Anguished Family Leads Fight Against Fatal Disease
An estimated 300 children in the United States have Niemann-Pick disease type C, a rare cholesterol disorder that is always fatal.
By a cruel quirk of fate and genetics, three of those children belong to Cindy and Mike Parseghian.
The Tucson couple had never heard of the debilitating disease before. And when they learned in 1994 that all but one of their four children had it, Cindy said, “we were devastated.”
But they were not defeated.
With the help of the children’s grandfather, Ara, a well-known former football coach at the University of Notre Dame, they formed the Ara Parseghian Medical Research Foundation to battle the genetic disorder.
Research supported by the $6 million they have raised so far played a key role in the announcement in July that federal researchers had identified the defective gene that causes Niemann-Pick.
Discovering the gene will make it possible for the first time to identify carriers who can pass the gene on to their children. Eventually, it will probably lead to new treatments.
But the impact will probably be felt well beyond the small number of families with a history of Niemann-Pick. The newly discovered gene apparently plays a key role in the movement and storage of cholesterol within individual cells--a subject about which researchers previously knew almost nothing. As scientists unlock its secrets, they expect to gain crucial new information about the genesis of heart attacks and strokes.
“By understanding this gene, we not only take a crucial step forward in understanding this devastating disorder, but we also gain insights into problems that affect every one of us,” said Zach W. Hall, director of the National Institute of Neurological Disorders and Stroke.
For the Parseghians, however, the discovery is bittersweet. They learned about it shortly after their son Michael died March 22, four days shy of his 10th birthday.
Any new treatments resulting from the discovery are unlikely to be available in time to help his sisters Marcia, 8, and Christa, 6.
“This is a race against time,” Ara Parseghian said.
How Disease Takes Its Toll
Niemann-Pick type C is a disorder in which low-density lipoprotein, the so-called bad cholesterol, accumulates in and eventually destroys cells of the brain, liver, spleen, lungs and bone marrow.
Cholesterol--a fat--is a component of cell membranes and an essential building block for steroid hormones. But too much of it can lead to clogged arteries, atherosclerosis and heart attacks.
Children with the disease often have jaundice at birth or shortly thereafter. As they near school age, they tend to develop an unsteadiness in walking, difficulty in controlling their limbs and problems in moving their eyes. As it progresses, they have difficulty with all forms of mental functioning and develop slurred speech. Death is caused by failure of one or more organs.
About 1 in 1 million children is born with the disease. It is a recessive genetic disorder, meaning that a child must inherit a copy of the defective gene from both parents to develop the disease.
If both parents carry the gene, as is the case with Cindy and Michael, each child’s odds of having the disease are 1 in 4. The odds that three children in the same family will have the disease are 1 in 64.
In Hollywood terms, Mike and Cindy met cute. Students at Notre Dame, where Mike played football for his father’s Fighting Irish in 1974, they studied in the same section of the library, lived in the same dorm and ate in the same dining hall. Eventually, Mike asked Cindy out and they married after graduation, he with a degree in premed, she in accounting.
After medical school at Northwestern, the couple moved to Tucson, where Mike took up practice as an orthopedic surgeon. In 1984, Ara, named after his famous grandfather, was born.
The first hint of a problem in Michael appeared when he entered kindergarten. He was clumsy, although not more than other children in the class.
“But in kindergarten,” Cindy recalled, “the others started progressing, while Michael kind of stagnated.”
The family pediatrician “gave Michael three small tests but found nothing. “He said, ‘If it was my child, I wouldn’t do anything,’ Cindy recalled. “But we just knew in our hearts and souls that something was wrong.”
They went to other doctors, but the results were much the same. Some said he suffered from cerebral palsy, others said they simply had no idea. Finally, after 16 months of doctor-hopping, physicians at Columbia University in New York City diagnosed his condition as Niemann-Pick type C, commonly called NPC.
The physicians had access to all of Michael’s previous tests, but the big clues, they told Mike and Cindy, were his eye movements and his enlarged spleen.
“As soon as they said that, our hearts went down to our toes because the two girls also had enlarged spleens,” Cindy said. “You can imagine the impact it had on us. The burden of having one child with it and compounding that with two more was just unfathomable.”
Tests confirmed that both Marcia and Christa had the disease, even though they bore no outward signs of the illness. Only the Parseghians’ firstborn, Ara, was spared.
When he found out that three of his grandchildren had the disease, Coach Ara, who lives with his wife, Katie, in Marco Island, Fla., was shattered.
“There was a period of probably a month of just pure anguish,” he said. “I’m a grown man, but there were times driving in the car by myself when I would just break down.”
But he and the family got back up. “We’re not gonna give up without a fight,” became his mantra.
As Family Fights, Help Pours In
Mike Parseghian had heard of Niemann-Pick but didn’t remember much about it. So he began contacting scientists at the National Institutes of Health to check on the status of research.
Cindy also began looking for ways to become involved.
There already was one group, the National Niemann-Pick Foundation, started by a group of parents. (Cindy later joined its board.)
The family thought about joining that foundation. But with Coach Ara’s prominence and Cindy’s accounting background, “we thought we could put together a more effective foundation to move dollars as quickly as possible into research,” she said.
Cindy and Ara started calling up Notre Dame alumni groups around the country. The response was immediate. The groups held fundraising dinners, golf tournaments and other events, often with one or more Parseghian as the guest of honor.
The rock group Chicago, whose manager Peter Schivarelli played football for Coach Ara, held a benefit concert at Notre Dame and is now donating a percentage of its box office receipts to the foundation up to a total of $200,000.
Students at Sunrise Drive Elementary School in Tucson, which the Parseghian children attend, conducted a million-penny drive that has now reached 1.9 million pennies.
“It was very hard for me at first to start asking for help because I always thought I was independent and self-sufficient,” Cindy said. “But once people have been asked and they see the need, they want to help.”
The foundation, headed by Cindy, is staffed entirely by volunteers and most of its equipment and other needs have been donated by local businesses. According to Cindy, 96% of all funds collected go to research. Most foundations spend 15% or more on overhead.
The Parseghians quickly recruited a scientific advisory board that guides allocation of the funds. One of the first grants went to a team headed by Peter G. Pentchev, a cell biologist at the National Institute of Neurological Diseases and Stroke in Bethesda, Md.
The first breakthrough in understanding the disease had actually come earlier, when researchers at the institute discovered in 1983 that cells from people with the disease did not process cholesterol properly. This allowed them to develop a diagnostic test in which skin cells from a patient are grown in the lab.
The blood and tissue samples provided by the test subjects ultimately led Pentchev and his team to the July discovery of the Niemann-Pick type C gene on chromosome 18, one of the 23 pairs of chromosomes that form the genetic blueprint of a human.
Pentchev, geneticist Eugene D. Carstea, who is now at the Saccomano Research Institute at St. Mary’s Hospital in Grand Junction, Colo., and their colleagues found eight different mutations in the new gene, which they called NPC1. But those mutations were present in only 95% of the Niemann-Pick families they studied.
This means there must be a second Niemann-Pick gene on another chromosome, said Dr. Michael Parmacek of the University of Chicago, who is medical director of the Parseghian foundation. This gene probably controls another step in the newly identified cholesterol pathway, and Pentchev’s team has already begun searching for it.
Simultaneously with the discovery of the human gene, a team led by geneticist William J. Pavan of the National Human Genome Research Institute in Bethesda reported that it had found the defective gene that causes a Niemann-Pick-like disease in mice.
That, too, was a key discovery. Normally, the first step after isolating a gene like NPC1 is to insert it in mice to produce an animal model of the disease, a process that can take two years or more.
Discovering a ready-made animal model will enable researchers to immediately begin looking at how the gene causes disease. More important, from the Parseghians’ viewpoint, the mice will provide scientists a valuable tool to test new drugs and therapies as they are developed.
Mourning One Child, Holding On to Others
The Parseghians are gratified by the discoveries.
“In this football game, we started in our own end zone and it looked like the field was slanted uphill,” Coach Ara said. “Now, we’re past the 50-yard line, the villain is in the end zone, and we are going to score.
“We don’t have the cure, but we are going to get the cure. This is a giant step forward.”
Sadly, however, that cure did not come in time to help Michael.
“Michael always thought he was a cowboy,” Cindy said. “When he was younger, he used to wear cowboy boots every day. He was the only child I ever knew who wore out cowboy boots before outgrowing them.”
He loved to ride horses and his favorite singer was Garth Brooks, whom he met last summer. He also loved karate, taking lessons right up until his death.
Michael’s death was unexpected because he had not been unusually sick. “We thought we had years left,” Cindy said.
But one morning in March, Cindy found him lifeless in his bed. Doctors believe he had a seizure during the night and was unable to breathe.
Michael’s death has taken its toll on Marcia and Christa, who know they suffer from the same disease. “We’ve seen a change in them the last few months from the psychological effect of seeing one of their siblings die,” Cindy said. The emotional toll, she noted, has taken a physical toll, with more colds and some difficulties in breathing.
Both girls started school last month, with Marcia in the third grade and Christa in kindergarten. “Marcia is real active, she loves karate and dance, she loves being around other children. We want to keep her doing activities that are real normal. She walks and runs, but her balance is getting a lot worse.”
For Christa, the disease has struck harder, sooner. The kindergartner moves stiffly. Her speech is so slurred that most people outside her family can’t understand her. “But they are both very happy, very loving,” Cindy said.
The Parseghian children take cholesterol-lowering agents on the chance that they will help, but it has not been proved that they do.
“As do all parents, we want to see their dreams come true,” Cindy said. “But we don’t focus on long-term dreams. We focus on short-term dreams.
“We never thought we would lose Michael as quickly as we did. Now, we have to step back and take each day with those children and make them as happy as we possibly can.”
For further information:
Ara Parseghian Medical Research Foundation
(520) 577-5106
https://www.azstarnet.com/~victory
National Niemann-Pick Disease Foundation
(804) 357-6774
