Mutations in X-linked lysosome-associated membrane protein gene (LAMP2; Danon
disease) produce a cardiomyopathy in young patients that clinically mimics 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.
To determine the clinical consequences of LAMP2 cardiomyopathy and the efficacy
of diagnostic and management strategies.
Setting and Design
Clinical course and outcome were assessed prospectively in 7 young LAMP2
patients (6 males) previously identified in our laboratory from the time of diagnosis
(ages 7–17; median 14) to October 2008. Phenotypic expression of this disease
was assessed both clinically and at autopsy.
Implantable defibrillators, cardioactive medications, and heart
Progressive heart failure/cardiac death, and transplant.
Over 7.3 ± 3 (SD) years of follow-up, and by 12 to 24 years of age, the
study patients developed LV systolic dysfunction (ejection fraction 25 ±
7[SD]%) 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). LV hypertrophy was particularly marked (maximum
ventricular septum, 29–65 mm; mean 44±15[SD]) including
2 patients with massive thickness of 60 mm and 65 mm at ages 23 and 15 years,
respectively. In 6 patients, at study entry a ventricular pre-excitation pattern was
associated with markedly increased voltages for maximum R- or S-wave (40–145 mm;
mean 74±38mm), and deeply inverted T-waves. Autopsy findings included a
combination of histopathologic features consistent with a storage disease (i.e.,
clusters of vacuolated myocytes), but also typical of HCM due to sarcomere protein
mutations (i.e., myocyte disarray, small vessel disease, myocardial scarring).
LAMP2 cardiomyopathy is a profound disease process characterized by rapid
clinical deterioration leading 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.