Novel Mutation in the α-Tropomyosin Gene and Transition From Hypertrophic to Hypocontractile Dilated Cardiomyopathy
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⇓).
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⇓).
Complete mutation screening of the protein coding regions and the exon-intron transitions in the α-tropomyosin (α-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.
Because the patient was raised by foster parents, the family members were not available for study.
It is assumed that α-TM variants account for <5% of familial hypertrophic cardiomyopathy (HCM).1 We found only the described single α-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 α-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 α-TM to the troponin complex. This residue is highly conserved throughout evolution.
In Japanese families, missense mutations in the α-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, α-TM variants may include a predisposition to develop this phenotypical variant of HCM.
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.
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.
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- Copyright © 2000 by American Heart Association
Yamauchi-Takihara K, Nakajima-Taniguchi C, Matsui H, et al. Clinical implications of hypertrophic cardiomyopathy associated with mutations in the alpha-tropomyosin gene. Heart. 1996;76:63–65.
Thierfelder L, MacRae C, Watkins H, et al. A familial hypertrophic cardiomyopathy locus maps to chromosome 15q2. Proc Natl Acad Sci U S A. 1993;90:6270–6274.