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. 2009 Mar 25;301(12):1253-9.
doi: 10.1001/jama.2009.371.

Clinical Outcome and Phenotypic Expression in LAMP2 Cardiomyopathy

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Free PMC article

Clinical Outcome and Phenotypic Expression in LAMP2 Cardiomyopathy

Barry J Maron et al. JAMA. .
Free PMC article

Abstract

Context: Mutations in X-linked lysosome-associated membrane protein gene (LAMP2; Danon disease) produce a cardiomyopathy in young patients that clinically mimics severe hypertrophic cardiomyopathy (HCM) due to sarcomere protein mutations. However, the natural history and phenotypic expression of this newly recognized disease is incompletely resolved and its identification may have important clinical implications.

Objectives: To determine the clinical consequences, outcome, and phenotypic expression of LAMP2 cardiomyopathy associated with diagnostic and management strategies.

Design, setting, and patients: Clinical course and outcome were assessed prospectively in 7 young patients (6 boys) with defined LAMP2 mutations from the time of diagnosis (age 7-17 years; median, 14 years) to October 2008. Phenotypic expression of this disease was assessed both clinically and at autopsy.

Main outcome measures: Progressive heart failure, cardiac death, and transplant.

Results: Over a mean (SD) follow-up of 8.6 (2.6) years, and by age 14 to 24 years, the study patients developed left ventricular systolic dysfunction (mean [SD] ejection fraction, 25% [7%]) and cavity enlargement, as well as particularly adverse clinical consequences, including progressive refractory heart failure and death (n = 4), sudden death (n = 1), aborted cardiac arrest (n = 1), or heart transplantation (n = 1). Left ventricular hypertrophy was particularly marked (maximum thickness, 29-65 mm; mean [SD], 44 [15] mm), including 2 patients with massive ventricular septal thickness of 60 mm and 65 mm at ages 23 and 14 years, respectively. In 6 patients, a ventricular pre-excitation pattern at study entry was associated with markedly increased voltages of R-wave or S-wave (15-145 mm; mean [SD], 69 [39] mm), and deeply inverted T-waves. Autopsy findings included a combination of histopathologic features that were consistent with a lysosomal storage disease (ie, clusters of vacuolated myocytes) but also typical of HCM due to sarcomere protein mutations (ie, myocyte disarray, small vessel disease, myocardial scarring).

Conclusions: LAMP2 cardiomyopathy is a profound disease process characterized by progressive clinical deterioration leading rapidly to cardiac death in young patients (<25 years). These observations underscore the importance of timely molecular diagnosis for predicting prognosis and early consideration of heart transplantation.

Figures

Figure 1
Figure 1
12-lead ECG (recorded at full standard) from a 16-year-old LAMP2 cardiomyopathy patient (#2 in Table 1) showing striking standard and precordial voltages and T-wave inversion.
Figure 2
Figure 2
LAMP2 cardiomyopathy in a 12-year-old boy with sudden death (Table 1; patient #1). A. At autopsy, massive asymmetric LV hypertrophy. Ventricular septal (VS) thickness is 65 mm (heart weight, 1425 grams), exceeding all hearts reported to date; LV cavity is small. Ao = aorta; LVFW = left ventricular free wall. B. Disorganized LV architecture. Adjacent cardiac muscle cells (myocytes), or groups of cells, are arranged at perpendicular or oblique angles. Masson’s trichrome stain x100. C. Area of LV wall, demarcated by the broken line in A, showing subepicardial necrosis and scarring. D. Abnormal intramural coronary artery with thickened wall and narrowed lumen. PAS stain x20. E. Intracardiac ventricular electrogram. The ICD elicited a defibrillation shock (arrow) which failed to interrupt ventricular fibrillation (280 beats/min). This event was repeated 5 times until ICD capacity was extinguished and death occurred.
Figure 3
Figure 3
LV myocardium from the same patient shown in Figure 1, with findings consistent with a metabolic storage disease. A. Clusters of myocytes with vacuolated sarcoplasm (stained red) embedded in an area of scar (stained blue) x100. B. At lower power, similar area of myocardium shows subepicardial distribution of scarring and vacuolated myocytes x40. C. High power photomicrograph showing a large empty myocyte surrounded by smaller vesicles in an area of replacement fibrosis x40. D. Small focal scars (stained blue) surrounded by viable myocardium x40. All photomicrographs stained with Masson’s trichrome.

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