Irene Bottillo1, Carla Giordano2, Bruna Cerbelli2, Daniela D'Angelantonio3, Martina Lipari3, Taisia Polidori3, Silvia Majore3, Enrico Bertini4, Adele D'Amico4, Diana Giannarelli5, Carmelilia De Bernardo3, Laura Masuelli6, Francesco Musumeci7, Andrea Avella8, Federica Re8, Elisabetta Zachara8, Giulia d'Amati2, Paola Grammatico3. 1. Medical Genetics Laboratory, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy. Electronic address: i.bottillo@gmail.com. 2. Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy. 3. Medical Genetics Laboratory, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy. 4. Unit for Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 5. Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy. 6. Department of Experimental Medicine, Sapienza University, Rome, Italy. 7. Department of Cardiac Surgery, San Camillo-Forlanini Hospital, Rome, Italy. 8. Cardiomyopathies Unit, Division of Cardiology and Cardiac Arrhythmias, San Camillo-Forlanini Hospital, Rome, Italy.
Abstract
BACKGROUND: Danon disease (DD) is a rare disorder characterized by cardiomyopathy, intellectual disability, and proximal myopathy. It is caused by mutations in the LAMP2 gene on X chromosome. Female patients most often present with late-onset cardiomyopathy and slow disease progression, but early-onset cases with unfavorable prognosis have been reported. CASE REPORT: We describe the clinical, pathological, and molecular features of a novel LAMP2 c.453delT mutation in a female patient with severe hypertrophic cardiomyopathy, Wolff Parkinson White (WPW) syndrome and rapid progression to heart failure, requiring heart transplant. Immunohistochemical analysis of LAMP2 in the explanted heart revealed a mosaic pattern of distribution, with discrete clusters of either stained or unstained cardiac myocytes, the latter being more frequent in the septum. These findings paralleled X chromosome inactivation within the myocardium. Interestingly, multiple foci of microscarring were found on histology in the Left Ventricle (LV) free wall and septum, in a close spatial relationship with remodeling and severe stenosis of intramural coronary arterioles. CONCLUSIONS: Our findings suggest that several features may contribute to the early and severe cardiac phenotype in female DD patients. The type of mutation may account for the early disease onset, while both the inhomogeneous distribution of LAMP2 loss and the presence of microvascular remodeling may be determinant in the rapid progression to heart failure.
BACKGROUND:Danon disease (DD) is a rare disorder characterized by cardiomyopathy, intellectual disability, and proximal myopathy. It is caused by mutations in the LAMP2 gene on X chromosome. Female patients most often present with late-onset cardiomyopathy and slow disease progression, but early-onset cases with unfavorable prognosis have been reported. CASE REPORT: We describe the clinical, pathological, and molecular features of a novel LAMP2c.453delT mutation in a female patient with severe hypertrophic cardiomyopathy, Wolff Parkinson White (WPW) syndrome and rapid progression to heart failure, requiring heart transplant. Immunohistochemical analysis of LAMP2 in the explanted heart revealed a mosaic pattern of distribution, with discrete clusters of either stained or unstained cardiac myocytes, the latter being more frequent in the septum. These findings paralleled X chromosome inactivation within the myocardium. Interestingly, multiple foci of microscarring were found on histology in the Left Ventricle (LV) free wall and septum, in a close spatial relationship with remodeling and severe stenosis of intramural coronary arterioles. CONCLUSIONS: Our findings suggest that several features may contribute to the early and severe cardiac phenotype in female DDpatients. The type of mutation may account for the early disease onset, while both the inhomogeneous distribution of LAMP2 loss and the presence of microvascular remodeling may be determinant in the rapid progression to heart failure.