Heart transplantation in adult patients with Danon disease presenting with hypertrophic cardiomyopathy phenotype

Background. Danon disease is a rare X-linked lysosomal storage disorder with multisystem involvement in man and with predominant heart affection in female patients. Cardiomyopathy is the most severe and life-limiting manifestation for both sexes, often requiring heart transplantation (HT) in early adulthood. It is recognized as one of the genetic causes of the hypertrophic cardiomyopathy (HCM) phenotype. Objective. To assess the prevalence and clinical characteristics of Danon disease adult patients with primary HCM phenotype who underwent HT. Patients and methods. 11 adult patients (8 female) with HCM diagnosis and HT history were enlisted. Targeted next-generation sequencing of 39 or 108-gene panels related to cardiomyopathies was performed. Carriers of pathogenic or likely pathogenic variants   in the LAMP2 gene were analyzed in detail. Results. In 3 out of 11 patients (27%, all were female) causing LAMP2 variants were identified: (1) start-loss variant c.T2C:p.Met1Thr, (2) intronic variant resulting in splicing alterations c.G865-1A, (3) nonsense-variant c.G962A: p.Trp321Ter. There were no signs of liver, muscular and nervous systems involvement, one patient had retinitis pigmentosa. The cardiac phenotype evolved from HCM to a dilated phase, with severe biventricular systolic dysfunction, atrial fibrillation, thromboembolic complications and high-grade ventricular arrhythmias (including ventricular fibrillation in one patient). Heart failure onset occurred at 26-29 years; HT was performed at 28–32 years. All three patients had chronic lymphocytic myocarditis diagnosed on myocardium histology. Conclusion. Genetic testing for the diagnosis of Danon disease should be considered in women with heart failure onset in young adulthood and hypertrophy, restriction and/or dilatation as the cardiomyopathy phenotype hallmarks. Myocarditis may contribute to progression of fibrosis and heart failure in these patients, but the role of immunosuppressive therapy remains to be clarified.

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