AUGUST 2004 VOLUME 2, ISSUE 8 P E D I A T R I C CARDIOLOGY TODAY RELIABLE INFORMATION IN PEDIATRIC CARDIOLOGY By Jeffrey A. Towbin, MD Over the past fifteen years, the genetic basis of various forms of heart disease have been studied and increased levels of understand- ing of the causes of these clinical disorders, the mechanisms of disease and clinical risk stratification have been gained. In this brief review, the current knowledge regarding the genetic basis of cardiomyopathies, arrhyth- mia disorders, and congenital heart disease will be described. In addition, insight into the use of this information for clinical care will be provided. CARDIOMYOPATHIES These disorders are classified into separate functional types including: 1. Dilated Cardiomyopathy (DCM). 2. Hypertrophic Cardiomyopathy (HCM). 3. Restrictive Cardiomyopathy (RCM), and (4) Arrhythmogenic Right Ventricular Dysplasia/cardiomyopathy (ARVD/C).(1) In addition, several other forms exist including Left Ventricular Noncompac- tion (LVNC) and overlap disorders with mixed functional types.(1) The genetic basis of these disorders has been studied since the late 1980s and pro- gress has been made for all forms. Hypertrophic Cardiomyopathy (HCM): This disorder, characterized by left ventricu- lar hypertrophy, systolic hypercontractility and diastolic dysfunction associated with myofiber disarray, is the most common cause of sudden death in young healthy sub- jects in the United States, particularly during athletics.(2) Genetic linkage studies initially demonstrated genetic heterogeneity; in other words, multiple different genetic loci on mul- tiple different chromosomes and a variety of different mutant genes leading to clinically similar disorders.(3) The first gene, b- myosin heavy chain, located on chromosome 14, was first identified by the Seidman Labo- ratory in Boston and was followed by the identification of 9 other genes.(3) In all cases, these genes encode sarcomeric pro- teins and include cardiac actin, cardiac tro- ponin T, cardiac troponin I, a-tropomyosin, myosin- binding protein C, titin, the essential and regulatory myosin light chains, and mus- cle LIM protein. Recently, non-sarcomere protein-encoding genes, including AMP kinase(4) and the a-iduronidase gene caus- ing Fabry Disease,(5) have been identified. Genotype-phenotype correlations were ini- tially performed on b-myosin heavy chain, a- tropomyosin, myosin binding protein C, and cardiac troponin T and differences in age of onset, severity of hypertrophy, and survival was reported.(6),(7) However, the studies were performed on a small number of geno- typed individuals and may not be representa- tive. Recently, Dr. Michael Ackerman’s labo- ratory has reported that many of these initial contributions are patient specific and not gene- or mutation-specific with clinical find- ings widely varying among mutated individu- als.(8) Therefore, risk stratification on the basis of genotype is fraught with danger. In addition, no clinical test for genetic screening of the HCM-causing genes has been avail- able to date, but a diagnostic laboratory in Boston is expected to begin to offer a fee- for-service genetics screen in the near fu- ture. Dilated Cardiomyopathy (DCM): This dis- order is characterized by a dilated left ventri- cle with systolic dysfunction.(1) Mitral regur- gitation and ventricular arrhythmias may be associated. Studies of the genetic basis of DCM were relatively slow to get underway, in part due to the late recognition that this dis- ease was genetically based. To date, nearly INSIDE THIS ISSUE Genetics of Heart Disease by Jeffrey A. Towbin, MD 1 Highlights of The American Society of Echocardiography’s 15th Annual Scientific Sessions 9 Highlights of the 2004 Barth Syndrome International Scientific/Medical and Family Conference by David G. Soergel, MD 11 Arthur J. Moss, UCLA Pediatric Cardiology Pioneer, Dies at 90 15 DEPARTMENTS Medical Conferences 8 Useful Websites 10 GENETICS OF HEART DISEASE PEDIATRIC CARDIOLOGY TODAY 9008 Copenhaver Drive, Ste. M Potomac, MD 20854 U.S.A. www.PediatricCardiologyToday.com © 2004 by Pediatric Cardiology Today (ISSN 1551-4439). Published monthly. All rights reserved. Statements or opin- ions expressed in Pediatric Cardiology Today reflect the views of the authors and are not necessarily the views of Pediatric Cardiology Today. WWW.PEDIATRICCARDIOLOGYTODAY.COM “The key to understanding the causes of heart disease at the molecular level is now coming to the end of phase 1, the identification of the genes involved.”
