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Late-Onset Hypertrophic Cardiomyopathy Caused by a Mutation in the Cardiac Troponin T Gene

N Engl J Med 1999; 341:1855-1856December 9, 1999

Article

To the Editor:

Familial hypertrophic cardiomyopathy is a heterogeneous disease caused by mutations in eight different genes that encode cardiac sarcomeric proteins. Relatives of affected persons are at low risk for the disease in later life if the electrocardiographic and two-dimensional echocardiographic findings are normal in early adulthood. The only reported exceptions are patients with mutations in the gene for cardiac myosin-binding protein C, in whom the disease typically develops in middle age.1,2 We describe a 57-year-old man with hypertrophic cardiomyopathy caused by a mutation in the gene for troponin T.

The patient presented with a three-year history of exertional dyspnea and recurrent syncope. At an insurance medical examination performed 10 years earlier, he had been asymptomatic, with no murmurs and normal electrocardiographic findings. His grandfather had died suddenly at the age of 60 years, and his father had died from carcinoma at the age of 84 years.

Physical examination revealed sinus rhythm, a blood pressure of 126/78 mm Hg, and systolic murmurs at the apex and left sternal edge. An electrocardiogram showed sinus rhythm, left ventricular hypertrophy, T-wave inversion, and deep QS waves in leads V₁ and V₂. A Doppler echocardiographic study revealed a septal thickness of 12 mm at the level of the mitral valve, systolic anterior motion of the mitral valve, and a peak left ventricular outflow tract gradient of 49 mm Hg. Left-sided cardiac catheterization showed no clinically significant coronary-artery stenoses. Genetic analysis revealed that the patient had a recognized disease-causing missense mutation, Arg278Cys, in exon 16 of the troponin T gene.3

Troponin T mutations account for approximately 15 percent of cases of hypertrophic cardiomyopathy, and such cases are characterized by an onset in adolescence, mild hypertrophy, and a high risk of sudden death. Until now, the only reported sarcomeric-protein mutations associated with disease in later life have involved the gene for cardiac myosin-binding protein C.1,2 The finding of a recognized disease-causing mutation in a patient with a documented onset of disease in middle age will therefore substantially alter the information given to the relatives of patients with troponin T disease with regard to the risk that the disease will develop in later life. This discovery also raises the possibility that some cases of unexplained sudden death from cardiac causes in middle-aged patients may be caused by troponin T mutations in association with mild myocardial hypertrophy or in its absence.

Perry M. Elliott, M.B., B.S.
Leon D'Cruz, M.Sc.
William J. McKenna, M.D.
St. George's Hospital Medical School, London SW17 0RE, United Kingdom

3 References

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   Charron P, Dubourg O, Desnos M, et al. Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene. Circulation 1998;97:2230-2236
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   Niimura H, Bachinski LL, Sangwatanaroj S, et al. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med 1998;338:1248-1257
   Full Text | Web of Science | Medline

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   Watkins H, McKenna WJ, Thierfelder L, et al. Mutations in the genes for cardiac troponin T and α-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med 1995;332:1058-1064
   Full Text | Web of Science | Medline

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   Ruth H. Willott, Aldrin V. Gomes, Audrey N. Chang, Michelle S. Parvatiyar, Jose Renato Pinto, James D. Potter. (2010) Mutations in Troponin that cause HCM, DCM AND RCM: What can we learn about thin filament function?. Journal of Molecular and Cellular Cardiology 48:5, 882-892
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   Franz Baudenbacher, Tilmann Schober, Jose Renato Pinto, Veniamin Y. Sidorov, Fredrick Hilliard, R. John Solaro, James D. Potter, Björn C. Knollmann. (2008) Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice. Journal of Clinical Investigation
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   Rajesh Thaman, Sami Firoozi, M. S. Hamid, William J. McKenna. (2002) Hypertrophic cardiomyopathy: Management issues in the new millennium. Current Cardiology Reports 4:3, 226-232
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   Perry M. Elliott. (2000) Natural history of hypertrophic cardiomyopathy. Current Cardiology Reports 2:2, 141-147
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