To the Editor: The long-QT syndrome and catecholaminergic polymorphicventricular tachycardia are the most common inherited cardiacchannelopathies.1 Although the disease mechanisms for thesetwo disorders differ, the resulting arrhythmias are similar,and both are triggered by sympathetic stimulation.2,3 We identifiedthe coexistence of the two diseases in one family.
A family with a history of recurrent sudden death was studied.During the past 30 years, nine members have died suddenly between7 and 40 years of age. A borderline QT interval corrected forheart rate (QTc) of 450 msec in one asymptomatic relative (identifiedas V-1 in Figure 1) was noted. Genetic testing revealed a heterozygousmutation in KCNQ1 (1343delC, p.P448fsX465), confirming the diagnosisof the long-QT syndrome type 1.4 A diagnostic molecular testfor this mutation was therefore performed in all consentingfamily members.
Figure 1. Key Extract of the Pedigree of Five Generations of a Family with the Long-QT Syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia.
Circles indicate female family members, squares male family members, solid symbols clinically affected family members, and open symbols clinically unaffected family members. Deceased family members are indicated by slashes through the symbols. Symbols with squares within squares and squares within circles indicate obligate carriers. Diamonds indicate persons for whom sex was unknown. The upper symbol below a circle or square indicates the presence (+) or absence (–) of the KCNQ1 mutation, and the lower symbol indicates the presence (+) or absence (–) of the RYR2 mutation in persons who underwent DNA testing. The boxed area is the part of the family in which the KCNQ1 mutation was introduced by marriage.
Subsequently, one girl (identified as V-13 in Figure 1) whodid not inherit the KCNQ1 mutation died suddenly at 13 yearsof age. In addition, several other noncarriers had symptomssuch as syncope. Resting electrocardiograms (ECGs) from thesefamily members did not show any abnormalities. During exercisestress testing, premature ventricular beats were detected. Asecond familial disorder was suspected. Therefore, family memberswere evaluated to identify members meeting the following criteria:symptoms or sudden death during sympathetic stimulation, normalfindings on a resting ECG, the absence of structural cardiacabnormalities, and premature ventricular beats during exercise.
A pedigree analysis indicated that the second disorder was characterizedby autosomal dominant inheritance. Given the propensity forsudden death during sympathetic stimulation in the absence ofstructural heart disease, catecholaminergic polymorphic ventriculartachycardia was considered to be the likely diagnosis. Sequencingof the cardiac ryanodine receptor 2 (RYR2) gene5 (the locusaffected in catecholaminergic polymorphic ventricular tachycardia)revealed a novel heterozygous mutation affecting the FKBP12.6-bindingdomain (c.7210CA, p.P2404T) that cosegregated with the phenotype.This mutation was absent in 200 healthy controls.
One living family member is a carrier of both mutations. Shehas clinical characteristics that are consistent with both disorders(i.e., a borderline QTc of 447 msec and premature ventricularbeats at a heart rate of 100 beats per minute). Despite therapywith beta-blockers, she had a sudden cardiac arrest at 17 yearsof age from which she was successfully resuscitated.
Our findings underscore the fact that even when a known geneticdisorder is present in a family, other clinically significantconditions may coexist. When there is doubt, the willingnessto reevaluate and explore alternative genetic diseases mightbe the key to putting together the pieces of a complex puzzle.
Britt M. Beckmann, M.D. Ludwig-Maximilians-Universität 81377 Munich, Germany brittmaria.beckmann{at}med.uni-muenchen.de
Arthur A.M. Wilde, M.D., Ph.D. Academic Medical Center 1100 DE Amsterdam, the Netherlands
Stefan Kääb, M.D., Ph.D. Ludwig-Maximilians-Universität 81377 Munich, Germany
Supported by a grant (05-CVD 01, to Drs. Wilde and Kääb)from the Leducq Foundation, Paris.
Dr. Kääb reports receiving a grant (BMBF 01-G50499)from the National Genome Research Network. No other potentialconflict of interest relevant to this letter was reported.
References
Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol 2006;48:e247-e346. [Free Full Text]
Priori SG, Napolitano C, Tiso N, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 2001;103:196-200. [Free Full Text]
Neyroud N, Richard P, Vignier N, et al. Genomic organization of the KCNQ1 K+ channel gene and identification of C-terminal mutations in the long-QT syndrome. Circ Res 1999;84:290-297. [Free Full Text]
Postma AV, Denjoy I, Kamblock J, et al. Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients. J Med Genet 2005;42:863-870. [Free Full Text]
A, p.P2404T) that cosegregated with the phenotype. This mutation was absent in 200 healthy controls. 
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