Monday, September 30, 2013 C9
HEALTH
ON THE TRAIL
OF A KILLER DNA tests can lead to early discovery and treatment of conditions such as Sudden Arrhythmia Death Syndromes that can strike without warning, writes Elaine Yau
B
efore Jennifer’s mother died in 2005, she would often faint early in the morning. Her family had no idea what was causing the fainting spells, but the last time it happened, the 53-year-old lapsed into a coma for six months and died. It was while she was in a coma when doctors found the cause: she suffered from Long QT Syndrome, a rare congenital disorder of the heart’s electrical system that predisposes sufferers to irregular heartbeats, fainting spells and sudden death. There’s a 50/50 chance that the condition will pass from an affected parent to child, so Princess Margaret Hospital ran a DNA test on Jennifer and found that she also suffered from the condition. “Many members of my family were DNA tested. My younger sister and I, my son, and my younger sister’s twin girls have it; my mum’s siblings have been spared. There’s no cure for the condition, but I am taking drugs to keep it under control,” says Jennifer. “It turned out the shrill ringing of the alarm clock caused my mum’s fainting spells, so I stopped using an alarm clock, and I avoid strenuous exercise, too. I have taken all the right precautions, and I am glad that I can live like an ordinary person.” Between 2008 and 2012, 289 young people aged from five to 40 died because of heart diseases. Seventy-two of the victims, or 25 per cent, were found to suffer from Sudden Arrhythmia Death Syndromes (Sads), a group of inherited cardiac rhythm disorders that can sometimes cause sudden cardiac death. However, DNA tests conducted at specialist labs such as the one at Princess Margaret Hospital help provide early diagnoses for congenital neurological, heart and
paediatric diseases, says Chloe Mak Miu, consultant pathologist at the hospital. The lab runs 300 DNA tests a year, and “over 10 are for rare heart diseases”. The human nuclear genome, which was fully sequenced in 2003, contains three billion DNA bases that make up approximately 25,000 genes, Mak says. Mutations in the genes lead to hereditary diseases such as Huntington’s disease Professor Tse Hung-fat, specialist in cardiology with Queen Mary Hospital, which also conducts DNA testing for heart diseases, says DNA tests help the early discovery of Sads and stop lives being cut short. “Some patients die from the first attack, and DNA tests can make diagnoses for those who have yet to suffer from that first attack. For some, the condition remains hidden unless triggered by the external environment,” Tse says. DNA tests and the study of
72 rare congenital heart diseases got a big boost recently following a donation to the Hospital Authority by businesswoman Shirley Chan Chow. Chan set up the Sads Hong Kong Foundation after her son died suddenly last year (story below). Tse says the post-mortem DNA tests carried out in 2013 to find the cause of Chan’s son’s death were the first of their kind performed in Hong Kong. “The cause was found to be Brugada Syndrome, a form of Sads,” Tse explains. “But such post-mortem DNA tests are
Dr Chloe their DNAMak Miu (left) an dD testing la boratory r Mok Ngai-shing . Photo: K .Y. Cheng in
The number of Hongkongers aged five to 40 who died of Sads from 2008 to 2012
difficult to do. They could be carried out on Chan’s son because his dad suffered from the same condition. “We were also lucky to have an electrocardiogram of the son. From the electrocardiogram, we could make a guess about the condition. If two patients in the same family have the same condition, and carry the same mutated gene, we can do the test,” adds Tse.
Sads involves two types of patients, says Tse. One type suffers from structural heart diseases like hypertrophic cardiomyopathy (the heart muscle becomes thick). The other kind suffers from nonstructural heart diseases. For that type, an autopsy on the heart won’t find an abnormality because problems with the electrical pathways in the heart cause the sudden death. “There are around five types of these electrical pathway heart problems, including Long QT Syndrome and Brugada Syndrome. Some 20 to 30 mutated genes can cause hypertrophic cardiomyopathy; more than 10 gene mutations lead to Long QT Syndrome,” says Tse. “Only 20 per cent of Brugada cases can be traced to the known mutated genes, with 70 per cent of cases remaining unknown. If there’s no living relative of the diseased patient, or an existing electrocardiogram, we can only do blind DNA
There is no cure for the condition, but I am taking drugs to keep it under control JENNIFER, SADS SUFFERER
testing, testing all the genes. That is very expensive, and the yield is very low. “In many of the patients I saw, their parents had died very young and they had no relatives with the condition. DNA testing is difficult to do in such circumstances,” Tse says. But Dr Mok Ngai-shing, consultant cardiologist and head of the cardiac team at Princess Margaret Hospital, says better procedures can be put in place to improve molecular autopsies of patients who died from unknown causes. “I have been collaborating with forensic pathologists for the last six months. They are always looking for help if they can’t find the reason for a death after an autopsy, as it means that they can’t give an explanation to family members. DNA tests are one of the ways to find a cause of death. The Hospital Authority has not yet got the mechanism to do it,” he says. “In Chan’s son’s case, [the body] was immersed in preservatives for some time, which had destroyed some of the DNA, something which makes our work more difficult. If we need to do the test, we must get fresh blood from the dead person and avoid immersing the tissue in preservatives.” With the support of the Sads Foundation, Mok will start a two-year project next year to study the prevalence and types of Sads as the underlying causes of sudden death among young
local victims. The study involves 40 sudden death victims and about 160 relatives of these victims. The study will include molecular autopsies of the victims, and DNA tests on the relatives. “Instead of trying each of the genes suspected of causing the condition as before, Hong Kong has taken a new technology from the West called ‘next generation sequencing’. “This is a broad screening of all the related genes. If we can find data from the two-year study to support this new technology, we have a better case to go to the Hospital Authority and ask for it to be funded for widespread application,” says Mok. Adds Tse: “Relatives of those who suffer from sudden death do not know such methods are available to check whether they also suffer from the congenital condition. These tests can prevent similar tragedies befalling them.” Mok says the results from the genetic tests can also help Hong Kong set up a database of rare diseases that affect local people. “Hong Kong lacks a database for rare congenital diseases. This does not just concern heart diseases. “Genetic diseases [caused by DNA mutations] are specific to different races. A database could help ascertain what kinds of congenital diseases afflict Hong Kong people,” Mok says. elaine.yau@scmp.com
LAB REPORT
Family tragedy spawns foundation
.............................................. Jeanette Wang jeanette.wang@scmp.com Folic acid deficiency ‘harms generations to come’ Folic acid deficiency can cause severe health problems in offspring, including spina bifida, heart defects and placental abnormalities. A new study published in the journal Cell reveals that a mutation in a gene necessary for the metabolism of folic acid not only affects the immediate offspring but can also have detrimental health effects on future generations. Researchers from the universities of Cambridge and Calgary observed mice in which a genetic mutation caused an abnormal folic acid metabolism, leading to similar effects to dietary folic acid deficiency. When either the maternal grandmother or the maternal grandfather had the mutation, their genetically normal grandchildren were at risk of a wide spectrum of developmental abnormalities. These developmental abnormalities were also seen in the fourth and fifth generations of mice. Excellent sources of folate include leafy vegetables, such as romaine lettuce, spinach, asparagus and turnip greens.
................................................ Kate Whitehead life@scmp.com
Antidepressant could fight deadly lung cancer A little-used class of antidepressants appears potentially effective in combating a particularly deadly form of lung cancer, according to a new study by researchers at the Stanford University School of Medicine. Scientists are now recruiting patients with smallcell lung cancer and other similar conditions for a phase two clinical trial to test their theory. The “repositioning” of an existing drug to treat a disorder other than the one for which it was originally approved is an example of how extremely large genetic and biological databases are changing medicine. “We are cutting down the decade or more and the US$1 billion it can typically take to translate a laboratory finding into a successful drug treatment to about one to two years and spending about US$100,000,” says Dr Atul Butte, associate professor of paediatrics at Stanford. There has not been a single efficient therapy developed in the past 30 years for small-cell lung cancer, which has a five-year survival rate of only 5 per cent, the researchers say.
When Dwayne Chow died suddenly last year his family was plunged into despair and confusion. The 31-year-old had always been happy and healthy. So what had happened? The night before, the family shared a meal, and Dwayne stayed over at his parents’ house. He seemed well when his mother Shirley Chan Chow gave him a hug before he went to bed. But Dwayne didn’t wake up the next morning. His death happened so fast that he never even went to hospital; he was taken straight to the mortuary. An autopsy failed to reveal what had happened. The toxicology tests were clear and the pathologist reported nothing wrong with his heart or brain. He’d had a full medical checkup a few months earlier which had come back positive. “We were totally lost, we didn’t understand. He led a very healthy life,” says Chan Chow. Because there was no known cause of death, a death certificate wasn’t issued for months. The police pestered the family with questions, making them go over the events of their last evening with Dwayne, and compounding their anguish. Racked by grief, Chan Chow began her own search for an answer. It was a quest that began online and then took her to Britain. Her investigations led her to establish the Sads Hong Kong Foundation, which she launched three months ago. Sads (Sudden Arrhythmia Death Syndromes) is a group of genetic heart rhythm abnormalities that can cause sudden death in young,
apparently healthy people. It’s an inherited condition, and each child of an affected parent has a 50 per cent chance of getting it. “I don’t want people to have to go through what I went through. I set up the foundation to provide a platform for people who suffer from Sads, to give them someone to call, and to educate people about it,” says Chan Chow. Death strikes out of the blue, but there are warning signs: fainting or seizures during
You make all kinds of excuses without knowing that these might be symptoms exercise or after a sudden shock, chest pains, shortness of breath during exercise, and a family history of unexplained sudden death under the age of 40. Dwayne exhibited some of those symptoms. Chan Chow recalls how he fainted once as he was getting out of a car. “I thought he’d twisted his ankle, but he hadn’t. And his heartbeat might have been a bit slower, but that can happen in the young and healthy. Sometimes he might be tired, but I thought he’d been working hard. You make all kinds of excuses, without knowing that these are all symptoms,” she says. On a trip to Britain, she visited the Sads Foundation, and learnt more about the “silent killer”. Discovering that Sads is a hereditary condition, she and
her immediate family went for a screening at the Princess Margaret Hospital when she returned, and she learned more about it. “Our close family members have been checked,” she says. “Unfortunately, it runs in the family. We didn’t know that before. But there are some ways of preventing it.” There are at least five different Sads-related conditions: Long QT Syndrome, Catecholaminergic Polymorphic
Ventricular Tachycardia, Short QT Syndrome and Brugada Syndrome. Dwayne suffered from the latter. Preventative care depends on the condition and symptoms, and ranges from avoiding certain drugs to taking beta blockers. Sads claims the lives of 4,000 young people in the US every year. In Britain, it kills 600. We don’t know how many young people die in Hong Kong due to Sads because there are no records, and it’s likely that many
cases are not identified, but Chan Chow hopes that will change. The foundation plans to fund research into Sads locally and keep statistics. So far, five families have approached the foundation asking for advice. “The five cases were all people with family members who have already passed away. They were lost and didn’t know what had happened, and they wanted someone to talk to,” says Chan Chow. “They were also concerned that it might be genetic, so we arranged for them to speak to doctors to see if other family members might be affected.” Not all doctors and hospitals here are familiar with Sads. But Chan Chow says she has relied on three for advice: the Queen Mary, Princess Margaret and the Prince of Wales. The foundation can give the names of private hospitals in an emergency. The Hong Kong foundation is directly affiliated with the US organisation, which was founded 20 years ago, and serves as a vast Sads resource. Much of that material has been translated into Chinese for the Hong Kong foundation’s website, Sadshk.org. “I truly believe that, in the battle against Sads, the critical difference between life and death lies in an awareness of Sads; an understanding and openness about what Sads is, and the availability of the appropriate prevention for those affected. These efforts will give us a chance of saving lives and stopping similar tragedies [to ours],” says Chan Chow. Public forum: What is Sads? October 6, 10.15am-noon, room S421 HKCEC. Free entry. In Cantonese.