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Long QT: The stranger beside usFeb 8, 2012 09:52 EST
The phenotype of the "long-QT syndrome" (LQTSy) is notorious for its generic visage. For centuries, "crime scenes" were devoid of fingerprints, and there were no weapons; autopsy reports were "normal" on "healthy" unsuspecting victims. Families could find no closure as they were left to mourn a senseless, tragic, and unexplained death. In the 1980 biography The Stranger Beside Me, Ann Rule described Ted Bundy as a well-liked and reliable coworker who in every regard appeared "normal." Because of his innate ability to blend in a seemingly peaceful coexistence, he remained virtually anonymous. Amazingly, he is now labeled as perhaps the most prolific serial murderer of all time. Like Bundy, the long-QT syndrome provides no obvious identifying physical characteristics. It offers no clue of its lethal potential until the moment of death in 10% to 15% of its victims. This weird twist of electrical short circuitry, a stowaway as an ion-channel mutation in our own mammalian DNA, commonly passes undetected from generation to generation. But like any other serial killer, if it can be identified and corralled, the greatest majority of its potential victims can be saved. A simple, painless, noninvasive electrocardiogram at a cost of $10 to $50 can propel a patient to safety, yet no screening programs are in place in our country. It is a venture flippantly labeled as simply "not cost-effective."
"And now . . . The rest of the story"
In the 1970s, a young woman in her 20s died in her own bed just days following an uncomplicated thyroid surgery. It was widely rumored that her surgeon "botched" the procedure; thus, he likely went to his grave thinking he may have been responsible. Her brother Jeff married my first cousin in a small intimate wedding I attended as a nine-year-old. I remember blushing at the very thought of them kissing in public. His mother became my patient 30 years later for evaluation of hypertension. Her ECG in the early 1990s yielded a slightly prolonged ST portion of her QT, although the overall QTc was normal. She had no syncope but was chronically dizzy, with only normal sinus rhythm documented by Holter. Her son Jeff (my cousin's husband) had a QT interval at the upper limits of normal with the same prolonged appearance of the ST segment but no history of fainting. His daughter Amanda had a preop ECG at my office for a minor surgery in her 20s, but it was normal. I strongly suspected this "longer-than-usual ST" in her father hinted at the cause of death in his sister but did not pursue the issue because his mother is still surviving well into her 80s, and there was really no good commercially available genetic test to confirm or deny my suspicion. I also mistakenly reasoned that "survival of the fittest" fit the long-QT scenario. I could not have been more wrong. If one is carrying this lethal gene, there is a 50% chance it will be passed on to one's children. Although the electrophysiologist has assured me that the QTcs were normal for those adult family members, I wish I had pursued it when genetic testing became more readily available.
The plot thickens
Ty was forced to stop competitive sports
Jeff's other daughter, Stacy, moved from Park City, KY to Kansas City, MO last year. They consulted a pediatrician for their daughter Ty for anxieties created by the newness of relocation. Ty's QTc interval was around 500 ms. At that very moment, we would begin to understand fully how 40 extra ms, a length on a heart tracing no greater than several hairs laid side by side, could change so many lives forever. Her brother Tanner was then tested, and his QTc was 490 ms. Gracie, the youngest, had a normal QTc. Ty and Tanner were placed on beta blockers. They were taken out of competitive sports, and alarm clocks were removed from their bedrooms. Caffeine was forbidden.
Their pediatric electrophysiologist, Dr Lana Tisma-Dupanovic at Children's Mercy Hospital in Kansas City, told them that the death rate for long QT syndrome "can be significantly reduced" if the patients are placed on beta blockers. She alluded to data (Priori/Napolitano) published in Circulation in 2008 in which beta-blocker therapy was demonstrated to decrease all events and cardiac arrest differently in different LQTSy types. For example, in LQTSy 1 they have been shown to decrease all events rate from 39% to 10% and cardiac arrest from 2% to 1%. In LQTSy type 2, beta blockers decreased all events rate from 58% to 32% and cardiac arrest from 8% to 6%. In LQTSy type 3 events were decreased from 57% to 32% and cardiac arrest from 18% to 14% only. "This is why I have recommended automated external defibrillator [AEDs] to be given for Ty and Tanner," she said.
Decision making is even more difficult in patients with a "borderline" QTc, syncope, and palpitations, many of whom will have a normal genetic test. "That is where it becomes difficult," Dr Tisma-Dupanovic said. Holters, stress testing, and the clinical presentation will guide therapy. "It has become more common to find the long QTc in children now that it is standard of care to perform an ECG anytime a pediatrician is contemplating pharmacologic therapy for [attention-deficit/hyperactivity disorder] ADHD and other emotional issues," Dr Tisma-Dupanovic added. Everyone who knows and loves this family is grateful someone was looking for it.
More twists of fate, yet
Amanda, with the normal ECG, was later found to have a completely different missense mutation in the SCN5A gene, a less lethal situation than her sister Stacy's mutation at the KCNH2 location. It is amazingly rotten "luck" to have not one but two QT-modifying genetic mutations in one family. Add this to our odd cystic-fibrosis gene (only 17 reported cases worldwide) and pheochromocytoma (my brother's recently confirmed mutation), and you see how unique we are as a cluster of individuals. We agreed, half-jokingly, "It is a wonder we don't all have gills," referring to the famed mutant Waterworld movie characters. If Jeff, the grandfather of Ty and Tanner, does not test positive for both of these genes, Sonya (our blood relative) will be placed under suspicion for a QT-modifying gene as well.
Genetic testing has come light-years in a decade
Genetic testing can avert tragedy
I dealt with a horrendous tragedy in our community over a decade ago. A nine-year-old boy collapsed on the sidewalk on his way to say good-bye to his 17-year-old brother, who had suffered brain death after an anoxic injury from a motor-vehicle accident. The family buried both of their boys on the same day. The mother had "seizures" at the funeral. A single daughter survived. At that point, the only QT genetic test available, according to the long-QT registry, was somewhere in Texas. They accepted genetic material from the deceased as a free service for research purposes. I was told sharply, "Do not call us back. We will call you. We are backlogged forever. It might be seven years." I called every other year but, as projected, it was around seven years when they finally pronounced the tests "inconclusive." I plan to contact them and redirect them unless they've already found their way to adequate testing.
"Will Ty and Tanner receive defibrillators at some point?" I asked their doctor. "They may, depending on their clinical course," said Dr Tisma-Dupanovic. "The size of the device can be problematic." In some extreme cases, she added, "Children as young as three months have received a device, but it is rare because it can take up a large portion of the abdomen, and there are other difficulties such as 'T-wave' oversensing in younger population that leads to inappropriate shocks, lead fracture, infections, and need change of leads as child grows." With regard to AEDs, an update is required when the patient's weight increases to greater than 10 kg. Because of the lack of implantable cardioverter defibrillator therapy in most children, she directs some aggressive changes in family dynamics. In some instances she recommends they purchase an AED and train all family members of a responsible age in cardiopulmonary resuscitation. Tanner now plays golf instead of baseball. Ty is pursuing art and writing. Their first-degree relatives are all being tested. "It is amazing how well they implemented the changes and dealt with the diagnosis," Dr Tisma-Dupanovic said. "Some families have a very tough time going through the phases of grieving when the diagnosis is made, with anger and denial," she said. "It is a pleasure to provide care for this family," she added.
How legislation can save lives
I asked Dr Tisma-Dupanovic what we could do now to help. "Some coaches are great about pulse checks and referring to a school nurse," she said. "I'd also like to push for the need for AEDs at all schools. They need education regarding the specifics of device utilization and how to maintain it," she said. "It needs a new battery every six months."
I recounted my failed efforts at that very legislation a few years ago when I traveled to Frankfort with the now-incarcerated KY State Representative Steven Nunn (who pleaded guilty to murder), begging for legislation for AEDs in each school, and even after a mother brought a picture of her deceased son, a baseball player, they turned us down flatly. They wouldn't legislate it because they couldn't fund it. Ty and Tanner's mom, Stacy, said, "Our insurance paid for an AED for each of the kids. We have Blue Cross/Blue Shield. They didn't even know how to go about getting us an AED and kept trying to get us a heart monitor to wear. I stressed 'portable' AED, and finally someone understood. I was amazed at the lack of knowledge, but they claimed no one had ever asked them about it. I think most people assume their insurance would not pay for an 'at-home' AED. But I persevered and asked three different people the same questions five different ways to get the answers. We had to go out of network for equipment, but I think they cost $1300 each." Stacy and Scott, according to Dr Tisma-Dupanovic, have been amazing parents in dealing with the long-QT issue, exhibiting both courage and persistence.
Affordability of testing
I contacted the managing director of Gene-Dx, Dr Sherri Bale, in Gaithersburg, MD and told her I had reviewed an amazingly detailed report on Amanda's testing. I was impressed with the 3.5 pages of family history and explanation, complete with a family tree. "For patients with no coverage, there is a $2500 out-of-pocket cost," said Sherri, "but we work with the insured to keep their personal cost to a minimum." Medicaid apparently doesn't participate in coverage for testing, and Medicare coverage is limited because most of those have other insurance. "For very specific genetic tests, the cost can be as low as $350," she added.
So, now you know the "rest of the story" as it unfolded in this beautiful young family, beginning with the day where everything changed for them, forever. A simple piece of paper and a tiny drop of ink have saved their children and their children's children for generations to come. An affordable 8x11-in electrocardiogram, painless and inexpensive, performed in less than 60 seconds by a caring pediatrician is all it required to identify this prolific serial killer. We are grateful that the "stranger beside us" who waited patiently, undetected and poised to take its prey, now threatens far less and can hide from this family no more.
(Story updated with corrections 2/11/12 6:15 am CST)