Supporting Families. Saving Lives.
By Rachelle Cook a student with CPVT
Imagine walking into your baby’s nursery in the morning, after a night of nervous tossing and turning, to find them blue and cold. You weren’t expecting this. There was no way you could have known this would happen; yet you blame yourself anyway. You tell yourself it was because you left him or her for so long. You tell yourself you are a bad parent but this is not your fault. 2,500 infants die suddenly every year.
Cardiac Channelopathies, such as Long QT Syndrome (LQTS) and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), are responsible for approximately 1/3 of autopsy-negative sudden deaths in the young (Tester 241). Although sudden death in the young is relatively uncommon, with an incidence between 1 and 5 per 100,000 patient-years (Tester 240), these diseases are highly treatable and these deaths preventable.
Post-mortem genetic testing for Cardiac Channel mutations has been completed on several populations of Sudden Infant Death Syndrome (SIDS) infants, revealing mutations in 5% to 10% of cases (Ackerman). That means that 125-250 infants can be saved per year. It is possible that many more children could be saved given that the true incidence of cardiac arrhythmias is unknown. Many of these diseases cannot be diagnosed post-mortem without genetic testing. Most coroners either don’t know about genetic testing or don’t have the resources to test every child. However, it is estimated that CPVT occurs in 1 in every 10,000 people and LQTS is estimated to occur in 1 in every 2,500 people. Just for comparison the incidence of childhood cancer is about 1 in 10,000 as well. So for every two children with cancer, there are six children with silent assassins just waiting to strike.
Arrhythmogenic events can happen at any time, any age. These diseases are truly unpredictable and potentially deadly. My event struck when I was 16 years old, rowing in a race as I had done many times before. Before I was a rower, I was a swimmer. Sports were not a new thing for me. I had been participating in competitive sports since I was six years old. For ten years, I went to practice and meets and regattas, not knowing I could fall over dead at any moment. My friend had her event running a race with her cousin when she was six years old. Another friend, at age 17, had a cardiac arrest in her high school weight room. She would have died without intervention from an automatic external defibrillator.
These diseases are likely more common than thought at the moment since sudden death is the sentinel event for >66% of LQTS-associated cases, and nearly all of the previously published CPVT1-associated cases (Tester 244). There seems to be a cardiac channelopathy gender effect. 80% of the LQTS-associated mutations have been detected in females, whereas 86% of CPVT1-associated mutations occurred in males.
The Long QT Syndrome is a hereditary, congenital cardiac channelopathy. It is characterized by delayed repolarization of the myocardium, QT prolongation, and increased risk for syncope (fainting), seizures, and sudden cardiac death with a structurally normal heart (Tester 241). It is an electrical issue, not a structural issue. Six genes are known to cause LQTS. Five encode for subunits of cardiac ion channels (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2) and 1 (ANK2) encoding for cardiac Ankyrin A, a structural protein that anchors ion channels to the cell membrane (Napolitano 2975). Among probands with only one genetic defect, mutations on the KCNQ1 gene were most the prevalent, with 49% of probands exhibiting this mutation. KCNH2 followed with 39% of probands with a mutation in this location. Coming in third is SCN5A with 10% of probands. The fourth and fifth most common mutations are, respectively, KCNE1 and KCNE2 (Napolitano 2976). Overall, mutations in KCNQ1 and KCNH2 account for 88% of successfully genotyped probands (Napolitano 2976).
As much as 20% of sudden unexplained deaths are caused by LQTS. Events reported as cause of death include sleep, exertion, and auditory triggers (Tester 241). There is a known link between exertional triggers and LQTS1. In contrast to this, in one study, 2/3 of LQTS1 patients died while they were sleeping, a time when one would not typically encounter physical exertion and rapid heart rate. Consistent with the link between LQT2 and the postpartum period, one patient died 4 months postpartum.
A normal QTc for men is <440 ms, while for women it is slightly longer at <460 ms. The mean QTc among genetically affected individuals is 474 ms, whereas a non affected family member QTc interval is around 406 ms (Napolitano 2977). The QTc among probands was significantly longer at 496 ms than among the affected family members. Using these guidelines, 40% of affected individuals cannot be identified by clinical assessment. Considering that carriers of LQTS mutations with a normal QTc, who cannot be identified by clinical evaluation (Electrocardiogram), have a 10% probability of cardiac events, such as cardiac arrest, by age 40 years if not properly treated (Napolitano 2978), these statistics are very concerning. As well as the fact that Crotti et al reported LQTS-associated mutations in 8.3% of SIDS patients (Ackerman 2980). Genetic testing is so important, because even if you have a normal QTc interval, you could still be at risk of sudden cardiac arrest or sudden cardiac death if you have the gene.
Pathogenic mutations involving the CPVT1- associated cardiac ryanodine receptor (RyR2) make up approximately 15% of the cases of Sudden Unexplained Death (SUD) where cardiac channelopathies have been implicated as a cause of death. Catecholaminergic Polymorphic Ventricular Tachycardia (abbreviated as CPVT henceforth) is a potentially lethal, genetic arrhythmogenic disorder of the heart (Ylanen). CPVT is estimated to affect approximately 1:10,000 people (Napolitano, Priori). CPVT is characterized by episodes of syncope (fainting) during exercise or strong emotional states. The polymorphic, or bidirectional, arrhythmias may not always result in syncope, they may only result in dizziness, palpitations and even convulsions (Napolitano,Priori). The arrhythmias are caused by the release of catecholamines during exercise or strong emotion (Napolitano, Priori). The arrhythmias normally self terminate, however sometimes they will not and ventricular fibrillation can occur and cause sudden death. The average age of onset is between seven and nine years of age however the first manifestation has occurred as late as forty years of age. Approximately 30% of symptomatic individuals have had or will have at least one cardiac arrest and up to 80% of symptomatic individuals will have or have had one or more syncopal episodes (Napolitano,Priori).
There are three genes known to cause CPVT. The first and most common is the RYR2 gene, which is autosomal dominant. It is responsible for encoding the cardiac ryanodine receptor channel or the calcium release channel (Napolitano, Priori). RYR2 is responsible for approximately 50-65% of CPVT. Sometimes this mutation is known as CPVT1 because it was the first mutation to be discovered and it is the most common mutation (“Cpvt”). Instances of SIDS have been associated with RYR2 mutations. Growing evidence shows that sudden cardiac death can be the first manifestation of CPVT caused by RYR2 (Napolitano, Priori).
The second most common gene is the CASQ2 gene, which is autosomal recessive. This gene is responsible for encoding calsequestrin, a calcium buffering protein of the sarcoplasmic reticulum (Napolitano, Priori). CASQ2 is responsible for approximately 1-2% of CPVT. Usually CASQ2 mutations appear more severe and more resistant to beta-blockers than the other mutations.
The third gene responsible is the TRDN gene, which is autosomal recessive. This gene encodes triadin, a CASQ2 and RYR2 partner protein that regulates sarcoplasmic reticulum calcium release (Napolitano, Priori). The proportion of all CPVT attributed to TRDN is currently unknown.
The mutations causing the disease are only identified in 55-65% of individuals with CPVT, so it is likely that other locations contribute to the disease pathogenesis.
No more than 12% of the genotyped probands harbor a De Novo (spontaneous) mutation; therefore, at least 88% of probands have inherited the disease, which suggests that familial forms are more common than was expected (Napolitano 2979). Even when patients of different geographical and ethnic origin are considered, close to 40% of patients carry mutation in 1 of the most frequently mutated codons that have been identified (Napolitano 2979). The data presented previously was mainly provided to renew thought of a universal screening program to identify potentially at-risk patients before a potentially lethal sentinel event. It is obvious that the more complete the screening process the higher the accuracy of the results of genetic testing (Ackerman 2980). However this comprehensive approach may be neither practical nor cost effective. The three tier approach proposed by Napolitano et al. may provide an alternative if the screening of all the genes is not feasible.
While the technology is new currently, and consequently expensive, as the technology gets more clinical use it will become cheaper to use. Also since most mutations are familial, once you know the gene that runs in a certain family, only that gene needs to be tested. So while a universal screening program would be very expensive at first, gradually the costs would decrease since each test would become cheaper and less full panel tests are needed. Furthermore, locus-specific algorithms for risk stratification and management of patients with LQTS and CPVT have been proposed and should be applied in clinical management (Napolitano 2975)
In the case of sudden death, molecular autopsy (postmortem genetic testing) should be considered as a standard part of the evaluation of an autopsy negative, unexplained death (Ackerman). A molecular autopsy could have a profound influence on surviving family members. Over 50% of genotype positive decedents (in this study alone) have found that most mutations are familial (Tester 245). Molecular autopsy could provide a life saving clue for the evaluation and management another surviving family member.