Around the time Kate Kane turned 3, her parents realized that their little girl had a big appetite. Unusually big. At mealtime, the Towson, Md., tot would finish everything on her plate and then demand more. Never satisfied by what the rest of the family was served, she would go hunting for food on kitchen counters and in the breadbox. Eventually, her parents had to put padlocks on the cupboards and an electronic deadbolt on the refrigerator.
That was at home. In the outside world, Jim and Kit Kane had to warn neighbors, relatives, teachers and babysitters not to give her anything to eat outside of her scheduled meals, no matter how hard she begged.
As Kate grew older, her parents had to block the phone numbers of all the pizza parlors and delis in town and have their address put on a "Do Not Deliver" list. (She once at age 12 had a local restaurant deliver to a house down the block whose owners were away on vacation.)
Kate Kane, now 22, stands 5-5 and weighs 235 pounds. In medical terminology, she is "morbidly obese" (more than 50 to 100 percent or 100 pounds overweight), like some 5 percent of the U.S. population. But while many overweight Americans may say they just cannot stop themselves from overeating, Kane really can't. She is driven every minute of her life by the feeling that she is starving, because of a defect in her DNA.
Kane has Prader-Willi syndrome (PWS), a genetic disorder that occurs in about one of 12,000 live births. First diagnosed in 1956, it has several features, including reduced fetal activity in utero, poor muscle tone at birth and feeding problems in infancy. Others may include underdeveloped sex organs, short stature, small hands and feet, and skin and hair color that is a touch lighter than everyone else's in the family. PWS children typically have developmental delays, and most have some form of cognitive impairment.
But the defining characteristic is hyperphagia -- in plain English, an insatiable appetite. Obesity is the inevitable result for people like Kate -- unless someone figures out how to help them.
The obesity epidemic among Americans at large has given medical researchers new incentive to understand what's happening to Kane. In theory, if they can find a way to reduce her appetite and get her weight under control, they can use the lessons learned to create treatments -- perhaps even the elusive "thin pill" -- for the obese people in the general population who struggle with appetite control.
Obesity has become one of the biggest medical problems of our time. In 1999-2000, an estimated 64 percent of U.S adults aged 20 years and older were overweight or obese (more than 20 percent overweight), according to the Centers for Disease Control and Prevention. Fifteen percent of U.S. children and adolescents aged 6 to 19 were considered obese.
Obesity is a health issue, a social issue and an economic one. Obese people are often perceived as lazy, self-indulgent and lacking in willpower -- not the kind of profile likely to further career advancement. Obesity, in this light, is seen as a character issue.
But the case of Kate Kane, and others with PWS, tells us that sometimes it really is just a matter of biology.
Kate had a very short umbilical cord -- an indication that something was amiss -- when she was born. She was also "floppy," or lacking in muscle tone, and couldn't eat; doctors had to deliver formula via a tube from her nose into her stomach. The first few months of her life were dominated by what doctors call "failure to thrive." Then she stabilized.
Around age 2, things started to change for the better. Or so her mom and dad thought. "Kate was so skinny and thin," Jim Kane recalled. "We kept trying to get her healthy and fatten her up. Then all of a sudden she's 2 years old and she's pretty heavy. And we said, 'Oh, good, she's turned the corner.' "
Only Kate, having finally started eating, couldn't stop. Her big appetite was not the only sign that something was amiss. "It was the whole package," said her father. "Social, learning and developmental difficulties, all things put together." A Johns Hopkins geneticist diagnosed Prader-Willi based on her symptoms, even though Kate tested negative for the single genetic defect researchers then linked to the condition. (Today, a test looks for three distinct genetic errors, any one of which is considered a PWS indicator.) It was Kate's case, in fact, that led Hopkins researchers to tie the disorder to more than one genetic defect.
PWS presents obesity researchers with a unique opportunity: the chance to study "pure obesity." It is one instance in which whatever causes overeating and weight gain is not related to external factors. Ethnic and dietary factors are not involved, and neither are socioeconomic or emotional issues. Not even exercise habits -- or lack thereof -- cloud the picture. People with PWS are endlessly hungry no matter what, because of something that involves only the body's internal mechanisms.
Doctors had no clue what caused PWS until 1981, when researchers discovered that many people with PWS shared an abnormality: a segment of genes missing from chromosome 15, one of 23 pairs inherited from our parents and found in every cell of our bodies. They found that about 75 percent of people with PWS had this abnormality.
This information offered obesity researchers some important direction. Said Robert Nichols, a geneticist at the University of Pennsylvania School of Medicine: "Once we know genetic pathways, like in the PWS, we can investigate whether there are any specific components of the pathway that are common pathways involved in obesity."
Defects in chromosome 15, it turns out, also characterize another condition, Angelman syndrome, which also has obesity as a cardinal feature. So, is chromosome 15 to blame for obesity in the general population? Researchers know nothing is ever that simple. Still, chromosome 15 may be a piece of the puzzle for at least some obese people.
The Ghrelin Factor
If researchers cannot yet isolate and repair genetic defects, they can perhaps discover what is going wrong at another level -- with the glands and hormones that control hunger and satiety.
An endocrinologist looks at a Kate Kane and sees a problem with the delicate system of metabolic controls that tells a human being it is time to stop (or start) eating. In a person with PWS, said Nicholls, "the feedback mechanism is missing that would tell the hypothalamus, 'Look, you've got plenty of energy, you don't need additional nutrients.' They're not getting this feedback and rather they're getting this feedback saying, 'You're starving.' "
Quite possibly this failure occurs in people other than those who have PWS, which again opens the possibility that research aimed at treating PWS would have benefits for others with "broken" metabolisms.
Duke University endocrinologist and researcher Andrea Haqq and others are following a hormone called ghrelin. Made in the stomach, it tells the hypothalamus to control appetite. The more ghrelin in your stomach, the more you want to eat.
Haqq found that ghrelin levels in children with PWS were four or five times higher than in age-matched controls. What if you tried to lower ghrelin levels in people with PWS, she wondered. Might that solve some of the hunger issues?
In a small pilot study, Haqq gave four PWS children octreotide, an antidiarrheal drug that has been shown to reduce ghrelin levels in healthy adults. Ghrelin levels, she said, "dropped by about 67 percent in these kids." More research is needed to observe long-term effects and determine if indeed lower ghrelin levels lead to reduced appetite.
Ghrelin's potential hasn't escaped the attention of the pharmaceutical industry. Several drug companies are investigating synthetic and natural compounds that may help regulate ghrelin levels.
Kate Kane, like others with PWS, will stop at nothing to get food. She has been known to sneak into the kitchen when the rest of her family is asleep. She has ordered deliveries over the phone when no one was listening. She has even shoplifted.
"I was right next to her" when it happened at a local Starbucks a few weeks ago, recalled her father. "I must have turned away or reached into my wallet, and she grabbed a muffin from the counter and stuck it down her shirt."
By now, Jim Kane has developed a sense for these things. Suspecting that his daughter had snatched something, he confronted her in the car. "You just know something is up," he said, "and she'll deny it till the cows come home. I found the thing and I walked back to the shop."
But Kate's parents are entirely on her side. In order not to embarrass her, they usually return later to hand back the goods Kate has taken and to explain the situation. They have even created a brochure that introduces Kate to store owners and other strangers as a young woman with a problem, asking for understanding and seeking cooperation.
One paragraph, co-authored by Kate, goes like this: "My appetite hardly ever goes away. If I see food or think food is around, then my thoughts are going to stray in that direction. . . . You can help me by locking up any lunches or snacks you may have. If I take something that is yours, it may seem like stealing but I really can't help it."
Kate, who graduated at age 18 from Towson High School, now lives in a Wisconsin group home for people with PWS, where she earns a small income from Harley-Davidson for stitching and packaging microfiber cloths for wiping down motorcycles. The job is performed inside the group home, where, of course, the cupboards and the refrigerator are padlocked. She could have a "fairly normal job," said her father, "if it weren't for the appetite."
A previous job -- as an assistant at a nursing home near Towson -- was short-lived. When she was hired, her father said, "we thought, 'Great. She loves old people. Personality-wise she is very compassionate and loves to help.' " She was fired the first week after she was discovered taking food and candy from residents' rooms.
What is it like when the thing you want most is locked away where you can't get it? Anyone who has ever gone on a diet will understand Kate's answer.
"I get angry," she said -- about that and people's lack of understanding. "People don't know what it feels like," she complained. "It makes me mad. . . . People call me fat . . . and [say] stuff behind my back."
Not coincidentally, anger management is an integral part of her therapy at the group home, and a constant struggle for many people with PWS.
Still, Kate Kane's advice to others who struggle with intense food cravings: "Keep stuff locked up."
Research, said Jim Kane, is beginning to produce some benefits for people with PWS. Growth hormones, for example, are being used experimentally to improve the height and muscle development of children with PWS, making them less conspicuous. Because of the hormones, the children also have higher levels of energy, which of course helps burn more fat.
"Twenty years from now those kids are going to have a very different life," he says.
In the meantime, Jim Kane, who is an active member of the Prader-Willi association, has been working hard to get more publicity and push for more funding for research on this disorder. He recently helped organize the annual family picnic for the PWS Maryland chapter, where, of course, he had to give thought to how much food to put out, and when to lock up the leftovers.
It went off well, he said, partly because he's developed a strategy on where to locate the group's advocacy materials, donation forms and information booklets: He places them on a small table right near the food. That, inevitably, will be where the kids congregate. And if the kids are there, so are their parents, keeping endless vigil on their children's eating habits.
* The Prader-Willi Syndrome National Association has good links to resources, scientific information and frequently asked questions about the disorder. Includes links to local chapters and a Spanish version. www.pwsausa.org/
* The National Institutes of Health offers patient information with links to current clinical trials: www.nlm.nih.gov/medlineplus/praderwillisyndrome.html.
Ranit Mishori is a family practice resident at Georgetown University/Providence Hospital.