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Re: Bilateral thoracoscopic cervical sympathectomy for the treatment of recurrent polymorphic ventricula

Dear Editor

In January’s edition of Heart we presented the fascinating case of a patient with long QT syndrome who was refractory to conventional pharmacological and pacing techniques.[1] Despite potassium and magnesium supplements, beta-blockade, implantation of a single, then dual chamber implantable cardioverter-defibrillator (ICD), amiodarone, nicorandil and mexiletine; the patient continued to experience life-threatening ventricular tachyarrhythmias, receiving more than 700 ICD discharges over a seven-month period. She was ultimately treated successfully with bilateral thoracoscopic cervico-thoracic sympathectomies.

It has been over 23-months since her bilateral thoracoscopic cervico- thoracic sympathectomies. I am pleased to report that she continues to make good progress. She has only had one repeat hospital admission for an episode of recurrent polymorphic ventricular tachycardia. This fortunately settled spontaneously over a 48-hour period without any alterations to her medication or ICD.

At the time of publication we were awaiting the result of mutation screening of the genes KCNQ1, KCNH2, KCNE1, KCNE2 and SCN5A. This has now revealed that the patient is heterozygous for a previously undescribed mutation in intron 3 of the SCN5A gene (IVS3-5C>A)* dramatically reducing the efficiency of the acceptor splice-site prior to exon 4. Most likely the mutation results in the occurrence of exon skipping phenomena and frame shifts leading to mRNA decay (haploinsufficiency) or the synthesis of truncated protein variants. With reduced SCN5A channel activity the patient would be expected to present with Brugada syndrome. The synthesis of truncated variants with exclusion of some segments and inclusion of other amino acids as a result of the synthesis of different splice-variants could explain the deviation from the Brugada phenotype.[2] Other mutations resulting in putative truncation of SCN5A, i.e. W156X and L1786X, have had different phenotypes.[2][3] Furthermore, haploinsufficiency of SCN5A in the mouse is associated with re-entrant ventricular tachyarrhythmias.[4] The precise explanation for the LQT3 phenotype in this patient must await further molecular and functional studies.

References

1. Turley AJ, Thambyrajah J, Harcombe AA. Bilateral Thoracoscopic Cervical Sympathectomy For The Treatment Of Recurrent Polymorphic Ventricular Tachycardia. Heart 2005;91:15-7.

2. Bezzina CR, Rook MB, Groenewegen WA et al. Compound heterozygosity for mutations (w156X and R225W) in SCN5A associated with severe cardiac conduction disturbance. Circ Res 2003;92:159-168.

3. Herfst IJ, Potet F, Bezzina CR et al. Na+ channel mutation leading to loss of function and non-progressive conduction defects. J Mol Cell Cardiol 2003;35:549-553.

4. Papadatos GA, Wallerstein PMR, Head CEG et al. Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene SCN5A. Proc Natl Acad Sci USA 2002;99:6210-6215.

*The mutation occurs in nucleotide no. 29298 in the genomic sequence ensg00000183873 (www.ensembl.org). Exons are numbered from the exon containing the start ATG codon at nucleotide no. 16967.

AJ Turley¹, E Behr², M Christiansen³, J Thambyrajah¹ and AA Harcombe⁴

1 Cardiothoracic Division, The James Cook University Hospital, Middlesbrough, UK
2 Cardiothoracic Unit, St George’s Hospital, London, UK
3 Department of Clinical Biochemistry, Statens Serum Institut, Copenhagen, Denmark
4 Cardiothoracic Division, Queens Medical Centre, Nottingham, UK