LETTER TO THE EDITOR
Reply
Matteo Vatta, PhD,
Bhagyalaxmi Mohapatra, PhD,
Shinawe Jimenez, MD,
Ximena Sanchez, PhD,
Neil Bowles, PhD,
Karla R. Bowles, PhD and
Jeffrey A. Towbin, MD
Baylor College of Medicine, Texas Children's Hospital, 6621 Fannin Street, MC 19345-C, Houston, Texas 77030
(Email: jtowbin{at}bcm.tmc.edu).
We would like to thank Drs. Finsterer and Stollberger for their comments. Our study (1) was performed on patients with left ventricular (LV) dysfunction associated with classic dilated cardiomyopathy (DCM) or left ventricular non-compaction (LVNC). All patients had standard echocardiographic evaluations and/or cardiac magnetic resonance imaging with selected cases having cardiac catheterization and angiography. Because the vast majority of patients evaluated either had classic autosomal-dominant inheritance and/or were of a young age, coronary angiography was not indicated in many of these subjects. In addition, no patient had evidence of regional wall abnormalities on echocardiography. The criteria used for definition of LVNC is that described by Chin et al. (2), Ichida et al. (3), Pignatelli et al. (4), and Towbin and Bowles (5), which is the accepted criteria by cardiologists. The patients screened were recruited from five centers; all of the patients were evaluated by cardiac and neurologic analyses. All nuclear family members were evaluated by cardiac exam and genetic screening; selected subjects (but the majority) were also screened neurologically. Regarding subject II:1 of family 065, she is the wife of an affected family member. Her echocardiogramwas read as normal, but the specific measurements were not available. It should be noted that she is not a "blood relationship" of the affected family members (except her daughter, whose father was affected). Symptomatically (as noted), the affected patients commonly complained of muscle fatigue and cramping as well as exercise intolerance. Because these patients were, in most cases, effectively treated for heart failure, these symptoms are beyond expectations for clinically stable, compensated cardiomyopathy and suggest a primary skeletal muscle functional abnormality. Cypher knock-out mice do have "clinical myopathy" that is probably more severe thanour patients as a result of the heterozygous nature of our mutations (and the total loss of function of the knock-out animals). This is common when comparing mouse knock-out models with autosomal-dominant human subjects. We have shown this to be the case here as well as in several other publications in which we identified causative genes for DCM ( -sarcoglycan, dystrophin, MLP,  -actinin2) (5,6), and LVNC (-dystrophin, G4.5) (3).
The 200 control patients are standardized controls as used in all genetic studies; none had DCM, LVNC, or cardiac disease (that is why they are called controls). Based on their comments regarding the knock-out animals and these statements regarding the control analyses, it is clear that Drs. Finsterer and Stöllberger (7) do not understand human molecular genetics and do not understand the genetic basis of cardiomyopathy. Their queries regarding the clinical data also demonstrate that they are clearly not cardiologists and have no experience or understanding of these clinical diseases. Furthermore, although we agree with their suggestion that studies of skeletal muscle in patients with LVNC should be considered, it should be noted that in their own publications, they are unable to study the skeletal muscle of over 50% of cases with LVNC. How they can suggest that 80% of cases have associated skeletal muscle disease is unclear because they themselves have failed to perform these analyses. Regarding the points raised about other causes of LVNC, we have now shown that LVNC is a genetically heterogeneous disorder with autosomal-dominant inheritance resulting from mutations in -dystrobrevin and Cypher/ZASP (1), as well as being associated with X-linked inheritance due to mutations in G4.5 (3). No genetic data are available to demonstrate mitochondrial inheritance thus far. Clearly, the disorder is complex, and further study is needed. Why ZASP mutations cause LVNC in some individuals and DCM in others is not yet known.
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References
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1. Vatta M, Mohapatra B, Jimenez S, et al. Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction J Am Coll Cardiol 2003;42:2014-2027.[Abstract/Free Full Text]
2. Chin TK, Perloff JK, Williams RG, et al. Isolated noncompaction of left ventricular myocardium: a study of eight cases Circulation 1990;82:507-513.[Abstract/Free Full Text]
3. Ichida F, Hamamichi Y, Miyawaki T, et al. Clinical features of isolated noncompaction of the ventricular myocardium: long-term clinical course, hemodynamic properties, and genetic background J Am Coll Cardiol 1999;34:233-240.[Abstract/Free Full Text]
4. Pignatelli RH, McMahon CJ, Bezold LI, et al. Left ventricular noncompaction characteristics in childrenundulating phenotype and differences from the adult population. Circulation 2003;108:2672-2678.[Abstract/Free Full Text]
5. Towbin JA, Bowles NE. The failing heart Nature 2002;415:227-233.[CrossRef][Medline]
6. Mohapatra B, Jimenez S, Lin JH, et al. Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis Mol Genet Metab 2003;80:207-215.[CrossRef][Medline]
7. Stöllberger C, Finsterer J, Blazek G. Left ventricular hypertrabeculation/noncompaction and association with additional cardiac abnormalities and neuromuscular disorders Am J Cardiol 2002;90:899-902.[CrossRef][Medline]
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