Introduction
Desmin, the primary muscle-specific intermediate filament protein, is encoded by the DES gene located on chromosome 2q35 as a single isoform with nine exons. Reference Hol and Capetanaki1 Structurally, desmin has a head, alpha-helical rod, and tail domains. Reference Maggi, Mavroidis, Psarras, Capetanaki and Lattanzi2,Reference Eldirany, Lomakin, Ho and Bunick3 As a key intermediate filament protein, desmin forms a crucial three-dimensional intracytoplasmic scaffold maintaining the structural and mechanical integrity of skeletal, cardiac, and smooth muscle cells. Reference Paulin and Li4 Consequently, pathogenic variants in DES can cause skeletal and cardiac myopathies or a combination of the two. These conditions are often termed desminopathy. Desminopathies are predominantly autosomal dominant conditions caused by the presence of damaging heterozygous DES variants. They typically present as adult-onset in the second to fourth decade, characterised by progressive skeletal muscle weakness, cardiomyopathy with associated severe arrhythmias, and respiratory insufficiency. The rarer autosomal recessive desminopathies due to biallelic variants in DES are related to an earlier age of onset and a more severe clinical phenotype. Heart failure, severe arrhythmias, and respiratory muscle involvement with respiratory failure are usually direct factors for poor prognosis. Reference Wahbi, Béhin and Charron5 Here, we reported an 11-year-old Chinese girl presenting with cardiomyopathy and severe conduction block, without skeletal muscle involvement. By the genetic analysis, a de novo heterozygous missense DES variant (c.152C > T/p.Ser51Phe) was identified.
Clinical presentation
An 11-year-old girl was admitted for syncope after climbing to the fourth floor. There was no prior history of similar syncopal episodes in the patient, nor was there a family history of similar syncope, hereditary arrhythmia, or cardiomyopathy. Developmental milestones were normal. On admission, her vital signs were stable, and physical examination showed a strong and regular heart rhythm. Laboratory tests showed markedly elevated serum levels of B-type natriuretic peptide and troponin. Serum creatine kinase was normal. The initial electrocardiogram showed left anterior branch conduction block, intraventricular conduction block, ST-segment and T-wave changes in extensive leads, and prolonged Q-T interval. Echocardiogram revealed an enlarged left ventricle and left atrium (50 and 42 mm, respectively) with normal cardiac function. The possibility of myocarditis could not be definitively ruled out, leading to the administration of anti-infective and myocardial nutrition therapy.
On the seventh night of hospitalisation, the patient experienced sudden onset of chest tightness and palpitations, accompanied by dizziness and blurred vision. Physical examination revealed signs of pale complexion, cold extremities, muffled heart sounds, and arrhythmia. Bedside monitoring indicated a complete atrioventricular block with a heart rate of 30 beats per minute. Consequently, the patient was urgently implanted with a temporary pacemaker. Nevertheless, she experienced recurrent episodes of severe bradycardia (minimum 22 beats per minute) attributed to a third-degree atrioventricular block, leading to multiple failed attempts to discontinue the temporary pacemaker. Re-examination of the electrocardiogram revealed junctional escape rhythm (ventricular rhythm), complete atrioventricular block, complete left bundle-branch block, T-wave and ST changes in a wide range of leads, and prolonged QT intervals (Figure 1a). Supplemental dynamic electrocardiogram showed ventricular premature beats and short bursts of ventricular tachycardia. MRI was used to assess the extent and degree of cardiomyopathy and cardiac function. Same as the echocardiogram, the MRI showed slight enlargement of heart chambers. Delayed enhancement imaging revealed a few areas of striated enhancement in the myocardium of the left ventricular lateral wall near the myocardium (Figure 1b). Due to the presence of high degree of atrioventricular block and ventricular tachyarrhythmia, the patient was at risk for syncope or sudden cardiac death. After obtaining parental informed consent, the patient received a permanent pacemaker together with an implantable cardioverter defibrillator. Then the patient experienced no further episodes of syncope, and markers of cardiac damage displayed gradual improvement.
(a) Complete atrioventricular block. (b) Echocardiography (left) shows enlargement of the left atrium and left ventricle. Delayed contrast enhancement (right) reveals a few striated enhancement in the myocardium of the lateral wall of the left ventricle near the myocardium (white arrow). (c) Pedigree of the family reported in the present study (above). The arrow depicts the proband. The circles correspond to the women. The squares indicate the men. Direct sequencing (below) showing the novel point variant c.152C > T (p.Ser51Phe) of the DES gene. (d) Alignment of DES orthologs in different species around the mutated amino acids residues. Hs = Homo sapiens; mm = Macaca mulatta; rn = Rattus norvegicus; ss = Sus scrofa; Bt = Bos taurus; gg = Gallus gallus; xt = xenopus tropicalis; cl = Canis lupus familiaris.
By whole-exome sequencing and Sanger sequencing, we identified the proband carried a de novo heterozygous missense variant (c.152C > T/p.Ser51Phe) (NM_001927.4) of the DES gene (PM6) (Figure 1c). It was absent from controls (1000 Genomes, The Exome Aggregation Consortium (ExAC) is a coalition of investigators seeking to aggregate and harmonize exome sequencing data from a variety of large-scale sequencing projects, and to make summary data available for the wider scientific community, and gnomAD) (PM2) and was predicted to be deleterious by different in silico software. PolyPhen2, Mutation Taster, and Provean predicted it as probably damaging, disease causing, and deleterious, respectively (PP3). Although the variant c.152C > T (p.Ser51Phe) located in Exon 1 of the DES gene was only classified as a variant of uncertain significance (PM2 + PM6 + PP3) according to the recommendations for variant classification by the American College for Medical. Protein alignments revealed the variant affects an amino acid highly conserved among species (Figure 1d).
Discussion
Desminopathy patients are predominantly autosomal dominantly inherited and typically manifest as adult onset between the second and fourth decades of life, with a few cases being inherited recessively or occurring as spontaneous mutations. Childhood-onset is rare and usually observed in autosomal recessive inheritance. Reference Claes, Schil, Dewals and Beysen6 The more rare autosomal recessive desminopathy usually manifests at an earlier onset age, with more severe phenotypes and faster progression compared with the dominant form. Reference Claes, Schil, Dewals and Beysen6 To our knowledge, currently 29 patients have been reported with recessive desminopathies. Reference Claes, Schil, Dewals and Beysen6–Reference Polavarapu, O’Neil and Thompson8 Among them, 79.3% (23/29) of patients with recessive DES variants developed the disease during childhood (before adulthood). Skeletal muscle involvement was present in 93.1% (27/29) and cardiac involvement in 65.5% (19/29) of carriers (both skeletal muscle and cardiac involvement in 58.6% (17/29), isolated skeletal muscle involvement in 34.5% (10/29), and isolated cardiac involvement in 6.9% (2/29)). Of the 29 reported patients, a total of nine deaths were recorded at the time, with a median age of 21.3 years. The primary causes of these early deaths were cardiorespiratory complications.
In our case, the proband developed post-exercise syncope in childhood, the electrocardiogram revealed severe conduction defects, and the echocardiogram showed dilatation of the cardiac chambers. Cardiac enzyme profiles were markedly increased. The patient had no complaints of limb weakness. The serum creatine kinase was normal, and physical exam suggested normal skeletal muscle strength. Compared with reported recessive desminopathy in paediatric patients, our patient presented with a much rarer isolated cardiac involvement, which brings a diagnostic challenge. Following early anti-inflammatory, anti-infective, and myocardial nutritional therapy, the patient’s condition resolved temporarily, and there were improved indices on review. However, the patient’s condition deteriorated dramatically, and she developed recurrent complete atrioventricular block. Therefore, we further considered the aetiology. Genetic testing identified a de novo variant in the DES gene. The variant was predicted to be deleterious by different in silico software and affected an amino acid highly conserved among species. Combined with the typical clinical manifestations, this variant was presumed to be pathogenic. Our case appeared to be explained by the hot phase of the myocarditis-like episode of the arrhythmogenic cardiomyopathy. Reference Bariani, Rigato and Cipriani9 Severe conduction block may be associated with high expression of desmin protein in the conduction system, especially in Purkinje fibres. Delayed enhancement revealed a little striated fibrosis, which may further impair the cardiac conduction system. Additionally, we noted that complete atrioventricular block appears to be a hallmark of the cardiac phenotype of desminopathy and may occur in combination with different forms of cardiomyopathy, even without skeletal muscle involvement, which may help improve the knowledge of the disease. Therefore, in individuals with prominent conduction block combined with myocardial damage, even without skeletal muscle involvement, the possibility of this disease should be considered. Genetic testing can provide a definitive diagnosis. Intermittent episodes of severe conduction block may hide the severity of the disease and thus increase the incidence of adverse cardiac events. Early detection and treatment of life-threatening arrhythmias may improve the poor prognosis of patients. Additionally, the disease may rapidly progress, leading to early death. Therefore, we highlight that a thorough evaluation is important for this kind of patient.
Data availability statement
Data will be made available on request.
Author contributions
SN drafted the main manuscript. All authors contributed to the writing and reviewing of the manuscript and approved the final manuscript for submission.
Financial support
This work was supported by the Medical Science and Technology Development Foundation of Jiangsu Commission of Health (ZD2021058), and Research Project of Maternal and Child Health of Jiangsu Province (F202023).
Competing interests
The authors declare no competing interests.
Ethical standard
The studies involving human participants were reviewed and approved by the institutional ethical committee of the Children’s Hospital of Nanjing Medical University. Written informed consent to participate in this study was provided by the participant’s legal guardian/next of kin.
