Correspondence
The Long-QT Syndrome
N Engl J Med 2000; 342:514-515February 17, 2000
- Article
To the Editor:
Ackerman et al. (Oct. 7 issue)1 describe extensive molecular analyses in a young woman who died suddenly as a result of the long-QT syndrome. They discovered a mutation in a gene encoding a cardiac ion channel that led to the correct diagnosis and treatment of an 18-year-old sibling who had a borderline prolongation of the QT interval corrected for heart rate (QTc). Even though the authors acknowledge that molecular testing is available only as a research tool, a reader might have the mistaken impression that it should now be part of routine evaluation on the basis of the following information in the report. The sibling's QTc was initially judged to be abnormal or equivocal by four of eight cardiologists, but only two recommended treatment. Once the results of DNA analysis were known, all eight cardiologists recommended treatment and three recommended the use of an internal cardioverter–defibrillator. This change in opinion highlights the main problem for clinicians dealing with a family with probable long-QT syndrome: there is no consensus on the QTc cutoff value for classifying a person as being at high risk for the long-QT syndrome, making cardiologists reluctant to rely on the QTc alone.
It is important to note that even when molecular testing can be arranged, an identifiable mutation will be found in only half to three quarters of the families with the long-QT syndrome. Thus, measuring the QT interval remains the only viable diagnostic test, even though it is less than perfect. In the case of a family in which the proband has a prolonged QTc and dies suddenly, the QTc cutoff value can be set lower for other family members than it would be in a low-risk population. In the article by Ackerman et al., the QTc in the 18-year-old sibling was 0.45 second1/2.
Vincent et al.2 studied persons with a documented mutation in a gene for a cardiac ion channel (KVLQT1) and their unaffected relatives. A QTc of 0.45 was noted in 78 of 83 affected persons (94 percent), with a false positive rate of 15 percent. Therefore, for every 100 first-degree relatives of index patients, 47 of 50 with the long-QT syndrome would be correctly identified, whereas 7 of 50 unaffected family members would be incorrectly identified as having the syndrome. Since beta-blockers are well tolerated and largely successful in preventing sudden death, an approach that involves giving medication to one unaffected person for every seven affected persons appears to be justified. In order to be effective, this type of approach would need to be generally agreed on. It may be time for practice guidelines to be developed by the American College of Cardiology and the American Heart Association.
2 ReferencesWalter C. Allan, M.D.
Foundation for Blood Research, Scarborough, ME 040741
Ackerman MJ ,Tester DJ ,Porter CJ ,Edwards WD . Molecular diagnosis of the inherited long-QT syndrome in a woman who died after near-drowning. N Engl J Med 1999;341:1121-1125
Full Text | Web of Science | Medline2
Vincent GM ,Timothy KW ,Leppert M ,Keating M . The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. N Engl J Med 1992;327:846-852
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Dr. Allan's comments reflect the promise and peril of genetic testing for the inherited long-QT syndrome. As we reported, genetic studies identified a mutation causing the long-QT syndrome and established a probable cause for the near-drowning and subsequent death of a previously healthy woman. The identification of this genetic defect allowed us to identify the syndrome in an asymptomatic sister of the patient, despite equivocal findings on electrocardiography. The test result also had a profound impact on the recommendations made by eight cardiologists who specialized in clinical electrophysiology. It is in this respect that the effect of genetic testing on clinical management requires clarification.
On review of the sister's electrocardiogram and QTc (which was 0.45 second1/2), only one of the cardiologists judged it to be definitely abnormal; three considered it equivocal (borderline), and four considered it entirely normal. In the absence of the genetic test results, only two of the eight recommended beta-blocker therapy, whereas there was a unanimous recommendation for such therapy after it was revealed that the sister shared the index patient's genetic defect. Clearly, the promise of molecular genetic testing is reflected by this family's tragedy: it proved to be a 100 percent sensitive and specific diagnostic marker; it identified persons potentially at risk before the occurrence of an adverse event, which in turn led to the use of prophylactic medication; and it contributed to the forensic evaluation of a patient with sudden, unexplained death.
Because of the profound impact of molecular genetic testing, we and others are screening for mutations in five genes associated with the long-QT syndrome on a research basis. Unfortunately, even if (or when) such methods become technically simpler and faster, the results of genotyping will be only 50 percent sensitive, since these five genes represent only half those associated with the long-QT syndrome. This point has led Dr. Allan to conclude that “measuring the QT interval remains the only viable diagnostic test, even though it is less than perfect.” Although 12-lead electrocardiography may be the only practical diagnostic test, we find its use entirely dissatisfying and insufficient in families such as that of our patient, in which the stakes are so high.
Persons with a false positive result would be committed to a lifetime of unnecessary medication. As “well tolerated” as beta-blockers may be, they are not without side effects. In addition, the lifetime prohibition against engaging in competitive sports that specialists feel obligated to impose on these patients has a very real effect, though one that is difficult to measure. For persons with false negative results, there is the potential of sudden death from cardiac causes. Ultimately, the promise of and hope for the future of these families lie in the use of molecular genetic testing.
Michael J. Ackerman, M.D., Ph.D.
Co-burn J. Porter, M.D.
Mayo Clinic and Foundation, Rochester, MN 55905
