A Life Saved By Genetic Sequencing

On her Instagram feed, Amanda Gonzalez-Bunster recently posted a photo in which she is, literally, the picture of health. She’s beaming. The camera’s flash bounces off her obsidian-black hair and the metallic foil flower pattern on her skirt. Her eyebrows, perfectly arched, convey poise and power. Gonzalez-Bunster, 35, looks like a business executive hamming it up after a long day in the office. 

Gonzalez-Bunster tagged her image with the hashtag “#sickgirlsclub.” This puzzling juxtaposition of health and illness comes from the insidious nature of her disease: it can hide in plain sight. For nearly two decades, it hid from medical specialists who searched for clues to find what ravaged this young woman’s body.  

Earlier this year, Gonzalez-Bunster began taking a medication that transformed her life and health. This was made possible by a team of Yale Medicine experts who used genetic sequencing to pinpoint the diagnosis: familial partial lipodystrophy type 3. This condition belongs to a group of rare disorders in which the body cannot produce fat tissue. The lack of fat cells—called adipocytes—sets off a cascade of other health problems, which can go undetected beneath the exterior of a person who looks perfectly healthy. “When I was little, I looked like an athlete—we used to joke about it,” Gonzalez-Bunster says.   

Neither Gonzalez-Bunster, nor her mother, Debbie, can recall anything unusual about her active childhood growing up in suburban Connecticut. As a 7-year-old, Gonzalez-Bunster visited her pediatrician, who requested a blood sample to test for high cholesterol as part of a then-progressive idea of screening for the earliest possible signs of heart disease. Everyone was confused when the child’s blood sample came back from the lab as unreadable. At the time, Debbie thought perhaps it was because her daughter had enjoyed a cupcake at a birthday party just before the blood draw. Given the child’s apparent health, the pediatrician decided to wait until the following year to test another blood sample—in the morning, before any food or drinks. When that one, too, came back unreadable, the pediatrician referred her to Columbia Presbyterian Medical Center’s newly founded lipid disorder clinic. 

There, they discovered a problem: Gonzalez-Bunster’s baseline triglycerides, the so-called “bad fat” levels, clocked in at 2,700 milligrams per deciliter. (Less than 150 is considered normal and healthy.) “If you let Amanda’s blood sit in a vial, it will separate into something that looks like chicken fat and a little bit of blood,” Debbie says. Spun in a centrifuge used to analyze blood samples, her blood takes on the consistency and color of strawberry cream. At the time, the slender 8-year-old was diagnosed with hypertriglyceridemia, a disorder usually found in obese or diabetic patients. With no lipid-lowering medications available for children, doctors could only encourage a low-fat diet and active lifestyle. Gonzalez-Bunster continued a carefree, busy childhood. 

She fell in love with swimming early on. By middle school, high school swimming coaches were coming to watch her on travel team circuits. As a high school freshman, she was already a star, competing in the freestyle, breaststroke, and relay. But, excited by her talent, her coaches pushed her too hard, too fast. In her sophomore year, she required surgery to repair her injured rotator cuff. At 15, the star swimmer ended her career. No one was prepared for what happened next. 

Not long after she stopped swimming, Gonzalez-Bunster felt a sudden, intense wave of nausea while hanging out at a neighbor’s house in Milford. A searing pain radiated through her abdomen, causing her to double over in pain. Her parents immediately phoned her doctor at Columbia Presbyterian, who wanted them to bring her immediately to the Manhattan emergency room where, after a few tests, he diagnosed her with pancreatitis, or inflammation of the pancreas. This diagnosis, like her hypertriglyceridemia, also seemed out of place. Pancreatitis is typically seen in patients with gallstones or those who drink too much. 

Over the next few years, Gonzalez-Bunster experienced frequent pancreatitis attacks. Her triglyceride levels would soar to 10,000 milligrams per deciliter. Visits to the emergency room were so frequent that the family bought a monthly pass in order to avoid costly parking fees. Each attack was followed by a hospitalization lasting several weeks or longer. Gonzalez-Bunster often had to be fed intravenously while doctors waited for her pancreas to recover. During those countless trips, her younger sister, Vanessa, memorized the locations of the hospital’s hot chocolate dispensing machines. “As a family, we had to find ways to laugh,” Debbie says. “We have a very black sense of humor. We adapted and learned to survive.”

When she describes what her tumultuous life was like during those years, Gonzalez-Bunster takes on a clinical tone. She hovers over poignant memories, while glossing over huge swaths of life that are painful to recall. She graduated from New York University with a degree in nutrition and immediately enrolled in a master’s degree program in social work at Fordham University. Though she tried to live a normal life, by 2006 the debilitating pancreatitis attacks made any normalcy impossible. Gonzalez-Bunster couldn’t eat many foods and felt tired all the time. She withdrew from graduate school, focused on her personal life and felt pleased by small victories, like making it through her wedding day in 2008 with no attack. “I literally felt like a ticking time bomb,” Gonzalez-Bunster says. However, a year later, on her first wedding anniversary, she experienced the worst pancreatitis attack in her life. 

Grasping at hope

Her pancreas had shut down completely. Doctors recommended surgery to remove the organ, which is responsible for regulating the body’s insulin levels and producing enzymes necessary for digesting and absorbing nutrients.  They also wanted to take out her spleen, which shares a blood supply with the pancreas. When she awoke from the surgery, Gonzalez-Bunster had her appetite back and began to feel healthy again, though she was now insulin-dependent. 

In 2011, Gonzalez-Bunster became pregnant. She delivered her son, Greyson, prematurely at 27 weeks, due to pre-eclampsia complications. He survived 36 hours, then died from a brain hemorrhage that commonly occurs in premature, white male babies. “For the first time in my life, I wanted to throw in the towel,” Gonzalez-Bunster says. “I wanted to be a wife and a mom, and I had gotten almost there.” Two years later, her husband decided he didn’t want to live with a chronically ill wife and walked out. Recounting this, Gonzalez-Bunster barely pauses as she moves closer to the present with her medical history. 

Gonzalez-Bunster moved in with her parents in Greenwich and began working at a nonprofit agency. But her health continued to deteriorate, and she repeatedly went to the hospital to be treated for bowel obstructions. Due to continuing health complications, she had to resign from her job. In 2015, surgeons recommended a total colectomy to remove her large intestine because scar tissue from the pancreatectomy had formed around her colon. Around the same time, Gonzalez-Bunster began vomiting blood due to esophageal bleeding during a stay at Greenwich Hospital. She was diagnosed with fatty liver disease, yet another disease for which she did not fit the typical patient profile. Doctors at Greenwich Hospital referred her to Yale Medicine’s Section of Digestive Diseases. While she was at Yale New Haven Hospital, Pramod Mistry, MD, PhD, a well-known hepatologist at Yale Medicine, happened to be making rounds. “One cannot help but be inspired by Amanda's resilience and courage,” Dr. Mistry says. “I was struck by her the moment I met her.” 

Finally, an answer

As her health began to stabilize during her hospitalization, Dr. Mistry began to wonder about his patient’s medical history. A specialist had made the  diagnosis of fatty liver disease after spotting globules of fat on her liver through ultrasound imaging. “To my mind, that was really odd, because fatty liver disease usually occurs in people who are overweight or obese,” Dr. Mistry says, adding that “no one had been able to figure out why she had trouble with lipid disorders.” He ordered a liver biopsy, which confirmed his concerns—she had both fatty liver disease and fibrosis. Dr. Mistry then decided that Gonzalez-Bunster needed genetic sequencing to identify the root cause of her multiple health problems. He enlisted the help of Silvia Vilarinho, MD, PhD, a physician-scientist who treats digestive and liver diseases and conducts research with the Genetics Department to find new diseases and potential treatments. 

Dr. Vilarinho sent a sample of Gonzalez-Bunster’s blood to the Yale Center for Genome Analysis in order to sequence the coding regions, collectively called the exome, of almost 20,000 human genes. When she received the results, she compared them against genomic databases of individuals without severe disease and searched for new or rare mutations that could explain Gonzalez-Bunster’s constellation of symptoms. A mutation on the PPARG gene stood out as the culprit. This gene plays a key role in the formation of fat cells. If these cells, called adipocytes, are absent in the body, then triglycerides—the bad fat—that are normally stored in fat cells end up floating in the bloodstream and accumulating in organs, especially the liver.  

Gonzalez-Bunster is thought to be one of only 31 people in the world to be diagnosed with familial partial lipodystrophy type 3. The Yale team also performed exome sequencing on her parents and found that neither had the mutation. This meant that Gonzalez-Bunster’s disease-causing mutation occurred “de novo," affecting only her genome.

A drug called metreleptin (the brand-name is Myalept) is helpful for patients with lipodystrophy. Because Gonzalez-Bunster’s body struggles make fat cells, it also doesn’t produce enough of a fat hormone called leptin. The drug works by increasing leptin levels in the body, which then helps lower triglyceride and blood sugar levels. 
She began taking metreleptin in March 2017 and noticed a difference immediately. “My energy levels improved,” she says. “It’s really been miraculous—how much it has changed my life for the better.” 

Earlier this year Gonzalez-Bunster re-enrolled in Fordham’s master’s degree program in social work, where she is starting again from the very beginning. Because she took classes more than 10 years ago, all of her previously earned credits had expired. That news was disappointing, but it didn't hold her back. Gonzalez-Bunster will graduate in May 2019 and plans to be highly involved with the lipodystrophy awareness patient group and become an advocate for rare diseases awareness in general. “I’m one of the healthier people with the disease,” she says, without a hint of irony. “I practice gratitude in my life and I feel I’ve been really lucky. Things could be so much worse.”