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Original Contribution
March 25, 2009

Clinical Outcome and Phenotypic Expression in LAMP2 Cardiomyopathy

Author Affiliations

Author Affiliations: Hypertrophic Cardiomyopathy Center of the Minneapolis Heart Institute Foundation, Minneapolis, Minnesota (Drs Maron and Almquist and Ms Haas); Baylor Cardiovascular Research Institute, Dallas, Texas (Dr Roberts); Heart Institute and Heart Failure Service, Sheba Medical Center, Tal Hashomer, Israel (Dr Arad); Division of Cardiology, Ospedelaiero Ospedali Galliera, Genoa, Italy (Dr Spirito); Children's Heart Clinic, Minneapolis (Dr Wright); Nemours Cardiac Center, Alfred I. DuPont Hospital for Children, Wilmington, Delaware (Dr Baffa); Department of Pediatrics, Medical University of South Carolina, Charleston (Dr Saul); Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts (Dr Ho); and Department of Genetics, Harvard Medical School, Boston (Drs J. Seidman and C. E. Seidman).

JAMA. 2009;301(12):1253-1259. doi:10.1001/jama.2009.371

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.