by Hope Jahren
Could Jill have not just one but two incredibly rare genetic diseases? The odds of Jill’s having Emery-Dreifuss were so rare that the prevalence isn’t even known; certainly more rare than one in a million. The odds of having partial lipodystrophy are probably somewhere between one in one million and one in 15 million. The odds of separately getting both by chance alone? It was one in far more than the number of people who have lived on Earth, ever.
Jill attended a medical conference at Hopkins during her internship, and, as she had with Emery-Dreifuss, she showed photos to doctors and told them she thought she had partial lipodystrophy. Just like before, they assured her it wasn’t the case. They jokingly diagnosed her with something a lot more common: intern syndrome. “Where you have a medical student being introduced to a lot of new diseases,” Jill says, “and they keep thinking they have what they’re reading about.”
This time Jill believed the experts, so she dropped it. One rare disease was enough. She went back to reading about Emery-Dreifuss. But pretty soon she dropped that too. She was learning more about all the cardiac problems—the average lifespan of subjects in case studies she read was around 40—and the stress landed her in the hospital. “I had two panic attacks that were brought on by the stress of reading all these things,” Jill says. “And I went to a counselor for a while and worked with my cardiologist. And we decided it was just too much information. It wasn’t healthy.”
So she stopped reading scientific literature. Cold turkey. No more medical research. No more DIY diagnosis. She started working as a writing instructor at community colleges and taught adult education at night.
She started dating and met Jeremy, the man she would marry. And though there was a 50-50 chance she would pass down her Emery-Dreifuss gene mutation, they decided to have a child. Jill’s pregnancy was normal, and her son, Martin, did not inherit the mutation. But after he was born, Jill’s physical problems accelerated.
She started having muscle twitches—not just little ones, in one muscle at a time, but from head to toe, for hours. Suddenly she was having to hold on to Jeremy to steady herself when she walked. “The best way I can describe it,” Jill says, “would be like where gravity is getting incredibly heavy.”
By Martin’s first birthday she could hardly walk. One day he was calling that he wanted mac and cheese. It was just a few feet to the kitchen. “I had six steps to take,” Jill says, “and I realized this is it. This is the last six steps I’m going to take.” After that Jill could not get up again.
Her father was losing his ability to walk at exactly the same time, so father and daughter transitioned to life in motorized scooters. Jill remembers seeing her father discouraged for the first time in his life. After one visit with a neurologist he told her, “I feel like I go there just to be weighed.”
Five years later Jill’s father told Jill’s mother that he was tired, so he moved from his scooter to his favorite chair. He bowed his head as if taking a nap, but he never woke up. His heart had finally failed, at the age of 63.
On the day her dad passed away, Jill and her siblings and a few relatives had dinner together at her mom’s house. Later that week Jill’s younger sister Betsy pulled Jill over to the computer to show her a picture.
People often asked Betsy what kind of workout she did, because the muscles in her arms were so well defined. But it wasn’t from the gym. Betsy’s arms had always been defined, and as she grew up, she wanted to know why. Jill told her that she might want to look into lipodystrophy but that doctors had told her years ago she didn’t have it. Betsy attended a meeting for people with lipodystrophy and there learned about an Olympic sprinter who was conspicuously missing fat. The picture Betsy showed Jill was, of course, of Priscilla Lopes-Schliep.
“She pulls up pictures of this extremely muscular athlete,” Jill says. “And I just took one look at it, and just . . . what?! We don’t have that. What are you talking about?”
But a week later, with the funeral out of the way, Jill got curious. She started Googling. Not just pictures of Priscilla running, but photos of her at home, just hanging around or feeding her baby daughter. She saw the same prominent veins, the same fall of clothing over shoulders and arms missing fat. The same visible divisions between muscles in the hips and butt. “It was just unmistakable,” Jill says. “It’s like a computer that can analyze a photo and get a match and be 100 percent sure that’s the same shoulder, that’s the same upper arm. I see the same veins, I see them branching this way. You just know and it’s hard to convey, how could you just know. But I knew we were cut from the same cloth. A very rare cloth.”
It was the third time Jill had made a visual lock on something rare. First it was with her family’s Emery-Dreifuss, then when she thought they had lipodystrophy, and now she thought that she and Priscilla just must have a mutant gene in common because of the exact same pattern of missing fat. But how then did Priscilla get a double helping of muscle while Jill’s muscles were scarcely there?
“This is my kryptonite, but this is her rocket fuel,” Jill says. “We’re like comic-book superheros that are just as divergent as can be. I mean, her body has found a way around it somehow.”
If this sounds familiar, it might be because it’s basically the plot of the Bruce Willis and Samuel L. Jackson movie Unbreakable, about comic-book superheros. Jackson plays a broken-boned, physically fragile man searching for his genetic opposite, a man born so strong he can survive any physical trauma. In the final scene, Jackson tells Willis he’s the guy.
Jill’s 12-year abstinence from medical literature was over; she wanted to enlist Priscilla in her genetic detective work. Partly out of curiosity, but also because if Priscilla’s body had indeed found some way to “go around” a lamin mutation that should cause muscle failure, it could be important for scientific research.
There was just one practical problem. Jill had no idea how to go about reaching Priscilla so that she could tell her all this. “I’ve had crazy ideas, like can I show up to Canada at a meet-and-greet or a track event?” Jill says. “You’re just going to get a restraining order at best. I mean, people will think you’re crazy if you’re on this motorized scooter and you’re going up to this hurdler. Nobody in security is going to let you by.”
A full year passed. That’s when I came in.
Jill happened to be in earshot of her television when I started yammering about athletes and genetics on Good Morning America.
“I thought, ‘Oh, this is divine providence. This is exactly what I’m looking for,’ ” Jill says. So she sent me an email, and then the package with original family photos, scientific papers, and the 19-page bound packet explaining her gene mutation and her theory that Priscilla also had a lamin mutation. Jill wanted my help getting in touch with Priscilla.
It just so happened that Priscilla’s agent and I followed one another on Twitter. So I sent him a direct message. I didn’t expect anything to come of it. I mean, I was telling a pro athlete that a stranger in Iowa wanted to talk to her about getting a genetic test. Luckily, Kris Mychasiw, Priscilla’s agent, is an extraordinarily nice guy. And he also knew that Priscilla constantly faced steroid whispers because of her musculature. After she won the Olympic bronze in 2008, some media in Europe began to openly accuse her. She ran at one meet in France specifically so that she could address the French media.
Kris passed on my request to Priscilla. “He was just like, ‘This lady in Iowa. She says she has the same gene as you, and wants to have a conversation,’ ” Priscilla recalls. “I was kind of like, ‘Um, I don’t know, Kris.’ ” But he told her just to have the conversation and see where it goes.
I talked to Priscilla first, and then she and Jill talked on the phone. Jill sent Priscilla the same 19-page packet she’d sent me. And it wasn’t any of the abstruse science that caught Priscilla, it was the childhood stories Jill shared about kids pointing at the veins in her legs. As a little girl, Priscilla would come home asking her parents to get the veins removed fro
m her legs because the boys were making fun of her. One of Priscilla’s cousins had looked into lipodystrophy, but nobody in the family had ever gotten a firm diagnosis, nor did they know much about the condition. They just knew there were a lot of strong and well-defined people in the family, especially the women. But there wasn’t much impetus to do a deep investigation. After all, when Priscilla was a kid she wasn’t falling like Jill, she was getting strong, and fast. She earned a track scholarship to Nebraska, where she became one of the best athletes in the university’s history and won a national championship. After college she turned professional and won her Olympic medal.
Still, when Priscilla would walk around at track meets, she’d hear people commenting, she says, “Oh look at her glutes, look at her arms, shoulders, calves. Oh look, look, look!” A picture of a male bodybuilder’s face was pasted onto a photo of Priscilla’s body—while she was straining to the finish line, attempting to make the Olympic final—and posted online. “That was pretty messed up,” Priscilla says. “I was really pissed off about that . . . A lot of people honestly believed I was taking steroids.”
Priscilla thinks that because of her physique, she was targeted for more than the normal amount of drug testing. (Targeted testing is a standard part of antidoping.) She was tested right after having her daughter, Natalia. At the World Championships in Berlin in 2009, she was tested just minutes before winning a silver medal. There’s not even supposed to be any drug testing that close to the race.
The following month, at a meet in Greece, someone stole her training journal out of her bag. It was at the very bottom, underneath expensive workout clothes and shoes, none of which were taken. Why steal a training journal? We’ll never know. But I’ve covered a lot of doping stories, and I’m convinced someone thought the journal contained her steroid regimen.
Jill and Priscilla spoke on the phone several times. Then, eight months after I introduced them, they agreed to meet in person. They picked a hotel lobby in Toronto, where Priscilla lived. Jill arrived first, with her mom.
She watched the clock. It ticked past the time they were supposed to meet. Jill got scared. This was a crazy thing she was doing. What if Priscilla had decided not to show? She watched the door. And when Priscilla walked in, Jill’s first thought was, “Oh my gosh, it’s like seeing family.”
Priscilla felt the same way. “It really was just a wow moment,” Priscilla says. “Like, do I know you?” The two women started flexing for one another, Priscilla’s muscles many times larger but with the same definition exposed by a lack of fat. They even retreated to a hallway in the hotel to compare body parts. “There is something real here,” Priscilla recalls thinking. “Let’s research. Let’s find out. Because how could the gene do this to you and this to me? That was what my question was. How?”
Jill offered Priscilla a cashier’s check, money that had been raised for research in a memorial fund after her father’s death. Jill hoped Priscilla would take it and use it to pay for a genetic test. And Priscilla agreed.
It took a year to find a doctor to test Priscilla. She visited several clinics. Some told her they just didn’t do that test. Others said they weren’t sure how to interpret the results, so they felt it wouldn’t be responsible to do the test.
Finally Jill went to a medical conference and approached the foremost expert in lipodystrophy, Dr. Abhimanyu Garg, who runs a lab at the University of Texas Southwestern Medical Center. He agreed to do both genetic testing and a lipodystrophy evaluation.
The results showed that Jill had been right. She and Priscilla do have a genetic connection. Not only do she and Priscilla both have lipodystrophy—the disease Jill had been told to cast aside back when she was an intern at Johns Hopkins—but they have the exact same subcategory of partial lipodystrophy, known as Dunnigan-type.
And Priscilla did indeed have a mutation on her lamin gene. Both women have a typo on the same one of their 23,000 genes. Priscilla’s is not the exact same “single-letter” typo that Jill has, though; it’s a neighbor typo. That splinter of distance in typo location seems to makes the difference. It’s why Jill has Emery-Dreifuss and Priscilla has fantastic musculature. (That said, there are people with Priscilla’s exact genetic typo who have both fat and muscle wasting.)
Dr. Garg called Priscilla immediately to give her the news. He caught her at the mall, shopping with her kids. “I was just dreaming about going out and getting a juicy burger and fries,” Priscilla says, “and Dr. Garg calls me and says, ‘I have your results.’ ” Priscilla asked if she could call him back later, after lunch. He said that she could not. “He’s like, ‘You’re only allowed to have salad. You’re on track for a [pancreatitis] attack.’ I was like, ‘Say what?’ ”
Despite her monstrous training regimen, Garg informed Priscilla that due to her unmonitored lipodystrophy, she had three times the normal level of triglycerides, or fat, in her blood. Garg has had a number of partial lipodystrophy patients with unusually large muscles who were good athletes, but none as muscular nor as athletically accomplished as Priscilla. He thought her training would probably protect her from the buildup of fat in her blood, but he was wrong. “I thought with her physical training, I’m not going to find much metabolic abnormalities,” Garg says. “But this was the one thing that was a severe problem on her blood testing.”
In other words, Jill had once again helped steer someone away from a medical disaster. She had prolonged her dad’s life, and now—once again with that cutting-edge medical tool Google Images—she caused the most intense medical intervention that a professional athlete had ever had. Priscilla called Jill to tell her. “I was like, ‘You pretty much just saved me from having to go to the hospital!’ ” Priscilla says. “Dr. Garg told me I have the gene and my numbers are out of the roof.”
Even Garg was startled by what Jill had done. “I can understand a patient can learn more about their disease,” he says. “But to reach out to someone else and figure out their problem also. It is a remarkable feat there.”
Priscilla has now overhauled her diet and started medication. She was recently recruited to try bobsled for Canada, which—if all goes well—could give her a chance to be the sixth athlete ever to win a medal in both the Summer and Winter Olympics. And with her genetic test, she hopes the steroid whispers will die down too.
A little more than a decade ago, when the first full human genome was sequenced, some medical futurists and optimistic doctors prophesied that we’d all bring our genetic information to the doctor’s office to get treatment personalized to our DNA. Not only has that not materialized, but for the most part, studies that scan entire genomes for disease-causing DNA “have not resulted in anything clinically useful,” says Heidi Rehm, a geneticist at the Harvard Medical School.
It’s not that there aren’t plenty of genes that matter, but it turns out that unraveling genetic causes of disease is a whole lot more complicated than that wishful thinking of a decade ago. Rather than single genes causing a disease—or any trait, really—it’s usually many small genes, each with a tiny effect, combining to influence a condition, and doing so in concert with lifestyle and other environmental factors.
Many rare diseases, though, actually are caused by single genes that alone have a large impact on biology. So those mutant genes have been far easier to locate. And sometimes when scientists can figure out what’s causing a serious and rare disease, they can begin to untangle more common ailments. “As you begin to understand these pathways,” Rehm says, “there will be milder versions of those rare diseases you can help to affect by understanding the outliers.”
For example, research on a rare gene mutation which gave people such low cholesterol levels it was a wonder they were alive led to a treatment for high cholesterol. An Alzheimer’s treatment may one day come from ongoing research on a small group of people in Iceland who have a version of a gene that protects their brains in old age.
Recently Rehm and a group of scientists started something called the Ma
tchmaker Exchange; it’s a kind of OkCupid for rare diseases, where people with uncommon conditions can be matched with other people with similar diseases and gene mutations, in the hope that it will spark new discoveries. After all, under normal circumstances Jill and Priscilla never would have ended up in the same doctor’s office. A person with a rare disease in their family will often have seen more cases and different manifestations of the disease than any doctor has.
Rehm herself discovered that Norrie disease, which causes loss of sight and hearing, is not only a neurological but also a blood-vessel disease when she found a Yahoo message board where Norrie patients were all discussing their erectile dysfunction. “I think there is a cultural change,” she says. “Physicians are recognizing the very important role of the patient in being not only an advocate for themselves but really a source of relevant information.”
Dr. Garg, who has studied lipodystrophy for 30 years, says that Jill and Priscilla are the most extreme cases of muscle development he has ever seen in lipodystrophy patients—on opposite ends of the spectrum, of course. What might be causing that?
Jill and Priscilla don’t have the exact same typo, or “point mutation.” Because of that they have one condition precisely in common—Dunnigan-type partial lipodystrophy—and another that is divergent as can be—their muscles. But the mechanism behind their difference is an important mystery. It might not surprise you by now that in search of an answer, Jill hit the scientific journals.
She alighted on the work of a French molecular biologist named Etienne Lefai. He does extremely technical work on a protein with the less-than-mellifluous name SREBP1. SREBP1 has long been known to manage fat storage. After a meal SREBP1 is helping each of your cells decide whether to use the fat that just arrived for fuel or store it for later.