Glycogen storage diseases presenting as hypertrophic cardiomyopathy.
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 gamma2 (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), alpha-galactosidase (GLA), and acid alpha-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, > or =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.
Arad
Michael
M
Division of Cardiology, Brigham and Women's Hospital, Boston, USA.
Maron
Barry J
BJ
Gorham
Joshua M
JM
Johnson
Walter H
WH
Saul
J Philip
JP
Perez-Atayde
Antonio R
AR
Spirito
Paolo
P
Wright
Gregory B
GB
Kanter
Ronald J
RJ
Seidman
Christine E
CE
Seidman
J G
JG
D055372:AMP-Activated Protein Kinases; D000293:Adolescent; D000328:Adult; D000368:Aged; D000465:Algorithms; D015703:Antigens, CD / Q000235:genetics*; D002312:Cardiomyopathy, Hypertrophic / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002648:Child; D003937:Diagnosis, Differential; D004562:Electrocardiography; D000795:Fabry Disease / Q000235:genetics; D005260:Female; D006003:Glycogen / Q000378:metabolism; D006008:Glycogen Storage Disease / Q000150:complications* / Q000175:diagnosis / Q000235:genetics; D006009:Glycogen Storage Disease Type II / Q000150:complications / Q000235:genetics; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000209:etiology; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics*; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
D015703:Antigens, CD; C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D009097:Multienzyme Complexes; D006003:Glycogen; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human