(Circulation. 2000;102:e112.)
© 2000 American Heart Association, Inc.
Images in Cardiovascular Medicine |
Novel Mutation in the 
-Tropomyosin Gene and Transition From Hypertrophic to Hypocontractile Dilated Cardiomyopathy
From the Department of Internal Medicine/Cardiology, Charite, Campus Virchow Klinikum, Humboldt Universität Berlin and Deutsches Herzzentrum Berlin, Germany.
Correspondence to Vera Regitz-Zagrosek, DHZB, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail zagrosek{at}dhzb.de
Awoman born in 1960 presented at age 14 years
with exertional dyspnea, sinus rhythm, and left ventricular
(LV) hypertrophy as shown by ECG. Hypertrophic
nonobstructive cardiomyopathy (HNCM) was diagnosed
by cardiac catheterization. An outflow tract gradient
at rest or exercise was excluded. An echocardiogram 5 years later
showed severe septal hypertrophy (Figure 1
). When the patient was 30 years old,
repeat right and left heart catheterization confirmed
HNCM (Figure 2). A biopsy showed myocyte
hypertrophy, only discrete signs of myocyte disarray, and
discrete interstitial fibrosis (eosin–van Gieson
stain, not shown) (Figure 3).
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When the patient was 37 years old, regression of LV
hypertrophy on the ECG and systolic dysfunction
were observed. The echocardiogram showed decreased systolic
function and wall thinning (septum 12 mm, posterior wall 8
mm, LV end-diastolic dimension 63 mm,
fractional shortening 16%). Cardiac catheterization
revealed a decreased LV ejection fraction (LVEF, 36%), slightly
increased end-diastolic ventricular volume
(Figure 4), and a significantly increased
LV end-diastolic pressure (28 mm Hg).
Ventricular tachycardia was documented, and an
internal cardioverter/defibrillator was implanted. At age 40 years, in
2000, severe systolic dysfunction was confirmed by 3D
echocardiographic reconstruction of the ventricle
(Figure 5).
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Complete mutation screening of the protein coding regions and the
exon-intron transitions in the 
-tropomyosin (-TM) gene identified
an A
T transversion at nucleotide position 595 (Figure 6). It changed the nucleotide
sequence in codon 180 from GAG to GTG, which results in the replacement
of the negatively charged amino acid glutamic acid (Glu) by a neutral
valine residue (Val). The mutation does not represent a simple
polymorphism, because it was not found in 100 normal control
samples.
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Because the patient was raised by foster parents, the family members were not available for study.
It is assumed that -TM variants account for <5% of familial
hypertrophic cardiomyopathy (HCM).1 We
found only the described single -TM mutation after systematic
screening of a large cohort of 110 symptomatic HCM patients
of European descent, which supports this assumption. Only 4 mutations
in the gene have been described so far. Codon position 180 of the
-TM gene was previously described as being affected by a different,
disease-causing, mutation in HCM (Glu180Gly).2 The
mutation Glu180Val occurs near a calcium-dependent troponin T–binding
domain that attaches -TM to the troponin complex. This residue is
highly conserved throughout evolution.
In Japanese families, missense mutations in the -TM gene have
already been associated with the rare progression of HCM to dilated
cardiomyopathy,3 and one of the
families described by Thierfelder et al4 with mutations at
the chromosome 15q2 locus exhibited a dilated phenotype
comparable to that of our patient. Thus, -TM variants may include a
predisposition to develop this phenotypical variant of HCM.
Acknowledgments
We gratefully acknowledge the excellent technical work of Heike Kallisch, and we thank L. Thierfelder for reviewing the manuscript and discussing his earlier work with us.
Footnotes
The editor of Images in Cardiovascular Medicine is Hugh A. McAllister, Jr, MD, Chief, Department of Pathology, St Luke’s Episcopal Hospital and Texas Heart Institute, and Clinical Professor of Pathology, University of Texas Medical School and Baylor College of Medicine.
Circulation encourages readers to submit cardiovascular images to the Circulation Editorial Office, St Luke’s Episcopal Hospital/Texas Heart Institute, 6720 Bertner Ave, MC1-267, Houston, TX 77030.
References
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[Abstract/Free Full Text]
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[Abstract/Free Full Text]
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