associated with variable heart involvement plus myopathy [12], but our proband's phenotype was dominated by RCM plus AVB, and he developed clinical signs of myopathy only 7 years after HTx.

Ours and other published studies indicate that DES-related diseases are fully penetrant, with clinical phenotypes ranging from pure myopathies and cardiomuscular disease to pure cardiomyopathies (DCM and RCM with AVB) [3,10,12,17,21] (present series). Two exceptions are reported to date documenting incomplete penetrance by the age of the expected clinical onset. Both have been observed in families carrying the I451M mutation. One is a family described by Dalakas et al. [3] in which three of six mutation carriers are affected and one is a family described by Li et al. in which two of four mutation carriers are non-affected [20]. The I451M is the only DES mutation that has been identified to date in proven sporadic (Myhamoto et al., 3/247 Japanese patients, 1.1%) [21] and familial DCM [20]. In our experience, DES mutations are uncommon in DCM (see Ref. [25] plus additional 39 DCM patients screened in the present study in whom we did not find DES mutations), but recur in the rarer RCM plus AVB in which desmin accumulation is found. The diagnostic work-up of patients with RCM and AVB should include EMB with ultrastructural study for the identification of desmin accumulation, DES analysis for mutation detection, neuromyological evaluation and family clinical and genetic screening. sCPK levels, which are routinely measured in cardiomyopathic patients, are largely uninformative: 5 of the 12 patients reported by Dalakas et al. [3] and 8 of 9 patients of the present series had normal sCPK values. A practical suggestion for clinical cardiologists is that patients with non-amyloid RCM and AVB should be also investigated by a neuromyologist. Vice versa, cardiologists should be specifically asked to investigate diastolic function in patients with DES myopathy: the echocardiographic evaluation provides the proper definition of the type of cardiomyopathy and simple measurements such as transmitral flow pattern (E/A ratio and deceleration time) will help early identification of diastolic dysfunction. The need for collaborative evaluations is further supported by the potential clinical heterogeneity of the phenotype in members of the same family, as in the case of family A: the son of proband A developed myopathy at the age of 15 and showed early diastolic dysfunction potentially preceding RCM only 3 years later. Furthermore, mild subsarcolemmal desmin deposits have also been shown to occur in patients without clinical signs of myopathy (Figs. 1b1 and 2b).

In conclusion, among the primary desminopathies whose most frequent classical phenotype is myopathy with or without heart involvement, a rare clinical phenotype characterised by RCM plus AVB may bring patients to the attention of the cardiologist. The absence of any clinical signs of myopathy may not help cardiologists to suspect a desmin storage-related RCM. Therefore, patients with non-amyloid familial RCM and AVB should undergo EMB, interactive cardiomyological evaluation and molecular analysis of the DES gene, which is a major candidate for this cardiac phenotype.


   Acknowledgement
 
This study was supported by research grants: "Ricerche Finalizzate e Correnti" I.R.C.C.S. Policlinico San Matteo, Pavia, Italy.


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

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