Abstract & Commentary
Synopsis: Danon’s disease or PRKAG2 mutations can present as HCM but are distinguished by the presence of pre-excitation on the ECG.
Source: Arad M, et al. N Eng J Med. 2005;352:362-372.
Unexplained left ventricular hypertrophy (LVH) on echocardiography often prompts the diagnosis of hypertrophic cardiomyopathy (HCM), which is now known to involve a variety of genetic disorders involving sarcomere proteins. Genetic disorders involving protein kinase (PRKAG2) mutations can cause cardiac glycogen depositions mimicking LVH. Thus, Arad and colleagues sought to distinguish HCM from glycogen storage diseases (GSDs) in 75 patients aged 12-75 years, with unexplained LVH by echo (wall thickness ³13 mm) by genetic analyses and clinical features. In 40 of these patients, sarcomere-protein mutations were found. The remaining 35 underwent gene analysis for GSDs. Fabry’s and Pompe’s diseases were not found, but LAMP2 (Danon’s disease) and PRKAG2 mutations were. Consequently, 2 additional cohorts were studied: 20 aged 9-58 years with massive LVH (wall thickness > 30 mm) and 24 aged 8 to 42 years with HCM, in whom the ECG suggested ventricular pre-excitation, a feature of GSDs. In the massive LVH group, GSD genes were not found. In the HCM patients with pre-excitation, LAMP2 and PRKAG2 mutations were found in 46%. LAMP2 was mainly found in males with cardiac symptoms beginning earlier than seen in typical HCM (age 8-15 years). Massive LVH and outflow gradients were seen in some of these patients. Also, creatine kinase and ALT levels were elevated. Arad et al concluded that Danon’s disease or PRKAG2 mutations can present as HCM but are distinguished by the presence of pre-excitation on the ECG.
Comment by Michael H. Crawford, MD
I was taught that pre-excitation was more common in HCM patients based upon observational studies. This study explains why, but in an unexpected way—these patients likely have GSD rather than traditional HCM due to sarcomere-protein defects. This is an important clinical observation, because GSDs have a worse prognosis and are more likely to have syncope and sudden death due to arrhythmias. PRKAG2 defects have a similar course to HCM, but Danon’s disease is especially lethal, so transplantation needs to be considered earlier. Wouldn’t you pick these patients up by family history? No, Danon’s disease is sporadic (PRKAG2 is familial). Wouldn’t these patients show other manifestations of GSD? No, in this series the PRKAG2 and Danon’s patients had few and mild other findings, and cardiac symptoms were their initial manifestations of disease.
Thus, if you see a patient with echo evidence of HCM with pre-excitation on ECG, think GSD, especially if it is a male with onset of cardiac symptoms at a young age and massive LVH. Danon’s disease can be distinguished for PRKAG2 mutations by the elevated CK and ALT in the serum of the former.
Dr. Crawford, Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco, is Editor of Clinical Cardiology Alert.