This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Doi, Y. L. Articles by Bouhour, J.-B. Search for Related Content PubMed Articles by Doi, Y. L. Articles by Bouhour, J.-B.

(Circulation. 1999;100:446-449.)
© 1999 American Heart Association, Inc.

Correspondence

Clinical Expression in Patients With Hypertrophic Cardiomyopathy Caused by Cardiac Myosin-Binding Protein C Gene Mutation

Yoshinori L. Doi, MD; Hiroaki Kitaoka, MD; Nobuhiko Hitomi, MD

Department of Medicine and Geriatrics, Kochi Medical School, Kochi, Japan

Manatsu Satoh, MD; Akinori Kimura, MD

Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

	Introduction

Top Introduction References Introduction  References

 
To the Editor:

Hypertrophic cardiomyopathy is a primary cardiac disorder, mostly genetically transmitted, with a heterogeneous clinical and morphological expression. Analysis of the clinical expression of several genetic alterations has previously focused mainly on unfavorable manifestations. In this regard, recent articles by Charron and colleagues¹ and by Niimura and colleagues² that describe delayed expression of cardiac hypertrophy and a favorable clinical course in patients with mutations in the gene for cardiac myosin-binding protein C (MyBP-C) are indeed important contributions to an understanding of phenotype-genotype correlations at the mild end of the spectrum of the disease. However, these reports did not include precise morphological distribution of left ventricular hypertrophy, which is of clinical importance in the diagnosis and management of patients with this disorder.

We had opportunities to study 6 probands from 6 small Japanese families living in Kochi prefecture who were found to have the same mutation in the cardiac MyBP-C gene: a 1-base deletion at codon 593 from TCC (Ser) to CC in exon 18.³ Of 30 adult family members screened, 14 were identified as having this MyBP-C mutation. Although disease penetrance was incomplete, 90% of all patients and 80% of those under the age of 50 years had cardiac hypertrophy. The mean maximal wall thickness was 21±3 mm. Most patients revealed hypertrophy of both the ventricular septum and the free wall: 14 with Maron type III, 1 with type I, 1 with type IV, and 2 with diffuse concentric hypertrophy. There was no patient with apical hypertrophy, which was characteristically reported among Japanese patients.⁴ It would be interesting and clinically valuable to know what kind of morphological patterns of left ventricular hypertrophy, assessed by 2-dimensional echocardiography, have been seen in the patients reported by Charron and colleagues.

Concerning the natural history, sudden cardiac death was not observed during a follow-up period of 54.5±57.1 months (range, 1 to 160 months) in our patients, and 3 patients reached the age of >70 years. However, it is worth noting that 4 patients gradually progressed to the stage of left ventricular dilation and dysfunction later in their lives, a fact that has not been reported previously.

This phenotype-genotype information will be of significant importance for the practicing clinician, because left ventricular hypertrophy, as well as left ventricular dilation and dysfunction, often occurs in elderly patients, particularly in association with systolic hypertension.

	References

Top Introduction References Introduction  References

 

1. Charron P, Dubourg O, Desnos M, Bennaceur M, Carrier L, Camproux A-C, Isnard R, Hagege A, Langlard JM, Bonne G, Richard P, Hainque B, Bouhour J-B, Schwartz K, Komajda M. Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene. Circulation. 1998;97:2230–2236.[Medline] [Order article via Infotrieve]
   
2. Niimura H, Bachinski LL, Sangwatanaroj S, Watkins H, Chudley AE, McKenna W, Kristinsson A, Roberts R, Sole M, Maron BJ, Seidman JG, Seidman CE. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med. 1998;338:1248–1257.[Abstract/Free Full Text]
   
3. Kimura A, Harada H, Park J-E, Nishi H, Satoh M, Takahashi M, Hiroi S, Sasaoka T, Ohbuchi N, Nakamura T, Koyanagi T, Hwang T-H, Choo J-A, Chung K-S, Hasegawa A, Nagai R, Okazaki O, Nakamura H, Matsuzaki M, Sakamoto T, Toshima H, Koga Y, Imaizumi T, Sasazuki T. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat Genet. 1997;16:379–382.[Medline] [Order article via Infotrieve]
   
4. Koga Y, Katoh A, Matsuyama K, Ikeda H, Hiyamuta K, Toshima H, Imaizumi T. Disappearance of giant negative T waves in patients with the Japanese form of apical hypertrophy. J Am Coll Cardiol. 1995;26:1672–1678.[Abstract]
   

Response

Philippe Charron, MD; Mohammed Bennaceur, MD; Richard Isnard, MD; Michel Komajda, MD

Service de Cardiologie

Lucie Carrier, PhD; Gisele Bonne, PhD; Ketty Schwartz, PhD

INSERM Unit 153

Anne-Claude Camproux, PhD

GERC, Département de Biomathématiques

Pascale Richard, PhD; Bernard Hainque, PhD

Service de Biochimie, Hôpital Pitié-Salpêtrière, Paris, France

Olivier Dubourg, MD

Service de Cardiologie Hôpital Ambroise Paré, Boulogne, France

Michel Desnos, MD; Albert Hagege, MD

Service de Cardiologie, Hôpital Boucicaut, Paris, France

Jean Marc Langlard, MD; Jean-Brieuc Bouhour, MD

Service de Cardiologie, Hôpital Laennec, Nantes, France

	Introduction

Top Introduction References Introduction  References

 
We thank Dr Doi et al for their comments about our article¹ on phenotype-genotype analysis related to the cardiac myosin binding protein C (MyBP-C) gene in familial hypertrophic cardiomyopathy (FHC). They screened Japanese families, found a mutation in the MyBP-C gene in 6 of them (14 adult members), and analyzed some of their clinical features.

They found that penetrance of the disease was incomplete, as in our experience, but was as high as 80% before 50 years of age. First, the penetrance of the disease depends heavily on the diagnostic criteria used, as was recently shown in children.² Therefore, it would be interesting to know the diagnostic criteria used by Doi et al. Second, in addition to the causative mutation or gene, many factors could modulate the expression of the disease and could explain the difference observed between the Japanese and French populations. These factors include mean age, sex ratio, modifier gene (such as the ACE I/D polymorphism),³ and unknown environmental factors.

Interestingly, a mean follow-up of 54 months was available in families studied by Doi et al, and no sudden cardiac death was observed. This confirms the good prognosis observed in our study in young subjects.¹ The fact that 4 patients progressed to left ventricular dilation and dysfunction is also in accordance with our findings, because we observed 4 cardiac deaths or transplantations related to congestive heart failure (mean age, 65±9 years) in our population. This evolution appears not specific of families with a mutation in the MyBP-C gene, because it was described in families with a mutation in the ß-myosin heavy chain gene.¹

Finally, the distribution of left ventricular hypertrophy (LVH) was not described in our study (it was not our purpose, because the distribution of LVH appears to be of little interest for prognostic implications). However, in 46 subjects with LVH, of the 76 carriers of a mutation in the MyBP-C gene, we found 2 (4.3%) subjects with Maron type I hypertrophy, 19 (41.3%) with type II, 24 (52.2%) with type III, and 1 with type IV (2.2%). As previously shown in FHC related to other genes,⁴ the morphological distribution of LVH was therefore variable in families related to the MyBP-C gene, even within a given family.

	References

Top Introduction References Introduction  References

 

1. Charron P, Dubourg O, Desnos M, Bennaceur M, Carrier L, Camproux A-C, Isnard R, Hagege A, Langlard JM, Bonne G, Richard P, Hainque B, Bouhour J-B, Schwartz K, Komajda M. Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene. Circulation. 1998;97:2230–2236.
   
2. Charron P, Dubourg O, Desnos M, Bouhour JB, Isnard R, Hagege A, Carrier L, Bonne G, Tesson F, Richard P, Hainque B, Schwartz K, Komajda M. Diagnostic value of electrocardiography and echocardiography for familial hypertrophic cardiomyopathy in genotyped children. Eur Heart J. 1998;19:1377–1382.[Abstract/Free Full Text]
   
3. Tesson F, Dufour C, Moolman JC, Carrier L, al-Mahdawi S, Chojnowska L, Dubourg O, Soubrier E, Brink P, Komajda M, Guicheney P, Schwartz K, Feingold J. The influence of the angiotensin I converting enzyme genotype in familial hypertrophic cardiomyopathy varies with the disease gene mutation. J Mol Cell Cardiol. 1997;29:831–838.[Medline] [Order article via Infotrieve]
   
4. Kimura A, Harada H, Park JE, Nishi H, Satoh M, Takahashi M, Hiroi S, Sasaoka T, Ohbuchi N, Nakamura T, Koyanagi T, Hwang T-H, Choo J-A, Chung K-S, Hasegawa A, Nagai R, Okazaki O, Nakamura H, Matsuzaki M, Sakamoto T, Toshima H, Koga Y, Imaizumi T, Sasazuki T. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat Genet. 1997;16:379–382.
   

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Doi, Y. L. Articles by Bouhour, J.-B. Search for Related Content PubMed Articles by Doi, Y. L. Articles by Bouhour, J.-B.