Published Online
on September 6, 2005

A more recent version of this article appeared on September 13, 2005

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Submitted on March 2, 2005
Revised on June 22, 2005
Accepted on June 28, 2005

Danon Disease as an Underrecognized Cause of Hypertrophic Cardiomyopathy in Children

Zhao Yang MD, Colin J. McMahon MB, Liana R. Smith BS, Jeathrina Bersola MS, Adekunle M. Adesina MD, PhD, John P. Breinholt MD, Debra L. Kearney MD, William J. Dreyer MD, Susan W. Denfield MD, Jack F. Price MD, Michelle Grenier MD, Naomi J. Kertesz MD, Sarah K. Clunie RN, Susan D. Fernbach BSN, James F. Southern MD, PhD, Stuart Berger MD, Jeffrey A. Towbin MD, Karla R. Bowles PhD, and Neil E. Bowles PhD^*

From the Departments of Medicine (Cardiovascular Sciences Program) (Z.Y., J.A.T.), Pediatrics (Section of Cardiology) (C.J.M., L.R.S., J.B., J.P.B., W.J.D., S.W.D., J.F.P., M.G., N.J.K., S.K.C., J.A.T., K.R.B., N.E.B.), Pathology (A.M.A., D.L.K.), and Molecular and Human Genetics (S.D.F., J.A.T.), Baylor College of Medicine, Houston, Tex; and Departments of Pathology (J.F.S.) and Cardiology (S.B.), Children’s Hospital of Wisconsin, Milwaukee.

^* To whom correspondence should be addressed. E-mail: nbowles{at}bcm.tmc.edu.

Background--Some patients with hypertrophic cardiomyopathy (HCM) or left ventricular hypertrophy also present with skeletal myopathy and Wolff-Parkinson-White (WPW) syndrome; mutations in the gene encoding the lysosome-associated protein-2 (LAMP-2) have been identified in these patients, suggesting that some of these patients have Danon disease. In this study we investigated the frequency of LAMP2 mutations in an unselected pediatric HCM population.

Methods and Results--LAMP2 was amplified from genomic DNA isolated from peripheral lymphocytes of 50 patients diagnosed with HCM and analyzed by direct DNA sequencing. In 2 of the 50 probands (4%), nonsense mutations were identified. In 1 family the proband initially presented with HCM as a teenager, which progressed to dilated cardiomyopathy (DCM) and heart failure. Skeletal myopathy and WPW were also noted. The teenage sister of the proband is a carrier of the same LAMP2 mutation and has HCM without skeletal myopathy or WPW. The other proband presented with HCM, WPW, and skeletal myopathy as a teenager, whereas his carrier mother developed DCM during her 40s. Skeletal and cardiac muscle sections revealed the absence of LAMP-2 on immunohistochemical staining.

Conclusions--LAMP2 mutations may account for a significant proportion of cases of HCM in children, especially when skeletal myopathy and/or WPW is present, suggesting that Danon disease is an underrecognized entity in the pediatric cardiology community.

Key words: cardiomyopathy • genetics • heart failure • Wolff-Parkinson-White syndrome

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