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ARVD/C Information Home Page • News
News Archive 1 - December 16, 2005 through September 7, 2006
PRESS RELEASE
Published: September 7, 2006
Johns Hopkins Medicine
Media Relations and Public Affairs
Media contact: David March
410 955 1534; dmarch1@jhmi.edu
Closing in on Lethal Heart Rhythm in Young Athletes:
New findings at Hopkins should improve screening and prevention
Johns Hopkins experts on the genetics of a potentially lethal heart rhythm defect that runs in families and targets young athletes report they have greatly narrowed the hunt for the specific genetic mutations that contribute to the problem.
Their new findings, described in the July issue of the American Journal of Human Genetics, should increase the accuracy of tests to identify those at risk for arrhythmogenic right ventricular dysplasia (ARVD), which is among the top causes of sudden cardiac death in the young and fit.
In February, the same team linked one-third of ARVD cases in their large database of patients to a dozen abnormal changes in a gene called plakophilin-2 (PKP2), which makes proteins involved in heart cell stickiness.
In the new study, confirming experiments elsewhere, the Hopkins team found four mutations in another sticky protein gene, Desmoglein-2 (DSG2), in five of 33 patients tested.
"This gene is highly expressed in the heart, where muscle tissue expands and contracts with the heartbeat," says senior study author and cardiac geneticist Daniel P. Judge, M.D. "Our results confirm that altered genes in the desmosomal cellular complex are responsible for ARVD. And now that we know the genetic roots of this disease, we can also create better blood tests for their proteins to predict who is at risk for developing this condition."
ARVD is characterized by weakness in the desmosome, or cell-to-cell binding structure. The inherited condition leads to the buildup of excess fatty and scar tissue in the heart’s right ventricle, causing irregular beats and – unless diagnosed and treated with drugs or implanted defibrillators – triggering a fatal heart rhythm disturbance.
Judge, an assistant professor at The Johns Hopkins University School of Medicine and its Heart Institute, says DSG2 mutations appear to account for at least 10 percent and possibly more of the estimated 25,000 deaths each year from ARVD.
"We expect a test for DSG2 mutations to be available to those with a family history of the condition before the end of the year," he says. The same Hopkins team developed a blood test to screen for PKP2 mutations. That test became available in May and is currently the only one available for detecting those at greater risk of the disease.
More than 400 people have been screened at Hopkins so far and of these, two-thirds have had serious enough forms of the condition to warrant implantation of a defibrillator, an electrical device that corrects any disturbances in the heart’s rhythm.
The Hopkins researchers identified the DSG2 mutation through genetic analysis of blood taken from 60 men and women already diagnosed with ARVD. All were part of a patient database created at Hopkins in 1998. The researchers focused on cell-adhesion proteins because they had already been linked to Naxos syndrome, which produced symptoms in the right ventricle similar to those documented in ARVD.
When scientists excluded their ARVD patients with PKP2 mutations, they were left with 33 who had no known genetic explanation for their condition. Additional testing revealed the four mutations in DSG2.
"We knew right away that we had found something very significant," says lead author Mark Awad, B.A., a medical and predoctoral sciences student at Hopkins. "The mutations were confined to a highly functional part of the gene and were highly conserved, meaning that evolution had not drastically changed the genetic sequence over time – the gene was kept the way it was because it was important to the heart’s normal function."
According to Awad, not everyone with a genetic mutation develops ARVD. He adds that further analysis of the condition’s genetic roots will help researchers to calculate the precise increased risk from each mutation for developing symptoms and dying. Previous research by the Hopkins team showed that familial ARVD generally strikes after puberty and its symptoms – dizziness, fatigue and fainting after exercise – may appear up to 15 years before diagnosis.
Funding for this study was provided by the Bogle Foundation, the Campanella family, the Wilmerding Endowments, the National Institutes of Health, the Donald W. Reynolds Foundation and the W.W. Smith Charitable Trust.
In addition to Judge and Awad, other researchers involved in this study, conducted solely at Hopkins, were Darshan Dalal, M.D., Ph.D., Eunpi Cho; Nuria Amat-Alarcon, M.S.; Cynthia James, Ph.D.; Crystal Tichnell, M.G.C, Sc.M.; April Tucker, M.G.C.; Stuart Russell, M.D.; David Bluemke, M.D., Ph.D.; Harry Dietz, M.D.; and Hugh Calkins, M.D. Calkins receives research support from device manufacturers Guidant, Medtronic and St. Jude. The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.
To contact Crystal Tichnell of the Johns Hopkins ARVD project:
Email: ctichne1@jhmi.edu
Phone: (410) 502-7161
By MICHELINE LONG
Published: May 10, 2006
News Notes:
• On TV May 11th at 11PM
According to Crystal Tichnell, MGC, Program Coordinator for the Johns Hopkins Hospital ARVD Program:
- "Latenight this Thursday, WJZ-TV (Baltimore's CBS affililiate) will air a story about a new clinical blood test for identifying people at greater risk of developing arrhythmogenic right ventricular dysplasia, or ARVD, a rare heart condition that runs in families and is among the top causes of sudden cardiac death in young athletes. Cardiac geneticist Daniel Judge M.D., an assistant professor at Hopkins who led development of the test which is only available at the Johns Hopkins Hospital, was interviewed for the story that airs at 11 p.m., Thursday, May 11th. Please check your local listings for the newscast."
• Clinical Testing for Plakophilin-2 (PKP2) Now Available at Johns Hopkins
News that clinical testing for plakophilin-2 (PKP2) is now available at Johns Hopkins was recently announced. Physicians can now submit samples for testing. You can learn more about it by clicking this link to go to a Johns Hopkins DNA Diagnostic Laboratory webpage.
Crystal, who is also a genetic counselor, has strongly encouraged individuals who wish clinical testing for PKP2 to undergo genetic counseling prior to being tested. She writes, "ARVD is a very complicated condition and the genetics are even more complicated." Available at the above mentioned "Johns Hopkins DNA Diagnostic Laboratory webpage" is a link to a document entitled, "Things Every Patient Should Know Before Consenting to a Genetic Test."
Genetic testing can bring forth many positive effects. Even so, those of us who have never received such testing are being told that there is a valuable preparation process through counseling, and prior to testing.
By CRYSTAL TICHNELL
Published: April 21, 2006
"Cardio What?: A Kids' Guide to Cardiomyopathy" was written to help children understand their own and/or their family member's diagnosis of cardiomyopathy, particularly inherited forms of cardiomyopathy. The suggested age group for this booklet is 8-13 years old. The booklet is a publication of the National Society of Genetic Counselors (NSGC). The Children's Cardiomyopathy Foundation also provided a grant for the production of this booklet. To order copies of this booklet, please contact the NSGC at FYI@nsgc.org or www.nsgc.org.
By MICHELINE LONG
Published: April 8, 2006
News Notes:
Articles recently published at the online site of "Circulation" reveal that 43% of two groups of ARVD diagnosed patients were affected by the plakophilin-2 (PKP2) gene mutation, while one group was only 14% affected by PKP2. A previously published article noted a study group that was 27% affected:
[Article 1] Mutations in Desmoglein-2 Gene Are Associated With Arrhythmogenic Right Ventricular Cardiomyopathy (Circulation. 2006 Mar 7;113(9):1171-9. Epub 2006 Feb 27.)
[Article 2] Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy (Nat Genet. 2004;36:1162–1164.)
[Article 3] Clinical Features of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Associated With Mutations in Plakophilin-2 (Circulation. 2006 Apr 4;113(13):1641-9. Epub 2006 Mar 20.)
[Article 4] Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy (Circulation. 2006 Apr 4;113(13):1650-8. Epub 2006 Mar 27.)
In article 3, those from the Johns Hopkins University School of Medicine wrote:
- "The purpose of our study was to validate the frequency of PKP2 mutations in another large series of ARVD/C patients and to examine the phenotypic characteristics associated with PKP2 mutations."
- "Until recently, 5 loci and 4 potentially causative genes encoding plakoglobin (JUP), desmoplakin (DSP), transforming growth factor-3 (TGFbeta3), and the cardiac ryanodine receptor RYR2) had been identified. However, only a small subset of ARVC patients showed mutations in these genes."
The recent articles brought forth other interesting information. The US article noted:
- "Presence of a PKP2 mutation in ARVD/C correlates with earlier onset of symptoms and arrhythmia. Patients with a PKP2 mutation experience ICD interventions irrespective of the classic risk factors determining ICD intervention in ARVD/C patients."
Evidently, the researchers in Groningen found otherwise per the onset of symptoms. They wrote:
- "Moreover, the presence or absence of a PKP2 mutation could not be related to age at onset, events during follow-up, or any specific clinical manifestation, except for negative T waves in V2 and V3 that were more frequently encountered in mutation carriers."
- "On the other hand, the absence of PKP2 mutations in nonfamilial ARVC cases suggests the possibility of a nongenetic origin, eg, myocarditis or alternatively a spontaneous mutation in another gene."
The discussion within the article written by those at Johns Hopkins includes the following:
- "The high percentage of patients with ARVD/C who were found to have pathogenic mutation in PKP2 highlights the potential utility of mutation analysis in this gene for families of an individual with ARVD/C. We and others currently recommend that all first-degree relatives of patients with ARVD/C undergo clinical screening for ARVD/C."
What is the significance of the 43% PKP2 gene mutation finding to those with ARVD?
Prior to learning that mutations in PKP2 could account for ARVD/C, only a small percentage of the world's ARVD patient population showed mutations in the known ARVD disease genes. In effect, only a small number of ARVD affected families could benefit from genetic testing. Recent news changes this situation dramatically. Researchers are closing in on the gene mutations that account for ARVD. As they do, and as clinical testing becomes available to find these mutations, more individuals and their families will be able to learn which ARVD disease gene affects them. Learning this opens the doors for a more focussed monitoring of affected family members. It also has the potential to shed light on how a particular form of ARVD, caused by a particular gene mutation, might first reveal itself or affect an individual over the long run.
By MICHELINE LONG
Published: April 5, 2006
Gratitude to Professor Dr. Gian Antonio Danieli of the University of Padua, Italy for providing edits to the following news article.
Another ARVD disease gene has been identified. Researchers have demonstrated that changes, known as "mutations", in the desmoglein-2 (DSG2) gene are associated with ARVD/C. This discovery brings the known number of ARVD disease causing genes to six. Certain mutations in the below listed genes have proven to be responsible for causing the following forms of ARVD:
The March 2006 edition of "Circulation" holds the article, Mutations in Desmoglein-2 Gene Are Associated With Arrhythmogenic Right Ventricular Cardiomyopathy (Pilichou K, Nava A, Basso C, Beffagna G, Bauce B, Lorenzon A, Frigo G, Vettori A, Valente M, Towbin J, Thiene G, Danieli GA, Rampazzo A.) The article is noted as coming "From the Departments of Biology (K.P., G.B., A.L., A.V., G.A.D., A.R.) and Cardiothoracic-Vascular Sciences (A.N., B.B., G.F.) and the Institute of Pathology (C.B., M.V., G.T.), University of Padua Medical School, Padua, Italy; and Department of Pediatrics, Section of Cardiology, Baylor College of Medicine, Houston, Tex (J.T.)."
This collaborative study was supported by NIH Grant U04 65652, by Italian Funds and by funds from European Community.
The following rather difficult text appears to explain "why" researchers pursued a study which eventually found DSG2 as an ARVD disease gene:
- "On the basis of previous findings on desmosomal genes involved in ARVC and on DSG2 expression in myocardial tissue, we hypothesized that mutations in human DSG2 could account for ARVC."
Prior to the study, the involved researchers were aware of several important facts. They knew that past scientific findings had proven that some forms of ARVD were due to mutations found in three genes (Plakoglobin, Desmoplakin and Plakophilin2) encoding proteins involved in “desmosomes”( molecular junctions which hold cells together). The researchers hypothesized that mutations in additional genes encoding proteins of desmosomes could lead to a similar effect, i.e. ARVD. Therefore, they attemped to analyze the gene Desmoglein-2 (DSG2) in a series of patients affected by ARVD.
Through a study approved by the University of Padua Medical School, 80 unrelated ARVD/C patients were screened for mutations in the "coding regions" of 3 of the known ARVD disease genes (DSP, PKP2, and TGFbeta3.) Screening for mutations in the other 2 ARVD disease genes, RyR2 and plakoglobin, was not done. This was because certain characteristics of the ARVD associated with RyR2 and plakoglobin were not found in the study subjects; none of them had "effort-induced polymorphic ventricular arrhythmias or gross skin and hair abnormalities."
The study's first screening for gene mutations located the disease genes responsible for the ARVD in 26 study subjects, those representing approximately one third (32.5%) of the study group. Thirteen patients, 16% of the group, were found to carry a mutation in DSP. Eleven patients, 14% of the group, were found to carry a mutation in PKP2. Finally, two patients, representing 2.5% of the group, were found with a mutation in TGFbeta3.
With the disease causing gene mutations of 54 study subjects yet unfound, the researchers screened for a possible mutation in desmoglein-2. Eight of the 54 patients, 10% of the study group, were found with one. The hypothesis of the researchers was correct, the study proved that mutations in human DSG2 could account for ARVC.
Noted in the conclusion of the article is this:
- "This is the first investigation demonstrating DSG2 gene mutations in a significant number of ARVC-unrelated probands. Cardiac phenotype is characterized clinically by typical ARVC features with frequent left ventricular involvement and morphologically by fibrofatty myocardial replacement and desmosomal remodeling. The presence of mutations in desmosomal encoding genes in 40% of cases confirms that many forms of ARVC are due to alterations in the desmosome complex."
As more disease causing genes are identified, more of those who have been diagnosed with ARVD will have the opportunity to learn which gene mutation has affected them. Once genetic testing locates the ARVD disease gene carried by one family member, other family members can be tested in order to learn if they are also carriers of the affected gene. The object of testing will be to detect which family members have the potential to develop ARVD. Not all carriers will do so. The hope is that the attentive and focussed monitoring of carriers will facilitate the earliest possible detection of a developing case of ARVD. Once ARVD has been detected, treatment can be determined. Ultimately, early detection and treatment of ARVD will prevent Sudden Death.
By MICHELINE LONG
Published: December 16, 2005
On December 13, 2005, an article was published on ConsumerAffairs.com. Entitled, Study Describes Dangerous Heart Condition in Young Athletes, Fainting In Connection with Exercise a Warning Sign, the article begins:
- "A Johns Hopkins study has provided the most comprehensive description to date of people most likely to develop a relatively rare heart condition, called arrhythmogenic right ventricular dysplasia (ARVD), known to be among the top causes of sudden cardiac death among young athletes."
Dr. Hugh Calkins of the Johns Hopkins ARVD Project is quoted as saying, "physicians need to know that this is a serious disease, and they should be on the lookout for its early signs and symptoms because it is an important cause of sudden cardiac death in apparently healthy young individuals." At this point in time, the symptoms that people are told to watch for are those that are "known or recognized" including palpitations (irregular or skipping heart beats), dizziness and fainting.
The article quotes Dr. Calkins as saying, "Preventive treatment with an implantable defibrillator appears to eliminate the risk of sudden death." In an article published in Current Treatment Options in Cardiovascular Medicine on December 7th, 2005, and written by Dr. KR Prakasa and Dr. Calkins of Johns Hopkins Hospital, it states:
- "We also recommend treatment of patients with ARVD/C with beta blockers and angiotensin-converting enzyme inhibitors."