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Previous Volume 352:362-372 January 27, 2005 Number 4 Next

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ABSTRACT

Background Unexplained left ventricular hypertrophy often prompts the diagnosis of hypertrophic cardiomyopathy, a sarcomere-protein gene disorder. Because mutations in the gene for AMP-activated protein kinase ₂ (PRKAG2) cause an accumulation of cardiac glycogen and left ventricular hypertrophy that mimics hypertrophic cardiomyopathy, we hypothesized that hypertrophic cardiomyopathy might also be clinically misdiagnosed in patients with other mutations in genes regulating glycogen metabolism.

Methods Genetic analyses performed in 75 consecutive unrelated patients with hypertrophic cardiomyopathy detected 40 sarcomere-protein mutations. In the remaining 35 patients, PRKAG2, lysosome-associated membrane protein 2 (LAMP2), -galactosidase (GLA), and acid -1,4-glucosidase (GAA) genes were studied.

Results Gene defects causing Fabry's disease (GLA) and Pompe's disease (GAA) were not found, but two LAMP2 and one PRKAG2 mutations were identified in probands with prominent hypertrophy and electrophysiological abnormalities. These results prompted the study of two additional, independent series of patients. Genetic analyses of 20 subjects with massive hypertrophy (left ventricular wall thickness, 30 mm) but without electrophysiological abnormalities revealed mutations in neither LAMP2 nor PRKAG2. Genetic analyses of 24 subjects with increased left ventricular wall thickness and electrocardiograms suggesting ventricular preexcitation revealed four LAMP2 and seven PRKAG2 mutations. Clinical features associated with defects in LAMP2 included male sex, severe hypertrophy, early onset (at 8 to 17 years of age), ventricular preexcitation, and asymptomatic elevations of two serum proteins.

Conclusions LAMP2 mutations typically cause multisystem glycogen-storage disease (Danon's disease) but can also present as a primary cardiomyopathy. The glycogen-storage cardiomyopathy produced by LAMP2 or PRKAG2 mutations resembles hypertrophic cardiomyopathy but is distinguished by electrophysiological abnormalities, particularly ventricular preexcitation.

Source Information

From the Division of Cardiology, Brigham and Women's Hospital (M.A., C.E.S.), and the Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute (M.A., J.M.G., C.E.S., J.G.S.) — all in Boston; the Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis (B.J.M.); the Department of Pediatrics, Division of Pediatric Cardiology, University of Alabama at Birmingham, Birmingham (W.H.J.); the Children's Heart Program of South Carolina, Medical University of South Carolina, Charleston (J.P.S.); the Department of Pathology, Children's Hospital and Harvard Medical School, Boston (A.R.P.-A.); the Department of Cardiology, Galleria de Genova, Genova, Italy (P.S.); the Children's Heart Clinic, Minneapolis (G.B.W.); and the Division of Pediatric Cardiology, Duke University Medical Center, Durham, N.C. (R.J.K.).

Address reprint requests to Dr. J.G. Seidman at the Department of Genetics, NRB Rm. 256, Harvard Medical School, 77 Ave. Louis Pasteur, Boston, MA 02115, or at seidman{at}genetics.med.harvard.edu.

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Glycogen Storage Diseases and Cardiomyopathy
Roos J. C.P., Cox T. M., Arad M., Maron B. J., Seidman J.G.
Extract | Full Text | PDF  
N Engl J Med 2005; 352:2553, Jun 16, 2005. Correspondence

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