[SCD-FORUM] 51E RE: Asymptomatic patient with Brugada syndrome. Dr. Li Zhang

[SCD Symposium]

Dear Dr. Ray:
   Thank you so much for contributing such an excellent question to  
www.scd-symposium.org. I wish experts Drs. Igor Splawski, Silvia  
Priori, and Michael Ackerman would be able to provide you the answer  
in satisfactory.
   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).
   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.

Sincerely,

Li Zhang, MD

--
Dr. Sergio Dubner
President of Scientific Committee

Dr. Edgardo Schapachnik
President of Steering Committee


>
> Dr. Li,
> Has genetic research analysis ruled out genetic allele chimerism  
> (at the
> time of organogenesis and embryological differentiation) to explain  
> the
> phenotypic variety of channelopathies or numerous clinical  
> manifestations? Another
> words are some alleles more likely to find or gravitate towards the  
> eighth
> nerve, RV, vs LV etc., while other regions of pacemaker cells  
> remain entirely
> normal?
> Richar-Ray/dba Richard Ray Jordan, M.D., SFM
>
>>
>> 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 ( Arch Cardiol Mex.  
>> 2006 Jan-Mar;76(1):52-8 ). Recently Dr. Shimizu's group  
>> demonstrated both depolarization and repolarization abnormalities  
>> [ Pacing Clin Electrophysiol. 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 Am J Physiol Heart Circ  
>> Physiol. 2006 Jul 28; [Epub ahead of print]
>> .
>> 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.
>>
>> Sincerely,
>>
>> Li Zhang, MD
>> LDS Hospital,
>> University of Utah School of Medicine
>> Salt Lake City, UT
>> USA
>>
>>>
>>> No that i know of. There are two studies which looked at TWA  
>>> (Japan and
>>> Germany) in Brugada syndrome. Neither one showed any correlation  
>>> with risk.
>>>
>>> Dr. Ramon Brugada MD FACC
>>> Associate Professor of Medicine
>>> Canadian Research Chair Genetics of Arrhythmias
>>> University of Montreal
>>> Director Clinical Cardiovascular Genetics Center
>>> Montreal Heart Institute
>>> 5000 Rue Belanger
>>> Montreal, QC H1T 1C8
>>> Canada
>>> ramon at brugada.org
>>>
>>>
>>>
>>>>
>>>> Dear Dr. Ramon Brugada,
>>>> As you have discussed in the answer to the question for an  
>>>> asymptomatic
>>>> patient with brugada syndrome, the use of EPS to risk stratify
>>>> asymptomatic patient is very controversial. The first symptom  
>>>> may be
>>>> sudden death in such patients. In such a scenario is there any  
>>>> role for
>>>> microvolt T wave alternans for risk stratifications and to  
>>>> decide the need
>>>> for ICD?
>>>>
>>>> Dr. Sunil Roy.  MD, DM
>>>> Senior Lecturer in Cardiology
>>>> Medical college, Calicut, Kerala, India
>>>> Email: sunilroytn at calicutmedicalcollege.ac.in
>>>>
>>>>
>
>

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