Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly.
BACKGROUND
Hypertrophic cardiomyopathy, a familial myocardial condition caused by sarcomere protein mutations, is usually recognized by early adulthood. Hypertrophic cardiomyopathy of the elderly has similar clinical features but, notably, a later age of onset and noncontributory family history. Causes of elderly-onset hypertrophic cardiomyopathy are unknown.


RESULTS
Eighteen women and 13 men diagnosed with late-onset hypertrophic cardiomyopathy were studied. Initial symptoms occurred at 59.3 (+/-12.3) years, and diagnosis was made at 62.8 (+/-10.8) years. None had family histories of cardiomyopathy. Echocardiography demonstrated maximal left ventricular wall thickness of 19.9+/-3.8 mm, systolic anterior motion of the mitral valve (58%), and, in 11 individuals, left ventricular outflow tract gradients (average, 63+/-42.8 mm). Sarcomere protein gene analyses revealed 8 sequence variants in cardiac myosin binding protein-C (1 nonsense, 1 splice acceptor site, and 3 missense), cardiac troponin I (2 missense), and alpha-cardiac myosin heavy chain (1 missense). Seven variants were not found in over 170 normal chromosomes; 1 variant (cardiac myosin binding protein-C Arg326Gln) also occurred in a healthy adult.


CONCLUSIONS
Hypertrophic cardiomyopathy of the elderly can be a genetic disorder caused by dominant sarcomere protein mutations. The distribution of mutations in elderly-onset disease is strikingly different (P<0.00001) from that of familial, early onset hypertrophic cardiomyopathy. Whereas defects in beta-cardiac myosin heavy chain, cardiac troponin T, and alpha-tropomyosin account for > 45% of familial hypertrophic cardiomyopathy, none were found here. Rather, mutations in cardiac myosin binding protein-C, troponin I, and alpha-cardiac myosin heavy chain caused elderly-onset hypertrophic cardiomyopathy.
Niimura
Hideshi
H
Howard Hughes Medical Institute and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Patton
Kristen K
KK
McKenna
William J
WJ
Soults
Johann
J
Maron
Barry J
BJ
Seidman
J G
JG
Seidman
Christine E
CE
D017668:Age of Onset; D000595:Amino Acid Sequence; D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000000981:diagnostic imaging / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D004452:Echocardiography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics; D012518:Sarcomeres / Q000235:genetics*; D016415:Sequence Alignment; D019210:Troponin I / Q000235:genetics; D000099163:Myosin Binding Protein C
D002352:Carrier Proteins; D009124:Muscle Proteins; D018995:Myosin Heavy Chains; D019210:Troponin I; D000099163:Myosin Binding Protein C