Copyright © 2006, European Society of Cardiology
Why the Brugada syndrome is not yet a disease: Syndromes, diseases, and genetic causality
From the Experimental and Molecular Cardiology groups, the Academic Medical Center Amsterdam, The Netherlands
* Corresponding author. Department of Experimental Cardiology, Academic Medical Center, Rm M0-108, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel.: +31 20 566 3267; fax: +31 20 697 5458. Email address: r.coronel{at}amc.uva.nl
Received 27 June 2006; revised 15 August 2006; accepted 12 September 2006
A syndrome is a collection of symptoms and clinical signs that often occur in concert and suggest a common cause. Contrary to a disease, the cause–effect relations and pathophysiological mechanisms of syndromes are unknown or at least incompletely understood. The unveiling of pathophysiological mechanisms underlying a syndrome is one of the most rewarding accomplishments of biomedical research. Definitions of a syndrome are often disputed (see, for example, the definition of heart failure [1]), and its identifying signs may change.
In some syndromes an association exists with a genetic mutation that is present in only a minority of patients. This apparent discrepancy can indicate that 1) standard genetic screening methods fail to detect mutations; 2) other (genetic) factors are required; 3) the genetic mutation establishes a modulating factor that is not causative but occurs in a higher frequency in the syndrome population. We will expand on these issues below.
Failure to detect a mutation can result from methodological limitations. Koopmann et al. described a duplication of a large part of the DNA sequence in the gene encoding the pore-forming channel subunit for the rapidly activating delayed rectifier K+ current [2]. The mutation was present in a family with long QT syndrome (LQTS) [2]. Aberrancies of this type are not detected by conventional mutation screening techniques. Other causes for detection failure are the size of the gene, which practically prohibits mutation screening (e.g. RyR2 in arrhythmogenic right ventricular cardiomyopathy/dysplasia) [3], or incomplete knowledge of intronic and/or promoter regions.
Second, the inferential presence of other (genetic) factors may explain the weak association between a syndrome and a genetic mutation. One can argue that the other factor then presents the true cause and that the initial mutation acts as a modifier. If the mutation is present in a high percentage of patients, it may act as a ‘second hit’ required for the expression of the phenotype. The latter appears to be the case with a mutation in Janus kinase-2 that occurs in various proportions in patients with different expressions of myeloproliferative disorder (MPD). In pairs of siblings belonging to a family with MPD and of which both members were affected with a form of the disease, only those with a Janus kinase-2 mutation had polycytemia vera [4]. This suggests that the primary cause for the MPD still needs to be identified and that the mutation is a ‘second hit’ required for one of the forms the disorder [4].
Multicausality may also partly explain the differences in disease penetrance and expression among known mutation carriers. For example, acquired LQTS is a common life-threatening disorder with uncertain etiologies that shares extensive clinical features with congenital LQTS. Individuals with normal or borderline QT interval may carry subclinical mutations in genes associated with LQTS, which makes them susceptible to life-threatening arrhythmias upon drug exposure [5]. Likewise, sequence variations in KCNH2 may potentially contribute to Brugada syndrome [6]. Another example is found in a haplotype in the promoter of SCN5A that can exacerbate conduction slowing in individuals with Brugada syndrome both with and without a mutation in that gene [7].
Third, if one of the criteria of a syndrome selects for a particular type of dysfunction that is causally unrelated or indirectly linked to the other criteria, a higher percentage of mutations related to this particular dysfunction will occur in the syndrome population than in the general population. With increasing stringency of the syndrome's criteria, the percentage of these mutations in the selected population will increase as well. This may suggest causality that may not be present.
An illustration of the difficulty in relating genetic defects to a syndrome is the Brugada syndrome, originally described with the criteria right precordial ST-segment elevation, bundle branch block, ventricular life-threatening arrhythmias, no structural cardiac abnormalities, and a familial occurrence [8]. These criteria suggested a genetic cause and a localized dysfunction in the right ventricular wall. The syndrome is associated with mutations in the cardiac sodium channel encoding gene SCN5A [9]. It was hypothesized that a potential mechanism of the arrhythmias is that of increased transmural dispersion of repolarization caused by reduced sodium channel function leading to phase-2 reentry [10]. The specific anatomic structure of the right ventricular outflow tract explained why this dispersion was not present in the entire heart [10]. Recently, criteria for the Brugada syndrome were extended and now include a provocation test and specific morphologies and amplitudes of the ST–T segments [10].
The Brugada syndrome is associated with sodium channel mutations in only 20% of patients. The matter of causality in the Brugada syndrome has not yet been resolved [11,12]. Probst et al. have described 11 families with carriers of sodium channel mutations and were not able to demonstrate a statistical link between the SCN5A mutation and Brugada syndrome [12]. Acquired forms of Brugada syndrome also exist [13]. Nevertheless, the Brugada syndrome is ranked among the ‘channelopathies’ as a disease caused by sodium channel dysfunction together with some of the congenital long QT syndromes [14].
The three explanations given above for the weak association between a syndrome and mutations should be considered for the Brugada syndrome. Replications, promoter mutations, or gross recombinational events at the SCN5A locus have not been reported, and the search for other (genetic) factors has not come to a clear conclusion. Nevertheless, the Brugada syndrome may act as a paradigm for the third explanation, selection.
Recently, it has been shown that the syndrome is related to structural abnormalities in the right ventricular wall [15,16]. These structural abnormalities are probably minute and dispersed and may not be detected by standard clinical investigation [15–17]. Structural myocardial alterations may cause conduction delay by increasing the length of the conduction pathways [18] or by branching of the activation waves (‘load mismatch’). Computer simulation studies have demonstrated that right precordial ST segment elevation, a central criterion of the Brugada syndrome, may be caused by localized conduction delay [15]. The criterion of ST segment elevation alone may thus select patients with conduction delay of any origin, genetic, structural, or pharmacological. As a consequence, the percentage of patients with cardiac sodium channel mutations is higher in the syndrome population than in the general population. This suggests a causal relationship between the mutation and the Brugada syndrome that may not exist. Understandably, provocation tests with a sodium channel blocker promote detection of the Brugada syndrome.
If the selection principle is operative in the Brugada syndrome, the percentage of mutations should be higher in the population conforming to the more stringent criterion of spontaneous right precordial ST segment elevation than in those patients with ST elevation only after a provocation test. This would not be the case if the SCN5A mutation were causally linked to the syndrome. It may also be postulated that in patients with SCN5A-associated Brugada syndrome, the structural changes are less evident than in those Brugada syndrome patients without a SCN5A mutation, because the former need a ‘second hit’ for the emergence of the critical signs that compose the syndrome. No data on these issues are presently available. Therefore, a positive genetic test involving the SCN5A gene can only be part of the diagnostic approach in the Brugada syndrome. It remains to be established whether the selection mechanism is operative in the Brugada syndrome and whether it can account for the higher incidence of mutations in the syndrome population compared to the general population.
An association between mutations and syndromes does not necessarily establish a cause–effect relationship. Classifying the Brugada syndrome as a disease (‘channelopathy’) caused by a cardiac sodium channel mutation is therefore premature.
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Acknowledgement |
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The authors gratefully acknowledge Michiel J. Janse for critically reading the manuscript.
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