- Email: [email protected]
Entwining electrical and hypertrophic cardiomyopathies
EDITORIAL COMMENTARY
Entwining electrical and hypertrophic cardiomyopathies Mark Alexander, MD From the Cardiology Department–EP Service, Children’s Hospital, Boston, Massachusetts. In 1991, Keating et al1 shifted the paradigm of heritable arrhythmias by identifying the linkage of familial long QT syndrome and the Harvey ras-1 gene. Rapidly the most common forms of heritable ion channel defects were described by genetic location, functional analysis, and clinical phenotype. These ion channel defects, which now include Brugada syndrome, Anderson syndrome and catecholaminergic polymorphic ventricular tachycardia, can be viewed primarily as electrical diseases or “electrical myopathies.” Parallel to these efforts were similar insights into the range of primary cardiomyopathies. Identifying defects initially in -myosin heavy chains and troponin I and now in multiple other sarcomeric proteins defined hypertrophic cardiomyopathy as a disease of sarcomeric proteins. Concurrent identification of the range of genetic deletions in less common variants of hypertrophic cardiomyopathy and in many dilated cardiomyopathies has increasingly shown both the underlying genetic nature and the heterogeneity of the disorders.2 In this issue of Heart Rhythm, Lo-A-Njoe et al3 describe two infants with isolated G406R missense mutation in the CaV1.2 L-type channel. Both infants had profound QT prolongation producing functional 2:1 AV block and subsequent polymorphic ventricular tachycardia. This study represents independent confirmation of the first variant of Timothy syndrome identified. The initial cellular and genetic description of Timothy syndrome was associated with a missense mutation to G406R in the CaV1.2 L-type channel.4 Splawski et al5 subsequently identified a more severe subtype (TS2) in which a second CaV1.2 mutation, G402R, produces more dramatic QT prolongation. These two new patients, whose QT intervals are longer and may have more spontaneous arrhythmia and 2:1 block than “typical” Timothy syndrome, raise the possibility of a second concomitant mutation that was not recognized. In the least it expands the range of arrhythmia severity associated with Timothy syndrome. Unlike patients with more typical long QT syndrome, the nearly 20 patients with Timothy syndrome described had significant hypertrophic myopathy with marked ventricular hypertrophy, decreased left ventricular systolic function, Address reprint requests and correspondence: Dr. Mark Alexander, Cardiology Department–EP Service, Children’s Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115. E-mail address: [email protected].
and congestive symptoms. In addition, frequent congenital heart disease and often central nervous system involvement with a spectrum of autism diagnoses were observed. Multiple dysmorphic features (notably syndactyly), when present, represent a potentially visible cardinal feature of this disorder, although interestingly they are absent in the two infants with combined G406R/G402R deletion. Management of patients with Timothy syndrome has been challenging, with high mortality observed. Combinations of pacing, sodium channel blockade with mexiletine, -adrenergic blockade, cervical sympathetectomy and, in infant 2, a nontransvenous implantable cardioverter-defibrillator may permit continued survival without risk of hypoxic-ischemic brain injury. Through management of life-threatening arrhythmias, multisystem involvement has become even more apparent with a spectrum of autistic behavior, despite the absence of hypoxic injury. With commercial testing now available for up to 75% of long QT genes, the clinician may ask why a case report of two more patients with an exceptionally rare disease is important. Commercially available tests are highly effective in identifying the common mutations in the majority of patients, and their positive predictive value is outstanding. However, commercial tests rely on patient selection for its negative predictive value. Indeed, the initial screening of Timothy syndrome patients, which included sequencing of known long QT genes, was not successful. Despite the negative testing, however, there was little clinical doubt that the patients shared an underlying disorder. Although rare, the clinical picture of these patients is reasonably distinct and likely will be recognized by experienced groups, if not as Timothy syndrome then at least as a severe, multisystem, probably genetic disorder. Management likely will remain somewhat empiric, drawing on prior knowledge of long QT syndrome. Identifying the role of calcium in this disorder raises the possibility that calcium channel blockers decrease the QT interval and hence the risk of torsades de pointes and 2:1 block. The empiric trial awaits further patients; therefore, both diagnosis and management have not been significantly altered by the genetic diagnosis. The continued evaluation and reporting of uncommon and distinctive patterns of ion channel defects have shaped our understanding of the nature of these disorders. With Timothy syndrome, our understanding focuses on the following. (1) Potentially lethal abnormalities of cardiac repo-
1547-5271/$ -see front matter © 2005 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2005.10.026
1370 larization can result from alterations in potassium, sodium, and now multiple calcium channels. (2) There are multiple examples of relatively arrhythmogenic ion channel defects without other cardiomyopathy and separate sarcomeric and other protein defects inducing cardiomyopathy with subsequent arrhythmia. Timothy syndrome represents an example of a defect that can induce arrhythmia mediated by specific cellular abnormalities (as opposed to macroreentry from hypertrophy/fibrosis/fatty infiltrate) and at the same time can induce global abnormalities in heart muscle function. (3) Effective management of the most life-threatening aspects of a disease, in this case the arrhythmia, may permit characterization of the longer-term consequences of those defects. Finally, this experience reaffirms what is rapidly becoming an axiom in medicine—that relatively similar phenotypes may result from distinct and previously unrecognized gene defects. The clinical implication remains that, given a compelling clinical diagnosis, therapy is directed at those findings. In parallel, we encourage and applaud our more laboratory-focused colleagues for exploring new options in their patients. For Timothy syndrome, the widely
Heart Rhythm, Vol 2, No 12, December 2005 branching “family trees” of electrical and classic cardiomyopathy show some entwining.
References 1. Keating M, Atkinson D, Dunn C, Timothy K, Vincent G, Leppert M. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science 1991;252:704 –706. 2. Antzelevitch C. Molecular genetics of arrhythmias and cardiovascular conditions associated with arrhythmias. J Cardiovasc Electrophysiol 2003;14:1259 –1272. 3. Lo-A-Njoe SM, Wilde AA, van Erven L, Blom NA. Syndactyly and long QT syndrome (CaV1.2 missense mutation G406R) is associated with hypertrophic cardiomyopathy. Heart Rhythm 2005;2:1365–1368. 4. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K, Tager-Flusberg H, Priori SG, Sanguinetti MC, Keating MT. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004;119:19 –31. 5. Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH Sanguinetti MC, Keating MT. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci U S A 2005;102:8089 – 8096.
Entwining electrical and hypertrophic cardiomyopathies Mark Alexander, MD From the Cardiology Department–EP Service, Children’s Hospital, Boston, Massachusetts. In 1991, Keating et al1 shifted the paradigm of heritable arrhythmias by identifying the linkage of familial long QT syndrome and the Harvey ras-1 gene. Rapidly the most common forms of heritable ion channel defects were described by genetic location, functional analysis, and clinical phenotype. These ion channel defects, which now include Brugada syndrome, Anderson syndrome and catecholaminergic polymorphic ventricular tachycardia, can be viewed primarily as electrical diseases or “electrical myopathies.” Parallel to these efforts were similar insights into the range of primary cardiomyopathies. Identifying defects initially in -myosin heavy chains and troponin I and now in multiple other sarcomeric proteins defined hypertrophic cardiomyopathy as a disease of sarcomeric proteins. Concurrent identification of the range of genetic deletions in less common variants of hypertrophic cardiomyopathy and in many dilated cardiomyopathies has increasingly shown both the underlying genetic nature and the heterogeneity of the disorders.2 In this issue of Heart Rhythm, Lo-A-Njoe et al3 describe two infants with isolated G406R missense mutation in the CaV1.2 L-type channel. Both infants had profound QT prolongation producing functional 2:1 AV block and subsequent polymorphic ventricular tachycardia. This study represents independent confirmation of the first variant of Timothy syndrome identified. The initial cellular and genetic description of Timothy syndrome was associated with a missense mutation to G406R in the CaV1.2 L-type channel.4 Splawski et al5 subsequently identified a more severe subtype (TS2) in which a second CaV1.2 mutation, G402R, produces more dramatic QT prolongation. These two new patients, whose QT intervals are longer and may have more spontaneous arrhythmia and 2:1 block than “typical” Timothy syndrome, raise the possibility of a second concomitant mutation that was not recognized. In the least it expands the range of arrhythmia severity associated with Timothy syndrome. Unlike patients with more typical long QT syndrome, the nearly 20 patients with Timothy syndrome described had significant hypertrophic myopathy with marked ventricular hypertrophy, decreased left ventricular systolic function, Address reprint requests and correspondence: Dr. Mark Alexander, Cardiology Department–EP Service, Children’s Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115. E-mail address: [email protected].
and congestive symptoms. In addition, frequent congenital heart disease and often central nervous system involvement with a spectrum of autism diagnoses were observed. Multiple dysmorphic features (notably syndactyly), when present, represent a potentially visible cardinal feature of this disorder, although interestingly they are absent in the two infants with combined G406R/G402R deletion. Management of patients with Timothy syndrome has been challenging, with high mortality observed. Combinations of pacing, sodium channel blockade with mexiletine, -adrenergic blockade, cervical sympathetectomy and, in infant 2, a nontransvenous implantable cardioverter-defibrillator may permit continued survival without risk of hypoxic-ischemic brain injury. Through management of life-threatening arrhythmias, multisystem involvement has become even more apparent with a spectrum of autistic behavior, despite the absence of hypoxic injury. With commercial testing now available for up to 75% of long QT genes, the clinician may ask why a case report of two more patients with an exceptionally rare disease is important. Commercially available tests are highly effective in identifying the common mutations in the majority of patients, and their positive predictive value is outstanding. However, commercial tests rely on patient selection for its negative predictive value. Indeed, the initial screening of Timothy syndrome patients, which included sequencing of known long QT genes, was not successful. Despite the negative testing, however, there was little clinical doubt that the patients shared an underlying disorder. Although rare, the clinical picture of these patients is reasonably distinct and likely will be recognized by experienced groups, if not as Timothy syndrome then at least as a severe, multisystem, probably genetic disorder. Management likely will remain somewhat empiric, drawing on prior knowledge of long QT syndrome. Identifying the role of calcium in this disorder raises the possibility that calcium channel blockers decrease the QT interval and hence the risk of torsades de pointes and 2:1 block. The empiric trial awaits further patients; therefore, both diagnosis and management have not been significantly altered by the genetic diagnosis. The continued evaluation and reporting of uncommon and distinctive patterns of ion channel defects have shaped our understanding of the nature of these disorders. With Timothy syndrome, our understanding focuses on the following. (1) Potentially lethal abnormalities of cardiac repo-
1547-5271/$ -see front matter © 2005 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2005.10.026
1370 larization can result from alterations in potassium, sodium, and now multiple calcium channels. (2) There are multiple examples of relatively arrhythmogenic ion channel defects without other cardiomyopathy and separate sarcomeric and other protein defects inducing cardiomyopathy with subsequent arrhythmia. Timothy syndrome represents an example of a defect that can induce arrhythmia mediated by specific cellular abnormalities (as opposed to macroreentry from hypertrophy/fibrosis/fatty infiltrate) and at the same time can induce global abnormalities in heart muscle function. (3) Effective management of the most life-threatening aspects of a disease, in this case the arrhythmia, may permit characterization of the longer-term consequences of those defects. Finally, this experience reaffirms what is rapidly becoming an axiom in medicine—that relatively similar phenotypes may result from distinct and previously unrecognized gene defects. The clinical implication remains that, given a compelling clinical diagnosis, therapy is directed at those findings. In parallel, we encourage and applaud our more laboratory-focused colleagues for exploring new options in their patients. For Timothy syndrome, the widely
Heart Rhythm, Vol 2, No 12, December 2005 branching “family trees” of electrical and classic cardiomyopathy show some entwining.
References 1. Keating M, Atkinson D, Dunn C, Timothy K, Vincent G, Leppert M. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science 1991;252:704 –706. 2. Antzelevitch C. Molecular genetics of arrhythmias and cardiovascular conditions associated with arrhythmias. J Cardiovasc Electrophysiol 2003;14:1259 –1272. 3. Lo-A-Njoe SM, Wilde AA, van Erven L, Blom NA. Syndactyly and long QT syndrome (CaV1.2 missense mutation G406R) is associated with hypertrophic cardiomyopathy. Heart Rhythm 2005;2:1365–1368. 4. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K, Tager-Flusberg H, Priori SG, Sanguinetti MC, Keating MT. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004;119:19 –31. 5. Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH Sanguinetti MC, Keating MT. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci U S A 2005;102:8089 – 8096.