| Abstract|| |
Restrictive cardiomyopathies in the pediatric population have diverse etiologies, including storage diseases like hemosiderosis, glycogenoses and desmin with its associated proteins. Desmin-related myopathy is a rare familial disorder of the cardiac and skeletal muscle characterized by intrasarcoplasmic accumulation of desmin-reactive deposits in the muscle cells. The patients commonly present with cardiac involvement such as conduction blocks and/or restrictive cardiomyopathy. Diagnosis of desmin cardiomyopathy depends on light microscopic evaluation of endomyocardial biopsy, where abnormal deposition of desmin can be documented on immunohistochemistry and ultrastructural examination. The index report presents the clinical, light microscopic and ultrastructural findings of desmin cardiomyopathy.
Keywords: Desmin cardiomyopathy, restrictive cardiomyopathy, Endomyocardial biopsy
|How to cite this article:|
Sharma S, Juneja R, Sharma G, Arava S, Ray R. Desmin-related restrictive cardiomyopathy in a pediatric patient: A case report. Indian J Pathol Microbiol 2013;56:402-4
|How to cite this URL:|
Sharma S, Juneja R, Sharma G, Arava S, Ray R. Desmin-related restrictive cardiomyopathy in a pediatric patient: A case report. Indian J Pathol Microbiol [serial online] 2013 [cited 2020 Jul 2];56:402-4. Available from: http://www.ijpmonline.org/text.asp?2013/56/4/402/125349
| Introduction|| |
Desmin is a 52 KD protein encoded by the DES gene in humans. It is the chief intermediate filament of the skeletal and cardiac muscle tissue that links the Z-bands to the subsarcolemmal cytoskeleton and maintains the structural integrity of the myofibrils. Desmin-related myopathies (desminopathies) are uncommon diseases caused by a mutation of the DES gene and form a heterogeneous group of severe skeletal myopathies, often accompanied by cardiomyopathy. They can present as restrictive cardiomyopathy (RCMP), syncopal episodes or sudden death due to conduction defects. ,
RCMPs have diverse etiologies like amyloidosis, sarcoidosis, hemosiderosis, glycogenoses, endomyocardial fibroelastosis, scleroderma and therapeutic radiation.  RCMP due to accumulation of desmin is a rare genetic disorder characterized by deposition of electron-dense granulofilamentous material immunoreactive for desmin in the sarcoplasm of the cardiomyocytes. Besides the restriction to diastolic ventricular filling, patients usually present with clinical or subclinical skeletal myopathy and varying degrees of atrioventricular block.  A pure cardiac phenotype with the absence of skeletal myopathy has been described in a study conducted by Arbustini et al. in 2006, where eight of nine patients of desmin cardiomyopathy had only RCMP and atrioventricular block. 
Here, we are presenting a rare case of desmin cardiomyopathy in a young female who was clinically diagnosed to have RCMP with an incomplete right bundle branch block (RBBB). Presence of subclinical skeletal myopathy was detected only on electromyography, which was performed following the histopathological diagnosis.
| Case Report|| |
A 7-year-old female child presented with insidious-onset, progressive dyspnea on exertion for 1.5 years. Physical examination revealed mildly elevated jugular venous pressure with prominent A-wave and palpable hepatomegaly. Chest X-ray showed generalized cardiomegaly [Figure 1]. Electrocardiography showed normal sinus rhythm with incomplete RBBB and left ventricular hypertrophy strain pattern.
Echocardiography revealed features of biventricular RCMP showing bilaterally enlarged atrial chambers, biventricular hypertrophy and diastolic dysfunction with a normal left ventricular ejection fraction (LVEF). The cardiac catheterization study revealed mildly elevated right ventricular (RV) pressures. Right atrial (RA) pressures that were mildly elevated at baseline increased further toward the end of the catheterization. Pulmonary arterial wedge pressure was raised to a mean value of 16 mmHg at baseline. RV angiography revealed an enlarged RV with severe dysfunction. Endomyocardial biopsy (EMB) was taken from the right ventricle.
Light microscopic examination revealed four fragments of endomyocardium. The endocardium was unremarkable. Myocardium revealed mild myocyte hypertrophy with nuclear enlargement and focal mild interstitial fibrosis. A few myofibers showed presence of intrasarcoplasmic eosinophilic hyaline inclusions [Figure 2]a. These inclusions were positive with Periodic Acid Schiff with and without pre-digestion by diastase. They appeared blue on Masson trichrome stain [Figure 2]b. Immunohistochemical staining for desmin antibody was performed using the avidin-biotin complex/peroxidase method and diaminobenzidine tetrahydrochloride as chromogen. An irregular patchy distribution and aggregation of desmin filaments was noted at places [Figure 2]c. For electron microscopy, the tissues were retrieved from paraffin blocks, processed and embedded in Epoxy resin. Ultrathin sections were stained with lead citrate and uranyl acetate. On examination, myofibrillar disruption, fragments of thin and thick filaments and deposits of dense, granulofilamentous material were noted in the sarcoplasm of an occasional myocyte [Figure 2]d.
|Figure 2: Photomicrograph of desmin cardiomyopathy showing (a) eosinophilic intrasarcoplasmic inclusions on hematoxylin and eosin stain (arrows, ×200), (b) Masson trichrome imparti ng blue color to these inclusions (arrows, ×200), (c) irregular patchy distributi on with focal aggregati on of desmin on immunohistochemistry (arrow, ×200) and (d) electron microscopy depicti ng the presence of granulofi lametous material in the sarcoplasm (×29,000)|
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A final diagnosis of desmin cardiomyopathy was thus made.
| Discussion|| |
Desmin-related myopathy is a familial disorder of the skeletal and cardiac muscles, characterized by intrasarcoplasmic accumulation of desmin-reactive deposits in the muscle cells and often accompanied by cardiac involvement. Although the age at first manifestation varies from infancy to 64 years, the condition is rare bellow 20 years of age, as in our case where the patient is 7 years old.  .
Typically, the illness presents with weakness in the muscles of the lower limbs, slowly spreading to involve the truncal, neck-flexor, facial, bulbar and respiratory muscles. Skeletal myopathy is often accompanied by concomitant cardiac involvement manifesting as RCMP, conduction blocks and arrhythmias, resulting in syncopal episodes or sudden death.  Patients with only RCMP and/or conduction defects in the absence of skeletal myopathy are frequently unrecognized unless desmin accumulation is specifically investigated in EMB by ultrastructural studies. 
Desmin is the most important intermediate filament of the cardiomyocytes, which helps in maintaining its overall structure and cytoskeletal organization. These filaments derive their names from their diameter (8-10 nm), which is intermediate between the myosin filaments (14 nm) and the actin filaments (5-7 nm). The intermediate filaments maintain a spatial relationship between the contractile apparatus and the other structural elements of the cell thus providing maintenance of cellular integrity, force transmission and mechanochemical signaling.  Along with the heat shock protein α-B-crystalline, and a linker protein plectin, desmin forms an organized network at the Z-band level that protects the structural integrity of the myofibrils during mechanical stress.  Defects in the function of desmin or in its associated proteins, plectin and α-B-crystalline, cause fragility of the myofibrils and weaken the sarcomere. This results in impaired contraction and myofibrillar damage over a period of years because of the cumulative effects of mechanical stress and muscle use. Various myofibrillar proteins like desmin, dystrophin, vimentin, β-spectrin and gelsolin accumulate in the muscle fibers of the affected patients in the form of intramyocyte inclusions containing myofibrillar material thus placing all of them in the broad category of a myofibrillar myopathy. Among these proteins, desmin has been linked to desmin myopathy as it is consistently present and is unusually abundant in patients with this disorder 
Desminopathy results from a mutation in the DES gene where, instead of forming protein filaments, it forms aggregates of desmin and other proteins throughout the cell causing weakness of the skeletal and cardiac muscle, eventually leading to cell death and replacement fibrosis. This aberrant protein aggregation leads to mitochondrial dysfunction, abnormal metabolism and altered cardiomyocyte structure.  Mutations in the other intermediate filament-associated proteins such as plectin and α-B-crystallin also cause myopathy similar to desmin myopathy.  Various missense mutations of the desmin gene have been reported. Although the majority of cases are sporadic, the most common pattern of inheritance is autosomal dominant. Autosomal recessive inheritance of desmin mutations has been described in a few patients with aggressive myopathy and cardiomyopathy.  Cardiomyopathy has been reported in up to 50% of desmin gene mutation carriers, with dilated cardiomyopathy and RCMP being the most prevalent form, but hypertrophic cardiomyopathy has seldom been reported. 
Light microscopy, including immunohistochemical analysis with anti-desmin antibodies on EMB samples, is not sufficient to provide a definite diagnosis of desmin accumulation. The diagnosis is provided by the ultrastructural identification of granulofilamentous deposits that immunoreact with antidesmin antibodies.  In contrast to cardiomyocytes, the light microscopic pattern of desmin accumulation in skeletal muscle is typical. There is either subsarcolemmal accumulation or heightened immunoreactivity of desmin in some muscle fibers that stand out in a background of normally stained adjacent fibers. This is one of the reasons why desmin accumulation diagnosis is more likely to escape detection when only a conventional light microscopy study of EMB is performed.  . If, for clinical reasons, a skeletal muscle biopsy is available and shows features diagnostic of desminopathy in a patient who also has RCMP or AV conduction disturbance, an EMB is not necessary for diagnosis. Desmin cardiomyopathy must be considered in the differential diagnosis of RCMP, especially in patients with AV block and skeletal myopathy. 
The finding of myocardial fibrosis is especially noteworthy, as observed in our case, because some desmin-related cardiomyopathies with myocardial fibrosis have been related to patient prognosis, including worsening of left ventricular function and an adverse outcome. 
Desminopathies are rare diseases with no specific therapy. The diagnosis does not influence the pharmacological management. They can be difficult to recognize because of the heterogeneity of the clinical characteristics within families and the lack of diagnostic specificity of the findings on muscle biopsy. But, the recognition of the desminopathies is important as it is often combined with cardiomyopathy, and, if unrecognized or unanticipated, can lead to syncopal episodes or sudden death due to conduction defects like atrioventricular block and arrhythmias. It is important to identify this entity on EMB, especially in those patients who primarily present with idiopathic RCMP without clinical skeletal myopathy, as in the present case.
| Acknowledgment|| |
The authors acknowledge the Department of Anatomy for providing access to the electron microscopy facility.
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Departments of Pathology and Cardiology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]