News

Against all odds

The tale of Amy Tinsley, the Belfast baby who became the first infant in the world to undergo a new drug treatment for a fatal genetic disorder - and the Winnipeg medical team that helped make it happen.

More on hypophosphatasia Working towards a cure It's a team effort

BY NELLE OOSTEROM
Winnipeg Health Region
Wave, May / June 2009

On a dairy farm just outside of Belfast in Northern Ireland, Leanne and Phillip Tinsley were happily looking forward to the birth of their second daughter. Their first, Shannon, was robust, healthy and a quick learner in every way. They had no reason to suppose that the life of their second child would be different. But it was. They almost lost her - several times - and her exceptionally rare condition would lead them on a desperate search for a cure in a far-off place they were only vaguely aware of - Winnipeg.

The first hint that something was wrong came when Leanne went in for a 20-week ultrasound at the local Lagan Valley Hospital. The technician was puzzled. Why could she not get a clear picture of the unborn baby's legs? A consultant with the Royal Belfast Hospital for Sick Children was brought in. A new ultrasound revealed that what had appeared to be a lack of clarity in the earlier scans was in fact a picture of very definite bone deformities and fractures. She had two fractured femurs and a broken arm. The bones of the five-month-old fetus were breaking in the womb.

The prognosis was grim. "To be honest, because she had shown fractures and severe deformities, they didn't actually expect her to survive," recalls Leanne. "They said, if she does survive, we'll take it from there."

The initial diagnosis was osteogenesis imperfecta type 3 - brittle bone disease. The Tinsleys were told that if their child survived birth, she could be treated with bone thickening medication. Even so, they could expect her to suffer between 40 and 100 fractures before puberty. The diagnosis could not be confirmed until she was born - if she was born. Leanne and Phillip - both devout Christians who rely heavily on their faith - prepared themselves for whatever was to come.

Although the odds were against her, on February 20, 2008, Amy Tinsley came into the world. Her delivery by caesarean section was witnessed by a small crowd of medical professionals craning their necks to get a look at the baby and see if the prevailing diagnosis was in fact correct. "The theatre was absolutely crammed full of people," Leanne says.

The doctors were looking for the signs of osteogenesis imperfecta, including blue sclerae (a blue tint to the whites of the eyes), a triangular face shape and a very narrow rib cage. "So she was born and the whole theatre was just dead silent. She was not crying," recalls Leanne. Nor did she have any signs of osteogenesis imperfecta.

"The doctor in charge said: 'It doesn't look to me like that's what it is.'"

Now they had a new problem. What was this mystery ailment that caused this baby's bones to break in the womb?

There was one telling clue. Just beneath each of newborn Amy's knees was a deep dimple. The Irish doctors delved into the medical literature and realized that what they were dealing with was an extremely rare genetic disorder known as infant hypophosphatasia - a metabolic (chemical) bone disease.

Treatment? There was none, their medical texts told them.

Prognosis? Infants born with this condition are not likely to live beyond a few months.

Still, the Tinsleys clung to the hope that their child had a benign form of the condition. Indeed, Amy seemed fine at first, says her mom. "She was pretty normal up to five months. She slept normally, she ate normally."

But then things changed, literally overnight. In mid-July, the Tinsleys left for a family holiday on Ireland's north coast. The day they left, unsettling symptoms began to show up. Amy's appetite suddenly dropped. She threw up her formula. Doctors treated her for reflux and urinary infections - "all your average baby things" - but nothing worked.

Leanne knew instinctively that these symptoms were connected to her bone disorder, even though her family doctors didn't agree. One evening, Amy became sick at every feeding and never closed her eyes all night. Alarmed, Leanne called Dr. Stan Craig, the baby's specialist in Belfast and said: "Look, I think this is connected."

Amy had in fact developed hypercalcemia - she had too much calcium in her blood. This was happening because the calcium was not depositing as mineral in the bones. Calcium and other bone minerals remained dangerously high in the bloodstream, resulting in severe constipation, nausea, vomiting, as well as weak, aching bones.

She was admitted to hospital in Belfast on August 22, 2008, with a broken arm and multiple fractures in her lower back. Although they did not know it then, Amy was not to return to her family's farm home until the spring of 2009.

Doctors in Belfast had no idea how to treat her. They literally searched the world for help. They consulted a European expert based in Paris. They learned that there was a drug company based in Montreal - Enobia Pharma - that was conducting phase one trials for a promising new drug to treat hypophosphatasia. But it would be six months before the drug received approval for testing in the European Union. By that time, Amy would be gone.

There was just one other option. There was a hospital in Canada that had just received approval to be the first in the world to try the drug out on an infant. "So basically they said, 'Look, if you are willing to go to Canada, we'll bring the drug back to the U.K. as quick as we can, if you get to Canada and get her started,'" Leanne recalls. For the Tinsleys, there was little choice. Time was running out for Amy. This was her last chance at life. "We had nine days to get organized and pack for our trip to Canada," says Leanne.

It was at the Winnipeg Health Region's Children's Hospital that the Tinsley family would come to meet Dr. Cheryl Rockman-Greenberg.

Nurse Diana Mitchell tends to Amy‘s needs during her stay at Children's Hospital.

It was as momentous a meeting for Rockman-Greenberg, who is Medical Director of the Child Health Program for the Winnipeg Health Region, as it was for the Tinsleys. The metabolic geneticist and her team had spent the past three decades researching hypophosphatasia.

The reason for their interest in this rare genetic disorder was not just academic. The worldwide incidence of hypophosphatasia is only one in 100,000, but the incidence among certain populations is much higher. In Manitoba's Mennonite community, for instance, the incidence is one in 2,500. Thus, doctors in the Winnipeg Health Region see about one severe case of infantile hypophosphatasia per year. "We here in Winnipeg have a great deal of experience in dealing with this condition," says Rockman-Greenberg.

In fact, the first report of a case of hypophosphatasia in the English language medical literature was published out of Winnipeg in 1935 by the late Dr. Bruce Chown, who is listed, along with Dr. John Bowman, as one of the Greatest Manitobans for his work in developing a vaccine that would prevent rhesus (Rh) disease in newborns. Chown called it renal rickets.

A few decades later, the chemical basis for the condition was identified. It was caused by the absence of the activity of an enzyme known as alkaline phosphatase. The enzyme is made in the liver, bone and kidney and helps strengthen the bones.

The condition can present in infancy, childhood or adulthood. Those stricken in childhood or adulthood can be treated for the symptoms. But infants cannot. "In most severe cases, the newborns invariably died, if not within hours of birth, within the first week of life," says Rockman- Greenberg. "Rarely would infants in our population survive for several weeks. But inevitably, the children succumbed because the bones were so weak and so poorly mineralized that they didn't have enough strength to breathe and they would die of respiratory failure."

Rockman-Greenberg first arrived at Children's Hospital 30 years ago. When she began to do research at the University of Manitoba in 1986, she wanted to find the basis for this "serious clinical problem that I was faced with in my daily practice of genetics." Teams of people at Children's Hospital and the University of Manitoba began to work together to identify the cause and answer questions such as: Why do some present at birth, and some later in life? And why does this variability exist even within the same family?

The research was initiated in consultation with the families and communities in which the disorder existed. It started by trying to identify the genetic cause of this disorder. Dr. Bernie Chodirker, who is now a medical geneticist and Rockman-Greenberg's colleague, began to study hypophosphatasia as part of his graduate program. "He really drove many aspects of the project, in terms of describing the clinical condition, the evolution of the disorder, and other biochemical features," Rockman-Greenberg says.

More than two decades later, the research project now involves a vast network of health professionals, such as geneticists, genetic counsellors, radiologists, doctors, nurses, chemists, pharmacists, allied health personnel, and other staff working directly with patients.

Advances in genetic technology - including the ability to isolate and identify DNA - meant they were able to determine that babies who presented with the disorder at birth had two copies of a very severe mutation in the gene coding for alkaline phosphatase. The juvenile and adult onset forms of the disorder are the result of one copy of a severe mutation being paired with the second, milder mutation. As a result of their research, screening for hypophosphatasia is available upon request to people who may be at risk of carrying the gene.

As the Children's Hospital team was unlocking the science behind the mutant gene, exciting advances were being made in the treatment of genetic metabolic diseases through the use of enzyme replacement therapy. "If you are missing the enzyme, you replace it," explains Rockman-Greenberg. "It sounds simple, but obviously if it were so simple, people would have done it a long time ago. The problem with this technology is first you have to know what the gene is that is responsible for the disease in question, what enzyme the gene codes for, you have to be able to isolate and make many copies of the gene to be able to produce, through recombinant DNA technology (gene splicing), the enzyme. Then you have to purify it, get enough quantity, and you have to be able to deliver it to the patient. And after you deliver it, you have to be sure that it gets where it has to go to do its effect. In this case, you have to get to bone." The research done by Rockman-Greenberg's team and many others worldwide helped the Montreal drug company Enobia Pharma to develop a drug that would carry the enzyme to the bone. When animal trials proved successful, the company approached Children's Hospital in October 2007 to be one of three centres (the others are in the United States) to conduct phase one trials to assess the safety of the drug, known as ENB-0040.

Rockman-Greenberg - who is also a Professor and Head of the Department of Pediatrics and Child Health at the University of Manitoba - admits she wondered where she was going to find the time to participate in the drug trial. "But there was never a doubt. I mean, this completes the full circle of starting with a clinical problem that is not treatable, researching it in the laboratory and then returning to the patient with a possible treatment. As an academic clinical scientist, this is what drives me and I have aspired to my whole career. And I, of course, said yes. I remember the day at the bedside of the adult patient who was to be the first human in the world to receive an injection of ENB-0040 for the first time, a treatment that had never been tried in a human before. You know, it was actually quite an emotional experience."

In Winnipeg, three adults received four injections over a one-month period last fall without any serious side-effects. At the same time, Rockman Greenberg worked to get quick approval for the compassionate use of the drug in infants. Thus, Health Canada and local research ethics boards at the University of Manitoba and the Health Sciences Centre gave the green light to have the drug administered to up to six severely affected infants.

"Once this became known in the medical community worldwide, that we were the only centre that had approval for infants as well as adults, we received a phone call from Enobia to see if we would accept an infant from Belfast with very severe infantile hypophosphatasia."

Amy met all the criteria for inclusion. "She was a very sick baby and I knew we had only a very narrow window of time," said Rockman-Greenberg.

Seven-month-old Amy and her family arrived in Winnipeg on Oct. 2, 2008. She was started on a low dose of the enzyme - which was given intravenously. Within 24 hours, Amy's blood calcium levels improved.

While the drug appeared to be working - to a degree - Amy's condition was continuing to deteriorate. Her stomach muscles were too weak to digest food, her chest muscles too weak to breathe. She aspirated into her lungs and also suffered a small lung collapse. She was put on a ventilator mask known as BiPAP - bilevel positive airway pressure. She suffered four serious episodes within three days. Each time her life was left hanging in the balance.

Leanne remembers the first episode. It happened while Amy was being treated as an outpatient. They were staying at Ronald McDonald House, a residence for families of children from out-of-town. Leanne and her mother, Lynne Booth, who is a nurse, were about to put Amy on her BiPAP ventilator for the night when they noticed the numbers on her heart-rate and bloodoxygen level monitors were dropping to dangerously low levels.

"All we could do was increase the oxygen, and thankfully she pulled out of it," Leanne recalls of the frightening event. The next day she was admitted back into hospital. Three similar emergencies followed. During the last one, the nurse on duty resorted to using an emergency handheld pressurized ventilator three times, but to no effect. Secretions were blocking her airways. But somehow, Amy returned from the brink yet again. Whatever was blocking her airways cleared and her heartbeat and oxygen levels returned to normal.

It was a rollercoaster of emotional upheaval for the Tinsleys and their extended family, who had made sacrifices to ensure Amy her best chance at survival. Phillip's father came out of semi-retirement to run the dairy farm while Phillip was away. Farm assistants were hired at extra expense. Leanne's mother and father took leave from their jobs so they could help Leanne when Phillip returned home. Leanne's sister-in-law also flew to Canada to help out. Fortunately, most expenses were paid for by either the drug company or health authorities in the United Kingdom. "Otherwise, we could never have done it," says Leanne.

Leanne Tinsley and daughter Amy

One adult always maintained a vigil at Amy's bedside. Leanne was often there 24 hours a day, sleeping in the room on a foldout cot, showering in the bathroom, keeping one eye on Amy and one eye on her heart and oxygen monitor.

The first few months were tough on Amy. She was required to wear the BiPAP mask virtually 24 hours a day. She would also be on oxygen 24 hours a day and would undergo a battery of tests at least once a week. She couldn't eat solid food, so she was fed through a yellow tube through her nose that remained in place. A second clear tube was put in place to remove a buildup of fluid from her stomach.

None of this was lost on Shannon, Amy's two-and-a-half-year-old sister. She often stayed in the hospital room, too, playing her unique little games. She became very familiar with the array of medical equipment in the room and often played at taking her mother's blood pressure. "All her dolls are tube fed," says Leanne. "She thinks every baby gets tube fed. She's definitely going to be a nurse or a doctor."

Family members went to The Forks, the Children's Museum, McDonald's and other places. And they also found fellowship at a local church - the West End Gospel Hall, which provided them with a car, meals and "anything we needed, they gave us before we had asked for it," says Leanne.

Every bit of support was needed, for there came a time when things looked very bleak. In early December, after Amy had suffered several worrying episodes, everyone directly involved met for a conference. Leanne was present in the room, her husband, who had by then returned to Northern Ireland, was connected to the meeting by conference call. With Amy's condition so unstable, some of the doctors involved in her care - but not involved in the study - were concerned that she would not survive."'If you want to have her home alive, take her home now,' that's what they said," says Leanne. "The other option was, as Rockman Greenberg said, 'Stay the course.'" It was a terrible dilemma. Did they want to risk having Amy die so far from home? After the meeting, Leanne returned to the room, not knowing what to do. She gazed at Amy, her face partly hidden under a ventilator mask, a feeding tube going directly into her small intestine, her little stuffed pink bunny clutched in her hand. Then, sick as she was, Amy did something completely unexpected.

"She looked up at me and smiled!" recalls Leanne, shaking her head in disbelief. "I felt then we couldn't take her home. We came to try the drug and we had to stick it out to the end. A lot of people had invested a lot of effort and, obviously, finances as well to make this happen. And basically, if we went home, we were most certainly going to lose her."

Amy did, in fact, improve. The dosage of her medication was increased - something that required approval from regulatory agencies - and that seemed to help. A week before Christmas, medical staff started weaning her off the ventilator. By mid-January, 2009 she was breathing on her own for up to seven hours a day. She became stronger and more vocal. Her appetite was returning.

"They can see definite improvement and mineralization building up in the
bones," says Leanne. "So it's just a matter of time for the bones to build up and the muscles to build up." By March, the EU had approved the drug for use in Ireland, and Amy was able to fly home. She will now receive injections of ENB-0040 three times a week, likely for the rest of her life.

"She really has made progress" Rockman- Greenberg says of Amy. "When she first arrived in Winnipeg, Amy was frail. She was required to wear BiPAP and oxygen masks all the time, and she was fed through a tube. Since the new year, she has gained five pounds and she is much brighter and happier. Her personality is really starting to shine through."

Rockman-Greenberg notes that by the time Amy left Winnipeg, she was only required to wear the BiPAP at night, and since returning home, the yellow and clear tubes have been removed and she is starting to eat solid food.

Amy's improvement over the last few months has been gratifying for Rockman-Greenberg and the rest of the Winnipeg medical team. The data from the research being done in Winnipeg depending on the outcome of clinical trials, could potentially save many lives. But Rockman-Greenberg is quick to point out that it takes hard work by many researchers around the world to make a breakthrough. "It should be recognized that reaching the point of initiating a clinical trial of any potentially important new drug requires contributions from people working in many areas of research and in many jurisdictions internationally," she says. "This begins with sustained government support for investigator- initiated basic laboratory research. This allows for creative new directions of research that may ultimately translate one day into improved patient care and clinical outcomes. Such has been the case for hypophosphatasia research in which contributions of international teams working in basic and applied scientific areas of research have ultimately culminated in clinical trials."

For the Tinsleys, meanwhile, it has been a long, long journey.

"It was an emotional roller-coaster," says Leanne. "I mean, before she was born, they didn't expect her to survive. Then, when she was diagnosed with having infantile hypophosphastasia, they didn't expect her to survive. When she got here and was having these problems, they thought she was gone.

"And she's still here. Despite all that's happened. That's all we can ask for."

Nelle Oosterom is a Winnipeg writer.

	About Wave Wave is published six times a year by the Winnipeg Health Region in cooperation with the Winnipeg Free Press. It is available at newsstands, hospitals and clinics throughout Winnipeg, as well as McNally Robinson Books. Read the May / June 2009 issue of Wave