Case 1 -

Desmin-Related Cardiomyopathy David Parham University of Oklahoma Health Sciences Center Oklahoma, OK

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Click here to download handout in 1-up pdf format for the current section Clinical History The patient is a 2 year, 3 month old African American male admitted for apneic episodes during sleep. On physical examination, vital signs included a heart rate of 123 beats/min, respiratory rate 32 breaths/min, and blood pressure 100/70 mm Hg. The only physical finding of note was a liver border 2-3 cm below the right costal margin. Echocardiography revealed cardiomegaly with left ventricular diastolic and systolic dysfunction, biatrial dilatation, pulmonary venous and venocaval diastolic flow reversal, moderate tricuspid stenosis, tricuspid regurgitation, and a small pericardial effusion. Cardiac catheterization found markedly elevated right and left ventricular pressures. Following biopsy and diagnosis, heart transplantation was performed, with removal of an explant consisting of right and left ventricle and the lower portions of dilated right and left atria. Case history and special stains courtesy of Dr. Ali Saad, Arkansas Children's Hospital. Case 1 - Figure 1 Gross image, pen and ink drawing. There is marked dilatation of the right atrium. Case 1 - Figure 2 Low power views of heart, showing unusual pattern of cytoplasmic myocyte inclusions. Case 1 - Figure 3 Low power views of heart, showing unusual pattern of cytoplasmic myocyte inclusions. Case 1 - Figure 4 Various high-power views of the myocytes, showing markedly eosinophilic cytoplasmic inclusions. Case 1 - Figure 5 Various high-power views of the myocytes, showing markedly eosinophilic cytoplasmic inclusions. Case 1 - Figure 6 Various high-power views of the myocytes, showing markedly eosinophilic cytoplasmic inclusions. Case 1 - Figure 7 Various high-power views of the myocytes, showing markedly eosinophilic cytoplasmic inclusions. Case 1 - Figure 8 The inclusions are strongly fuscinophilic with trichrome stains. Case 1 - Figure 9 Desmin staining highlights scattered inclusions. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: Gross examination of the cardiac explant revealed a markedly dilated right atrial remnant and decreased right ventricular chamber. Microscopic studies revealed numerous myocytes with eosinophilic cytoplasmic inclusions. Trichrome stains highlighted these inclusions, and Congo Red, PAS, elastic stains were unremarkable. Immunostains revealed variable and often intense desmin staining in the inclusions. Actin stains were unremarkable. Electron microscopic studies revealed subplasmalemmal and intracellular granulofilamentous material. Differential Diagnoses: For restrictive cardiomyopathy: Endocardial fibroelastosis Cardiac amyloidosis Hemochromatosis Connective tissue and inflammatory diseases Metabolic storage diseases Neoplasms For desmin-related myocardiopathy, deletions or mutations may affect: Desmin Cardiac troponin T and I (TNNI3) Alpha cardiac actin αB-crystallin (desmin-related molecule) "Unknown desmin-related genes" Final Diagnosis: Desmin-related cardiomyopathy Case Discussion: Forms of cardiomyopathy include dilated, hypertrophic, and restrictive types. Restrictive cardiomyopathy, as seen in this patient is characterized by increased stiffness of the ventricles, compromised diastolic filling, and preserved systolic function. Radiologically and grossly, there is typically marked dilation of the atria and normal or decreased ventricular chambers. Restrictive cardiomyopathy can be caused by mutations of sarcomeric protein genes, usually related to desmin. Diagnosis of desmin-related cardiomyopathy may be accomplished by ultrastructural analysis, which shows granulofilamentous inclusions, particularly in submembranous regions. Work-up of the biopsy should include PAS stains to rule out glycogen storage disease, Congo Red stains to rule out amyloid, and elastic stains to rule out elastic tissue- related disorders. Immunostaining for desmin and actin is helpful, as the inclusions will be desmin-positive and actin-negative. Genetic testing may be indicated, as the lesion is autosomal dominant and often affects other family members. Segment of exons 1 and 3 of the desmin gene may show deletions. Review of the Literature/Treatment Options (if applicable): Desmin-related cardiomyopathy is a form of so- called "idiopathic" restrictive cardiomyopathy and also causes dilated cardiomyopathy (1-2%) and ventricular non- compaction. Most forms are caused by deletions in the desmin gene, causes abnormal molecular interaction of the filamentous structure of the heart. Desmin is a major Z- band protein; it organizes the structure and binds the actin-myosin filament bundles to the plasmalemma. Other proteins, such as alphaB-crystallin, are also involved in this process, and their mutations may have a similar effect. Patients may present to the cardiologist with syncopal episodes related to arrhythmias, which include A- V block and atrial fibrillation. Desmin mutations typically affect the skeletal muscle as well as the heart, although patients may have subclinical or mild disease. Muscle biopsies show similar findings, as well as rimmed vacuoles. One case report also described similar changes in coronary artery smooth muscle. Rare reports of neuropathy have appeared, with descriptions of axonal spheroids filled with neurofilamentous aggregates on nerve biopsies. This suggest other intermediate filaments besides desmin may occasionally be affected. Treatment currently is symptomatic (diuretics, anti- arrhymthics), followed by heart transplantation. Conclusion(s): Desmin-related cardiomyopathy should be suspected in biopsies of patients with restrictive cardiomegaly, particularly with a family history. Examination should be directed towards finding myocyte inclusions, and electron microscopy is recommended. Genetic testing is usually indicated. References: Bertini E, Bosman C, Ricci E, Servidei S, Boldrini R, Sabatelli M, Salviati G. Neuromyopathy and restrictive cardiomyopathy with accumulation of intermediate filaments: a clinical, morphological and biochemical study. Acta Neuropathol 1991;81:632-640. Sabatelli M, Bertini E, Ricci E, Salviati G, Magi S, Papacci M, Tonali P. Peripheral neuropathy with giant axons and cardiomyopathy associated with desmin type intermediate filaments in skeletal muscle. J Neurol Sci 1992;109:1-10. 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