title: A novel LAMP2 mutation associated with severe cardiac hypertrophy and microvascular remodeling in a female with Danon disease: a case report and literature review.
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.
  
  
  METHODS
  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.
authors: Medical Genetics Laboratory, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy. Electronic address: i.bottillo@gmail.com.
authors: Irene
authors: I
authors: Bottillo
authors: Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy.
authors: Carla
authors: C
authors: Giordano
authors: Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy.
authors: Bruna
authors: B
authors: Cerbelli
authors: Medical Genetics Laboratory, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
authors: Daniela
authors: D
authors: D'Angelantonio
authors: Medical Genetics Laboratory, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
authors: Martina
authors: M
authors: Lipari
authors: Medical Genetics Laboratory, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
authors: Taisia
authors: T
authors: Polidori
authors: Medical Genetics Laboratory, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
authors: Silvia
authors: S
authors: Majore
authors: Unit for Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors: Enrico
authors: E
authors: Bertini
authors: Unit for Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors: Adele
authors: A
authors: D'Amico
authors: Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy.
authors: Diana
authors: D
authors: Giannarelli
authors: Medical Genetics Laboratory, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
authors: Carmelilia
authors: C
authors: De Bernardo
authors: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors: Laura
authors: L
authors: Masuelli
authors: Department of Cardiac Surgery, San Camillo-Forlanini Hospital, Rome, Italy.
authors: Francesco
authors: F
authors: Musumeci
authors: Cardiomyopathies Unit, Division of Cardiology and Cardiac Arrhythmias, San Camillo-Forlanini Hospital, Rome, Italy.
authors: Andrea
authors: A
authors: Avella
authors: Cardiomyopathies Unit, Division of Cardiology and Cardiac Arrhythmias, San Camillo-Forlanini Hospital, Rome, Italy.
authors: Federica
authors: F
authors: Re
authors: Cardiomyopathies Unit, Division of Cardiology and Cardiac Arrhythmias, San Camillo-Forlanini Hospital, Rome, Italy.
authors: Elisabetta
authors: E
authors: Zachara
authors: Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy.
authors: Giulia
authors: G
authors: d'Amati
authors: Medical Genetics Laboratory, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
authors: Paola
authors: P
authors: Grammatico
mesh_terms: D006332:Cardiomegaly / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D056726:Genetic Association Studies; D052120:Glycogen Storage Disease Type IIb / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D052119:Lysosomal-Associated Membrane Protein 2 / Q000235:genetics*; D009154:Mutation; D014927:Wolff-Parkinson-White Syndrome / Q000235:genetics
chemical_list: C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2
keywords: Cardiac hypertrophy; Danon disease; Genotype–Phenotype correlations; LAMP2; Lysosomal vacuoles; Microvascular remodeling; X-chromosome inactivation study (XCI)