Mutations in the X-linked lysosome-associated membrane protein gene (LAMP2; Danon disease) produce a morphologic phenocopy of sarcomeric hypertrophic cardiomyopathy (HCM) in young patients, characterized by extreme left ventricular (LV) hypertrophy and pre-excitation. However, the natural history of this newly recognized cardiomyopathy is incompletely resolved. Seven young asymptomatic patients with LAMP2 cardiomyopathy were identified at ages 8 to 15 years; 6 were male. LV hypertrophy was particularly marked (septal thickness 25– 65 mm; mean 42±17) in the presence of nondilated LV cavity. On each ECG, Wolff-Parkinson-White pre-excitation pattern was associated with markedly increased voltages (74±38mm for R- or S-wave). Over the 7±3 year follow-up from initial cardiac diagnosis, all 7 patients experienced particularly adverse disease consequences associated with progressive LV wall thinning and cavity dilatation and systolic dysfunction (ejection fraction, 29±7%) by the ages of 12 – 24 years (mean 20). Of the 7 patients, 5 either died of progressive heart failure, had heart transplantation or were considered for a donor heart; 2 others had sudden death events, including one fatal ventricular tachyarrhythmia refractory to defibrillator therapy and one appropriate defibrillator shock in an asymptomatic female survivor. Pathologic examination of hearts at autopsy showed histopathologic findings compatible with both HCM due to sarcomere protein mutations (i.e., extensive myocyte disarray, intramural small vessel disease, myocardial replacement scarring), and also evidence of a storage disease process (i.e., clusters of myocytes with vacuolated sarcoplasm within fibrotic areas). Heart weights, 1266 and 1425 grams, are the most substantial recorded for hypertrophic cardiomyopathies. LAMP2 cardiomyopathy is a uniformly profound, and particularly deleterious disease entity, causing refractory heart failure with systolic dysfunction as well as sudden death in young patients < 25 years of age. This novel phenocopy of sarcomeric HCM underscores the power of molecular diagnosis for predicting prognosis, and should also raise consideration for intervention with early heart transplantation.
Variable Phenotypic Expression Including Late Presentation of Hypertrophic Cardiomyopathy in LEOPARD Syndrome with P.Q510E Mutation in PTPN11 Gene
