Updated December 2006
Andrew D. Krahn MD FRCPC
Coworkers:
| Michael Gollob MD* | Cardiology |
George J. Klein MD | Cardiology |
Allan C. Skanes MD | Cardiology |
Lorne Gula MD | Genetics |
Robert A. Hegele MD | Genetics |
Raymond Yee MD | Cardiology |
Bonnie Spindler RN | Research Nurse |
From the Division of Cardiology and the Ottawa Heart Institute*, University of Western Ontario, London Ontario Canada and University of Ottawa, Ottawa Ontario Canada Supported by a grant from the Heart and Stroke Foundation of Ontario (NA3397 Krahn). Dr. Gollob is supported by the Heart and Stroke Foundation of Ontario and the Canadian Institute of Health Research.
Introduction
The congenital long QT syndrome (LQTS) is a rare disorder (incidence 1:10 000 – 1:15 000) characterized by prolongation of the QT interval on the surface ECG, recurrent syncope and sudden death. There are two major clinical variants, the Romano-Ward syndrome, which shows autosomal dominant inheritance, and the Jervell and Lange-Nielson syndrome that is characterized by autosomal recessive inheritance and congenital deafness. The latter is extraordinarily rare.
The Sticky Door
Most patients with LQTS have inherited a genetic mutation that causes formation of an abnormal potassium channel in the heart, leading to a prolonged QT interval. This problem can be illustrated in the analogy of the “sticky door”. With each heartbeat, the heart is activated by an electrical signal. This can be thought of as an electric door that requires 1/10th of a second to open, and 3/10ths of a second to close. This door has 3 hinges; 2 potassium channels and 1 sodium channel. If one of these hinges is “sticky”, the door takes too long to close, leaving the door “open” to abnormal electrical impulses that may lead to fast heart beating. Patients with LQTS are born with a defective or sticky hinge, leaving them prone to abnormal electric door behavior. This is often a problem when the door is challenged by a sudden increase in opening rate, such as when the heart speeds up with exercise, emotion or when the phone or alarm clock rings. The sticky hinge has more trouble keeping up when the heart suddenly speeds up. Treatment of LQTS is primarily focused on preventing stress on the defective hinge by preventing sudden heart acceleration (beta blockers). Current research is focusing on developing therapies directed at “greasing up” specific hinges. This is the case with use of Mexilitine in the uncommon form of LQTS caused by a sodium channel abnormality (LQT3). The following is a more detailed description of the genetics of mutations that cause abnormal cardiac ion channels (hinges).
Genetics
DNA is a 4 letter alphabet that is a blueprint for manufacturing cells in the body. A mutation is an abnormal letter or group of letters that is present in the gene that can lead to abnormal cell or protein production. Many of these are some form of “typo”. In most cases of LQTS, a normal gene is inherited from 1 parent, and an abnormal gene with the “typo” is inherited from the other parent.<