<HTML><BODY style="word-wrap: break-word; -khtml-nbsp-mode: space; -khtml-line-break: after-white-space; "><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">Dear Dr. Ray:</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; "> Thank you so much for contributing such an excellent question to <A href="http://www.scd-symposium.org/"><FONT class="Apple-style-span" color="#002FD7">www.scd-symposium.org</FONT></A>. I wish experts Drs. Igor Splawski, Silvia Priori, and Michael Ackerman would be able to provide you the answer in satisfactory.</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; "> With very limited knowledge, my premature response to your question is no. A negative genetic testing result by a standard approach cannot ruled out the possibility of somatic mutation caused diseases. Two years ago, Dr. Splawski, et al identified the disease-causing mutation G406R in Cav1.2 calcium channel gene in most of sporadic cases with Timothy syndrome (LQT8). Two of affected children are siblings, and the DNA extracted from the parents' blood sample do not have the mutation. However, Igor found the mutation in their mother's buccal swab DNA sample (from oral mucosa), suggesting she is a mosaic. It means G406R arose de novo during her early development. (Splawski, et al Cell, 2004;119:1-20).</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; "> Last night I had a great interest reading Dr. Calum MacRae's commentaries (MacRae, et al J. Clin. 2006, Invest;116:1825-28) regarding an excellent study conducted by Dr. Garcia-Gras, et al. J. Clin. Invest 2006;116:2012-21 (suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. I wish those information could be helpful to you as well.</DIV><P style="margin: 0.0px 0.0px 0.0px 0.0px"> </P><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">Sincerely,</DIV><P style="margin: 0.0px 0.0px 0.0px 0.0px"> </P><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">Li Zhang, MD</DIV><BR><DIV> <SPAN class="Apple-style-span" style="border-collapse: separate; border-spacing: 0px 0px; color: rgb(0, 0, 0); font-family: Helvetica; font-size: 12px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; text-align: auto; -khtml-text-decorations-in-effect: none; text-indent: 0px; -apple-text-size-adjust: auto; text-transform: none; orphans: 2; white-space: normal; widows: 2; word-spacing: 0px; "><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">--</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">Dr.<SPAN class="Apple-converted-space"> </SPAN>Sergio<SPAN class="Apple-converted-space"> </SPAN>Dubner</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">President<SPAN class="Apple-converted-space"> </SPAN>of<SPAN class="Apple-converted-space"> </SPAN>Scientific<SPAN class="Apple-converted-space"> </SPAN>Committee</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; font: normal normal normal 13px/normal Lucida Grande; min-height: 16px; ; font-family: Lucida Grande; font-size: 13px; "><BR style="font-family: Lucida Grande; font-size: 13px; "></DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">Dr.<SPAN class="Apple-converted-space"> </SPAN>Edgardo<SPAN class="Apple-converted-space"> </SPAN>Schapachnik</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">President<SPAN class="Apple-converted-space"> </SPAN>of<SPAN class="Apple-converted-space"> </SPAN>Steering<SPAN class="Apple-converted-space"> </SPAN>Committee</DIV><DIV><BR class="khtml-block-placeholder"></DIV><DIV><BR class="khtml-block-placeholder"></DIV></SPAN></DIV><DIV><BLOCKQUOTE type="cite"><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; min-height: 14px; "><BR></DIV> <DIV>Dr. Li,</DIV><DIV> Has genetic research analysis ruled out genetic allele chimerism (at the </DIV><DIV>time of organogenesis and embryological differentiation) to explain the </DIV><DIV>phenotypic variety of channelopathies or numerous clinical manifestations? Another </DIV><DIV>words are some alleles more likely to find or gravitate towards the eighth </DIV><DIV>nerve, RV, vs LV etc., while other regions of pacemaker cells remain entirely </DIV><DIV>normal?</DIV><DIV>Richar-Ray/dba Richard Ray Jordan, M.D., SFM</DIV><BR><DIV> <SPAN class="Apple-style-span" style="border-collapse: separate; border-spacing: 0px 0px; color: rgb(0, 0, 0); font-family: Helvetica; font-size: 12px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; text-align: auto; -khtml-text-decorations-in-effect: none; text-indent: 0px; -apple-text-size-adjust: auto; text-transform: none; orphans: 2; white-space: normal; widows: 2; word-spacing: 0px; "></SPAN></DIV><DIV><BLOCKQUOTE type="cite"><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; min-height: 14px; "><BR></DIV> <DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">Then we should ask oursselves why is so Dr. Ramon Brugada. Without a clear understanding of the disease nature, we may be always in the dark in terms of risk stratification. If Brugada syndrome were a primary repolarization disorder, one would expect the repolarization instability such as microvolt T wave alternans prior to the onset of VT/VF. As a matter of fact, the majority of VT/VF patients showed positive late potentials ( <A href="javascript:AL_get(this,%20'jour',%20'Arch%20Cardiol%20Mex.');"><FONT class="Apple-style-span" color="#002FD7">Arch Cardiol Mex.</FONT></A> 2006 Jan-Mar;76(1):52-8 ). Recently Dr. Shimizu's group demonstrated both depolarization and repolarization abnormalities [ <A href="javascript:AL_get(this,%20'jour',%20'Pacing%20Clin%20Electrophysiol.');"><FONT class="Apple-style-span" color="#002FD7">Pacing Clin Electrophysiol.</FONT></A> 2006 Oct;29(10):1112-21]. In the past our main focus was the consequence of reduced INa to the phase 1 repolarization in the RV epicardium and the transmural dispersion of repolarization, which may be part of the story. The slow activation propagation in ROVT region due to reduced sodium current itself should not be overlooked <FONT class="Apple-style-span" size="2"><SPAN class="Apple-style-span" style="font-size: 10px;">Am J Physiol</SPAN></FONT><A href="http://209.200.10.92/cgi-bin/t50/ezlclk.fcgi?id=870"><FONT class="Apple-style-span" size="2"><SPAN class="Apple-style-span" style="font-size: 10px;"><FONT class="Apple-style-span" color="#71AC69" size="3"><SPAN class="Apple-style-span" style="font-size: 12px;"> </SPAN></FONT><FONT class="Apple-style-span" color="#71AC69">Heart </FONT></SPAN></FONT></A><FONT class="Apple-style-span" size="2"><SPAN class="Apple-style-span" style="font-size: 10px;">Circ Physiol. 2006 Jul 28; [Epub ahead of print]</SPAN></FONT><FONT class="Apple-style-span" size="2"><SPAN class="Apple-style-span" style="font-size: 10px;"> </SPAN></FONT></DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">. </DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">Channelopathies especially SCN5A mutations can lead to structural abnormalities although many are undetectable by routine work up. Those structural alterations (macroscopic or microscopic) could also be the substrate to re-entrant ventricular tachyarrhythmias and sudden VT/VF death.</DIV><P style="margin: 0.0px 0.0px 0.0px 0.0px"> </P><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">Sincerely,</DIV><P style="margin: 0.0px 0.0px 0.0px 0.0px"> </P><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">Li Zhang, MD</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">LDS Hospital,</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">University of Utah School of Medicine</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">Salt Lake City, UT</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">USA</DIV><BR><DIV><BLOCKQUOTE type="cite"><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; min-height: 14px; "><BR></DIV> <DIV>No that i know of. There are two studies which looked at TWA (Japan and</DIV><DIV>Germany) in Brugada syndrome. Neither one showed any correlation with risk.</DIV><DIV><BR class="khtml-block-placeholder"></DIV><DIV>Dr. Ramon Brugada MD FACC</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">Associate Professor of Medicine</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">Canadian Research Chair Genetics of Arrhythmias</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">University of Montreal</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">Director Clinical Cardiovascular Genetics Center</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">Montreal Heart Institute</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">5000 Rue Belanger</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">Montreal, QC H1T 1C8</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; ">Canada</DIV><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; "><A href="mailto:ramon@brugada.org">ramon@brugada.org</A></DIV><BR><DIV> <SPAN class="Apple-style-span" style="border-collapse: separate; border-spacing: 0px 0px; color: rgb(0, 0, 0); font-family: Helvetica; font-size: 12px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; text-align: auto; -khtml-text-decorations-in-effect: none; text-indent: 0px; -apple-text-size-adjust: auto; text-transform: none; orphans: 2; white-space: normal; widows: 2; word-spacing: 0px; "><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; "><BR class="khtml-block-placeholder"></DIV><DIV><BR class="khtml-block-placeholder"></DIV></SPAN></DIV><DIV><BLOCKQUOTE type="cite"><DIV style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; min-height: 14px; "><BR></DIV> <DIV>Dear Dr. Ramon Brugada,</DIV><DIV>As you have discussed in the answer to the question for an asymptomatic</DIV><DIV>patient with brugada syndrome, the use of EPS to risk stratify</DIV><DIV>asymptomatic patient is very controversial. The first symptom may be</DIV><DIV>sudden death in such patients. In such a scenario is there any role for</DIV><DIV>microvolt T wave alternans for risk stratifications and to decide the need</DIV><DIV>for ICD?</DIV><DIV><BR class="khtml-block-placeholder"></DIV><DIV>Dr. Sunil Roy. MD, DM</DIV><DIV>Senior Lecturer in Cardiology</DIV><DIV>Medical college, Calicut, Kerala, India</DIV><DIV>Email: <A href="mailto:sunilroytn@calicutmedicalcollege.ac.in">sunilroytn@calicutmedicalcollege.ac.in</A></DIV><DIV><BR class="khtml-block-placeholder"></DIV><BR></BLOCKQUOTE></DIV></BLOCKQUOTE></DIV></BLOCKQUOTE></DIV><DIV><BR class="khtml-block-placeholder"></DIV><BR></BLOCKQUOTE></DIV><BR></BODY></HTML>