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In the hunt for a mutant gene Monday April 10, 2000 - The Hotte family's large size and high incidence of Parkinson's disease are a researcher's dream. This special report explains how the secrets encoded in their genes could help uncover a cure. On Remembrance Day 1998, Hector and Therese Hotte, a lively couple who love to entertain their large, close-knit French-Canadian family, hosted an unusual party. About 30 family members, including most of the Hottes' seven children, went to the large house in Vanier that Hector built 40 years ago. Therese bustled about offering beer and wine. The group laughed and chatted. They waited their turn as, one by one, each person descended into the finished basement. Hector's desk was covered with a clean tablecloth. Here, a nurse carefully drew four vials of blood from each person's arm. A young doctor named David A. Grimes asked them to perform a series of hand exercises, wrote down medical history and collected signed consent forms. "It was a fun day," said Francine Hotte, 39, the Hottes' only daughter. "A vampire party." Later, as they tucked in to lasagna, garlic bread and salad, the family talked about the partnership they had just struck with medical science. For years the Hottes had wondered why so many people in their family got Parkinson's disease, a disorder of the central nervous system. The tremors, shuffling walk, stiffness, slowness of movement and loss of balance seemed to be inherited from the Hotte side. Now they had taken a first step toward a mind-boggling kind of knowledge -- the secrets encoded in their genes. Dennis Bulman, the scientist in charge of the project, told them with confidence that the blood samples would eventually reveal a gene defect that is linked to Parkinson's disease. The implications were both sobering and exciting. Who in the family would turn out to carry the gene? Would the discovery lead to better treatments or a cure? Could the disabling disease be prevented or its progression stopped? How many other families carried the same defect? Up to 100,000 people in Canada are affected by Parkinson's disease, including about three per cent of the population over 65. Having a family member with the disease increases the risk to five or six per cent. But the Hottes have a far greater risk. If one of the parents carries the mutated gene, they have a 50/50 chance of passing it on to their children. It's not known at what rate they'll go on to develop Parkinson's disease. Hector Hotte could think of 11 people besides himself who had it, including a sister and brother. Nine were still living and three had died. "Researchers salivate when they come across these big families," said Dr. Grimes. "These rare families provide us an opportunity to narrow down a certain region of DNA and identify a gene that has a mutation in it." A large Newfoundland family provided the genetic material that helped U.S. scientists find a leading cause of colon cancer -- a discovery that made international headlines in 1993. And the two known mutant genes for breast cancer discovered in 1990s involved studies of numerous cancer-prone families. Both discoveries have led to potentially life-saving genetic tests that can alert people to their risk of developing breast or colon cancer. Genes contain the basic information about how a human body carries out its duties from conception until death. They determine a person's individual characteristics -- everything from hair and eye colour to the likelihood of developing cancer. The size of the family and the fact that most live in the national capital region made them even more valuable to researchers. "The more individuals we have, the higher the chance of finding this change," said Dr. Grimes. "This type of study depends on families," added Mr. Bulman. "Without their participation, disease gene discovery won't occur." In total, researchers have collected blood from about 80 family members spanning four generations. "It's a bit scary," said Solange Oliveira, a 25-year-old nurse who is pregnant and whose grandmother had Parkinson's. "I hope that when my baby reaches the age of getting this disease they will have a cure for it." Hector Hotte, now 76, had always been an active and outgoing man. He spent 37 years as a postman and 22 years on Vanier city council. But about eight years ago he began to change. He lost weight. His right leg and arm began to shake. His face felt numb and he stopped smiling. He started to avoid people. His much-loved cottage needed a new dock, but the former handyman ignored it. "I can't do it," he said angrily. In 1992, a neurologist confirmed what Hector had quietly suspected. The family affliction had struck again. There is no blood test for Parkinson's, and most cases are diagnosed by physical examination. Famous people with Parkinson's include actor Michael J. Fox, former boxing champ Muhammad Ali and Pope John Paul II. The symptoms of Parkinson's are due to a deficiency in the production of a chemical called dopamine. This lack of dopamine results from the death of dopamine-producing cells in the brain. Scientists are eager to find out what causes the cells to die. Learning what causes the brain's deterioration might make it possible to design drugs to slow down the progression of the disease or prevent it. Hector's son Michel, a 47-year-old RCMP officer in Montreal, felt sad watching his father withdraw and wondered if he would suffer as cruelly as Michel's aunt Yvette. Yvette Vezina, who lived in Hull, was stricken in 1959 at age 39. A mother of 10, she delivered her last two babies after the shaking had set in. Only about 10 per cent of Parkinson's sufferers get ill before age 40. Yvette was a robust woman who sang French songs as she did housework and woke her brood for school with tenderness. She began to complain that she couldn't peel potatoes quickly or tie her young ones' shoes. Within five years, Yvette was unable to walk. "At age 10, when other girls were playing with dolls I was looking after five younger brothers and sisters," recalls her daughter Lyse Oliveira, 49. "It was like I didn't have a mother." Yvette got sick before effective drugs were available. She had two experimental brain operations in Montreal, but they seemed to do more harm than good. She began walking backward after one of them and lost most of her speech after another. She died in 1979, at age 59, in a chronic-care hospital. Hector recalled a cousin who had taken levadopa, a drug that replaces dopamine. It is the most effective way to reduce the disability of Parkinson's, but after a few years it causes the body to jerk and twist involuntarily. His cousin's limbs had lashed out wildly in all directions. Hector refused to take the drug and continued to deteriorate for the next two years -- until a lucky chain of events would change his life, and promise to earn his kindred a place in medical history. In 1994, Therese Hotte spotted an ad in the Citizen for a trial of a new drug for Parkinson's called Mirapex, which does not have the side effect of involuntary movements. It was the first time Hector visited the Parkinson's clinic at the Civic site of the Ottawa Hospital. He was accepted into the trial and within two weeks his symptoms almost completely disappeared. "It did miracles for my father," said his daughter Francine. Over and over, they thanked Dr. J. David Grimes, director of the Parkinson's clinic, for restoring Hector. "We really trusted him," said Francine. "He's such a compassionate, gentle man." Dr. Grimes, now 60, created the Parkinson's Clinic in 1977, where he helped advance the development of many new drugs and experimented with surgery. He believed strongly that research would lead to better treatments, and in 1988 he founded the Loeb Research Institute at the Civic site. Dr. Grimes knew what it was to struggle with serious health problems. A rare lung disorder that began in 1986 resulted in a double lung transplant in 1991, and the required anti-rejection drugs led to the development of successfully treated Hodgkin's disease in 1995. In the late '70s and early '80s, Dr. Grimes helped Dr. Andre Barbeau of Montreal (considered the father of Parkinson's research) conduct a survey of Parkinson's patients. They found that there was an increased incidence of the disease in the families of Parkinson's patients. One of the patients in that study was Sylvio Hotte, one of Hector's cousins. "It's funny, but there's so much Parkinson's in this family," Therese once said to Dr. Grimes. But over the years, most evidence suggested that an environmental, not heredity, factor was responsible for Parkinson's disease. Interest in Parkinson's genetics exploded in 1997 when researchers reported that they had found a gene responsible for the disease in a large Italian family. The gene, which carries instructions for making a protein called alpha-synuclein, will probably only account for a few per cent of all Parkinson's cases. But hundreds of scientists around the world have turned their attention to alpha-synuclein, trying to discover how it actually leads to having Parkinson's disease. They have already discovered that alpha-synuclein is found in the abnormal build-up of protein -- called Lewy bodies -- that appear in the brains of all Parkinson's patients. Two more abnormal genes named "parkin" and "ubiquitin hydrolase" have been found to be associated with Parkinson's. By then, Dr. Grimes was treating a number of people from the Hotte family. A hereditary link seemed clear and the research climate was ripe to approach them for a study. Hector and Therese agreed right away and promised to bring their family on board. "Even if it does not help us immediately, it will help others in the future," said Hector. Meanwhile, Dr. Grimes set about recruiting research partners. The lead gene hunter in the Hotte study is Dennis Bulman, a 40-year-old with a PhD in genetics, who has been involved in screening for genes for multiple sclerosis. Mr. Bulman, a genetics professor at the University of Ottawa medical school, also helped to discover the gene for a disorder called episodic ataxia, which causes loss of limb control. It turned out to be the gene for familial hemiplegic migraine as well, the first migraine gene ever identified. The clinical research is being conducted by Dr. Grime's son, David A. Grimes. He is a 33-year-old neurologist with advanced training in molecular genetics, and was the one who attended the blood-gathering party at Hector's house. The younger Dr. Grimes took over as director of the Parkinson's clinic last year after his father retired. "Eventually we're going to find the mutation," says Mr. Bulman. "It's guaranteed." The Bulman Lab: Genes cloned while-U-wait: 50¢ The sign outside Dennis Bulman's lab at the Ottawa Hospital Research Institute reveals a sense of humour about the Wild West science of genetic analysis practised within. This is where blood from the Hotte family is being scrutinized by a four-member team, which includes Mr. Bulman, two technicians and a post-doctoral fellow. A human being has 100,000 genes, made up of three billion DNA units that spell out instructions for every function a human body carries out. Identifying a mutant gene is a process of narrowing the region where it might be hiding. "We're searching for a needle in a very big haystack," says the younger Dr. Grimes. "We're looking for one specific change out of three billion. The funny thing is, we can do this." The first step is to take the blood samples and isolate the white blood cells where the DNA resides. The DNA, which contains each person's unique genetic code, looks like white stringy cotton floating in a tube. Then the researchers take identifiable snippets of DNA (called markers) from all the people and compare them, looking for patterns that exist among the people with Parkinson's. If they match, chances are good that the gene that caused the disease sits somewhere near that marker. The next step is to try to record which chromosome the gene is located on. Each person has two sets of 23 chromosomes, one set given by each parent. Once they've identified a region of a chromosome, it narrows the field to an area that might contain 200 to 300 genes. They will slog through these in order to detect the culprit, by using technology called PCR or polymerase chain reaction, and DNA sequencing. PCR makes millions of copies of DNA, needed to produce enough material to work with. DNA sequencing is a way to read the genetic code. Comparing the genetic code of those with Parkinson's and those without will reveal the mutation. Mr. Bulman predicts they will find the gene in the next two to three years. The gene they discover may have already been studied, but never related to Parkinson's. The researchers are dipping into the growing pool of data flowing out of the Human Genome Project and available on public databases. This project, led by the U.S. and Britain, is a heroic expedition to map out a blueprint of the human race by 2003. A working draft will be ready later this spring. Remarkably, by taking blood from Yvette's widower, Rolland, and her 10 children, the researchers were able to reconstruct her genetic makeup. And by determining the genetic markers in Hector's family and his first cousins, they've been able to reconstruct DNA markers in their parents and grandparents -- thus reconstructing two more generations of the family. Although most cases of Parkinson's disease are probably not inherited, studying rare families like the Hottes provides crucial clues to how the disease occurs. So far, the study has cost $50,000, but that doesn't include salaries or capital expenses such as $300,000 for gene sequencing machines. Funding came from the Parkinson's Foundation of Canada, the Loeb Research Institute and the Ottawa Hospital Research Institute. Mr. Bulman has applied to the Medical Research Council for $300,000 to continue the study for the next three years. Mr. Bulman has created a Hotte family tree used for following the inheritance of Parkinson's through several generations of the family. With that map and DNA, researchers have been able to narrow down the search from 23 chromosomes to one chromosome, and from 100,000 genes to fewer than 200 genes. One day soon, this map will foreshadow who is at risk of getting the disease. Once a mutation is found, genetic counselling will be available to the Hotte family. They must decide if they want to be told whether they carry the gene. Considerations will include impact on health insurance, employment as well as emotional repercussions. Solange Oliveira, 25, would be curious to know the result. "Maybe I will be better prepared to deal with it." But her mother, Lyse Oliveira, a 49-year-old secretary, would not want to know her destiny. "I wouldn't be able to live like my mother," she says. "I want to live day-to-day." If preventive treatments are developed, researchers will need to sit down with medical ethicists and decide whether to approach affected members of the family. Discovering the gene would be only the first step. The researchers would then try to figure out what it does. "Once you understand the biology of what causes these dopamine cells to die in patients, then you can interrupt it or block it," said the younger Dr. Grimes. Drugs could be tailored to each particular type of gene mutation or actually block brain cells from dying prematurely. Genetic tests may be able to foreshadow the disease. Genetic therapy holds out the promise of preventing the disease. "The drug companies are pumping hundreds of millions of dollars into genetic studies with the idea that this is going to be the way to go in the future," said Dr. Grimes. The identification of this gene may lead to identification of other genes in Parkinson's. It could also provide clues to other neurodegenerative diseases, the most common of which is Alzheimer's. Parkinson's experts say a cure is less than 10 years away. "It's just a matter of getting all the pieces of the puzzle together," said Dr. Grimes. Rick Hotte, a 53-year-old airport employee who lives in Ottawa, knows the benefits of research. Rick, who began to get Parkinson's symptoms in his 40s, is the beneficiary of drugs developed on patients like his father, Sylvio, a watchmaker who died in 1983. Sylvio was also in his 40s when he was diagnosed with Parkinson's in 1965. Somewhere at the Parkinson's Clinic, there is an old training video that shows Sylvio with his limbs flailing uncontrollably. "I've been very fortunate," says Rick, a father of two. "Drugs have controlled what I have. I'm still able to work and function normally. Dr. Grimes said I will never be like my father." He is intrigued by the genetic study. "Anyway I can help I will. Hopefully they will find something so my kids and grandkids will benefit from it." by Maria Cook The Ottawa Citizen <http://www.ottawacitizen.com/city/000401/3857800.html> janet paterson 53 now / 41 dx / 37 onset a new voice: http://www.geocities.com/janet313/ 613 256 8340 PO Box 171 Almonte Ontario Canada K0A 1A0