Boston, MA- In glycogen storage diseases, enzymes responsible for metabolizing muscle glycogen not only cause systemic diseases, but involve the heart as well. A study published in the January 27, 2005 issue of The New England Journal of Medicine by Michael Arad, M.D., et al from Brigham and Women’s Hospital in Massachusetts, showed that cardiac disease can be the initial and predominant manifestations of defects in human glycogen metabolism. It was found that specific glycogen metabolism mutations, LAMP2 and PRKAG2, causes multisystem glycogen-storage disease and can also present as primary cardiomyopathy. Thus, genetic analysis can establish the cause, treatment and familial risk of unexplained left ventricular hypertrophy. 

Seventy-five unrelated patients with hypertrophic cardiomyopathy were prospectively enrolled for genetic analyses of sarcomere-protein mutations. Maximal left ventricular wall thickness ranged from 13 to 60 mm. Forty sarcomere-protein gene mutations were identified in these 75 patients. More specifically, two LAMP2 and one PRKAG 2 mutations were identified in probands with prominent hypertrophy and electrophysiological abnormalities. Thus, genetic analyses of patients with these mutations were performed. Of the 24 patients with increased left ventricular wall thickness and electrocardiograms with ventricular preexcitation revealed four LAMP2 and seven PRKAG2 mutations.  
Inclusion of LAMP2 and PRKAG2 mutations in the differential diagnosis of unexplained left ventricular hypertrophy is important for patient care. LAMP 2 mutations accumulate glycogen in lysosomes and PRKAG2 mutations accumulate glycogen throughout the myocyte. The study mentions these mutations may have a common mechanism for ventricular preexcitation in both glycogen-storing abnormalities. These mutations increase the risk of arrhythmias as shown by preexcitation patterns on electrocardiograms, by accessory pathways on electrophysiological evaluation and by patients’ histories of supraventricular tachyarrhythmias, syncopal episodes and sudden death. Additionally, cardiomyopathy due to PRKAG2 mutations is also compatible with long-term survival, while cardiomyopathy due to LAMP2 mutations have poor prognosis.  

These results suggest that there should be an inclusion of LAMP2 and PRKAG2 mutations in the differential diagnosis of unexplained left ventricular hypertrophy and preexcitation patterns on electrocardiogram. Patients with such abnormalities should undergo clinical and genetic evaluation for glycogen storage disease. This information is important for appropriate prognoses, treatment strategies and defining familial risk. 

Co-authors: Barry J. Maron, M.D., Joshua M. Gorham, B.A., Walter H. Johnson, Jr., M.D., Philip Saul, M.D., Antonio R. Perez-Atayde, M.D., Paolo Spirito, M.D., G regory B. Wright, M.D., Ronald J. Kanter, M.D., Christine E. Seidman, M.D., and J.G. Seidman, Ph.D.