Clues to gene disorder that spurs overeating

The brick house at the end of Orchard Street in Marcus Hook looks perfectly ordinary from the outside. But every time the door opens, a screeching alarm goes off - a warning to keep the three young adults who live there from leaving on their own.

Inside, the kitchen is barricaded behind a heavy oak door, always locked. But Erin Kilgallon, 30; Gabriella "Gabi" Eisen, 31; and Richard Rinaldi, 31, are not under house arrest. They did nothing to deserve this imprisonment.

They were all born with Prader-Willi syndrome, a genetic condition that leaves them unable to control their eating - unable to ever feel full. Without such restrictions, many people with Prader-Willi can balloon up well above 300 pounds.

Scientists say this is not about gluttony or self-control. These people feel the way most of us would if facing starvation.

From studying them, scientists are gaining insights into hunger, obesity, and the ways our genes shape behavior and destiny.

These patients can help researchers "better understand the genes and brain circuits that are driving the current childhood obesity epidemic," said geneticist Theresa Strong at the University of Alabama at Birmingham whose son, 16, has Prader-Willi.

So, while the syndrome affects just one in every 10,000 to 20,000 births, research has already led to insights with sweeping applications.

Until recently, the genetic underpinnings of the disease were a puzzle. People with Prader-Willi seemed to have all the right genetic code, with something keeping key parts of it silent.

Solving that riddle helped open a new scientific vista known as epigenetics - the study of materials that surround genes and influence their function. In Prader-Willi, chemical "tags" were silencing some crucial genes.

Despite all the leaps in understanding, most people with the syndrome are still hungry.

While many people with Prader-Willi have intellectual disabilities, others fall into the normal IQ range. Strong's son attends a regular high school, though he gets some special assistance, she said.

Many could live independently as adults, she said, if not for the danger that they would eat themselves to an early death.

Eisen and Kilgallon say they're happy with the food they get at their group home, which is run by Elwyn, a Media-based nonprofit. The facility uses a combination of charitable donations and state and county funding to care for people with various disabilities.

When Mustapha Kanneh, the Elwyn home's assistant program manager, unlocks the kitchen, it sets off another ear-piercing alarm. Inside, the cabinets and refrigerator are also locked, just in case.

The meals are planned by a nutritionist, and a personal trainer comes by several times a week to guide workouts in the basement gym.

People with Prader-Willi have a weight-control double whammy, since they tend to have low metabolisms, said Michele Edgecumbe, director of operations for Elwyn.

Eisen and Kilgallon get about 1,200 calories a day for maintenance, an allotment that would cause most people to shed pounds fast.

Today, most children with Prader-Willi are given human growth hormone, which often puts them into the normal range of height and improves muscle tone.

Because they grew up before it was available, Eisen and Kilgallon are tiny - well under five feet, and at first glance easy to mistake for school-age children.

Kilgallon said she enjoys watching Cops and riding on her favorite horse, Patrick, at Thorncroft Equestrian Center. She hesitated when asked what her favorite food is, but Eisen, sneaking behind her, said it's coffee, with a sly smile. Her favorite, she said, is carrots.

Kilgallon then was interrupted by a call from her boyfriend, Justin. Talking to him is another favorite pastime. The two met when Justin lived in the house, though he has since moved back with his mother.

Scientists have found that those with Prader-Willi have abnormally high levels of a hunger-causing hormone called ghrelin, which is secreted by the brain and the stomach. But experiments with drugs designed to block ghrelin haven't worked. And so they're delving deeper into the problem.

The syndrome was identified in 1956 by a team of Swiss doctors, including Andrea Prader and Heinrich Willi.

By the late 1980s, a couple of inexplicable puzzles were stumping the field, said University of Pittsburgh geneticist Robert Nicholls, who helped unravel them.

He said many cases were associated with a missing chunk of DNA from Chromosome 15. (Beyond the more famous X and Y chromosomes, humans carry 22 other pairs, labeled 1 through 22.)

But not everyone with the syndrome had this missing piece of DNA, Nicholls said. And, weirder still, some people who seemed to be missing the same piece of Chromosome 15 had a different disorder called Angelman's syndrome, characterized by more severe mental disabilities, little speech, but no particular issues with food.

Eventually, Nicholls said, scientists realized that if the broken chromosome came from the mother's egg, it would lead to Angelman's syndrome, and if it came from the father's sperm, it would lead to Prader-Willi. It was the first time anyone had found a genetic disease that worked this way.

Nicholls suspected this was the result of a process called imprinting, a sort of external coding that can make the same genes work differently, depending on whether they are inherited from the father or mother.

The phenomenon was discovered in mice at Philadelphia's Wistar Institute in the early 1980s, but there had been no evidence it happened in humans - at least not then.

Nicholls later discovered another clue from Prader-Willi patients who seemed to have all intact chromosomes. He found that they had inherited both copies of Chromosome 15 from their mothers.

Humans are supposed to get one chromosome from each parent, said Nicholls, but it doesn't always work that way.

In theory, getting both copies of a chromosome from the mother shouldn't lead to a genetic disease. But it does in Prader-Willi because there's no Chromosome 15 from the father, and crucial genes on the mother's copies are rendered inactive by imprinting. It's as if those genes are missing.

Imprinting is just one form of epigenetics - which applies to any sort of packaging around DNA that doesn't change the genetic code but influences how it's expressed.

Attempting to parlay this into a new treatment, Nicholls and others have tried to mimic the disease in genetically altered mice.

But the recipe for doing this isn't obvious. The missing piece of Chromosome 15 has more than four million characters of genetic code, said Uta Francke, a researcher at Stanford University who has spent more than a decade working on Prader-Willi.

Which parts mattered?

Luckily, she said, in the last three years they have identified three unusual cases where people with the disease were missing a much smaller piece of Chromosome 15.

Studying them, she pinpointed a gene called SNORD116, which is copied more than 40 times in the critical region. It codes for an obscure biological entity called a snoRNA, which appears to be like a middle manager, doing something to sort and regulate other types of RNA. They're still trying to figure that one out, Francke said.

In 2008, she created a strain of genetically modified mice missing this particular gene. What she found was that they did have issues with food, but not quite the same ones seen in humans with Prader-Willi.

They ate more, and like Prader-Willi patients, didn't know when to stop once they started, she said. But unlike people, this didn't make them fat.

"This was a real surprise," Francke said. "Somehow they have a mechanism to deal with these calories." They seemed to compensate for the extra food by burning up more calories, though they didn't exercise more than ordinary mice.

So the mysteries remain.

Francke is determined to keep working so people with Prader-Willi can stop needing to be imprisoned in their homes, and many others can lose weight: "We need to figure out how to get this urge to eat under control."