In 2014, Barbara Small was a pediatric nurse at Children’s Hospital of Philadelphia, enjoying her work, her family, and traveling with her husband, Dave. She was an active 55-year-old until she broke her hip in a bike accident.
A week after surgery to repair her hip, her vision became blurry. She went to the walk-in clinic at Penn Presbyterian’s Scheie Eye Institute and learned that her optic nerve was damaged, but that it didn’t have anything to do with her accident or surgery.
Soon after, she awoke one morning and couldn’t control her left side. The emergency room doctor told her she’d had a stroke and sent her to a neurologist. An MRI revealed she had a brain lesion, apparently an area of tissue that had been damaged by the stroke.
Over the next few years, as her eyesight continued to deteriorate, repeated MRI’s showed more brain lesions. Small visited a low-vision specialist, retinologist, endocrinologist, hematologist, rheumatologist and three cardiologists. She was tested for multiple sclerosis, diabetes, and a host of other diseases. She didn’t have any of them.
“I didn’t think they would ever find anything, that the tests would all be negative,” recalled Small, now 63. “I wasn’t optimistic about getting a diagnosis but I felt like I could overcome and manage whatever was wrong.”
Doctors did diagnose a number of issues, including retinopathy, a disease of the retina that can impair vision, and neovascularization, the growth of blood vessels that are part of abnormal tissue, such as tumors, and of course, those lesions on her brain. She was also seeing a physical therapist for balance issues. But what connected these diagnoses remained elusive.
Small often thought about her mother, who died while in her 40s of an illness that was never diagnosed. When Small graduated from nursing school, she looked at her mother’s medical records, which showed hardening of the arteries, arterial sclerosis, collagen disease, cardiac arrhythmias, and liver and kidney failure.
“They summarized it as multisystem failures,” Small said.
Her mother, who died in 1969, hadn’t displayed any brain or eye symptoms, however. And her father, who lived into his late 80s, never spoke about his wife’s illness.
In January 2018, almost four years after Small’s first symptoms, her neurologist sent her for genetic testing.
“When I saw the geneticist, I said, ‘This will be my last doctor,’” Small said. “The geneticist tested me for four different genetic diseases that involve the brain and the eye and I tested positive for the TREX 1 gene mutation.”
Small was diagnosed with RVCL — retinal vasculopathy with cerebral leukoencephalopathy — an extremely rare, inherited disease with no known cure.
“Patients with RVCL are typically healthy until the fourth or fifth decades of life, and then they suddenly start to develop a variety of symptoms that can affect multiple organs, but especially the brain and the eye,” said Jonathan Miner, associate professor of medicine and director of the RVCL Research Center at Penn Medicine.
“It’s a relentless disease that results in premature death in 100% of cases, in many cases within five or 10 years of onset.”
As devastating as the news was, Small also had some measure of relief to be able to put a name to her constellation of issues.
“I thought they would never find anything, that I would just have these odd symptoms,” she recalled. “Luckily, I had good doctors at Penn who did the research and were on this journey with me, trying to figure it out. They gave me a lot of resources so I felt very well-informed.”
Uncovering Small’s diagnosis was difficult because RVCL is so rare — just 43 families in the world are known to have it.
“I suspect there are many more RVCL patients who just haven’t been diagnosed yet,” Miner said. “The disease can be confused with other diseases, like multiple sclerosis, lupus or brain tumors.”
Disease of the retina is a hallmark of RVCL, but it can look very similar to diabetic eye disease.
“The patients will end up losing vision, can develop glaucoma or blood vessel disease in the retina, dementia, cognitive impairment, memory problems, difficulty speaking or walking, and stroke symptoms,” he said. “A lot of patients have kidney, liver or thyroid disease. In all cases, without having a genetic test, these findings can end up being attributed to something else.”
Within families with the disease, 50% will inherit the mutation that causes RVCL, and 100% of those with the mutation will develop the disease, Miner said. Since her diagnosis, Small’s family has undergone genetic testing that has uncovered more cases, including in one of her daughters and her brother. Small suspects that her mother had it, too, though her symptoms were different from her own.
Small’s brother, James Davis, 67, discovered that he had RVCL in July 2021. He had been getting injections in his right eye to treat vision problems for several years and later developed glaucoma. Otherwise, he felt fine — until he didn’t.
“In June of 2021, I had extreme fatigue, loss of appetite, problems with my right eye, and funky walking,” said Davis, who lives in Plymouth, Minn.
An MRI showed lesions concerning for possible malignancy, so he was expecting he might need treatment for brain cancer. When he shared the news with his sister, she put him in touch with Miner, who asked Davis to hold off on seeking additional evaluation until he had genetic testing. The test confirmed that Davis, too, had the TREX 1 gene mutation.
“It was a big shock,” said Davis. “We talked to our financial planner to be sure there’s sufficient money for my wife, Dale, and we’re trying to enjoy things as much as we can because my life expectancy is a lot shorter than we planned.”
Davis’ son is 27 and plans to have genetic counseling and testing soon.
Shortly after Small’s diagnosis, her daughters Kimberly Antonelli, 35, and Lindsay Ward, 32, had genetic counseling, and were told that many people don’t want to be tested because they fear the results — and think that they can’t do anything about them. They saw it differently.
“Getting tested was a very easy decision for me,” said Ward, who lives in West Deptford. “Knowledge is power. But it was a very hard eight weeks waiting for the results.”
She was especially anxious for her son, Declan, now 4. She does have the mutation, which means Declan might, as well.
“I had prepared myself for the worst,” she recalled. “In a weird way I felt it was a positive for my mom because now we’re in this together. I always try to see the bright side of things but obviously I was devastated. To think my future might not be as long as I had anticipated was hard.”
Hoping to become pregnant again, Ward went through preimplantation genetic diagnosis (PGD,) a laboratory procedure used in conjunction with in vitro fertilization (IVF) to reduce the risk of passing on inherited conditions.
“We had seven embryos. Four had the mutation and three did not,” she recalled. “I did three rounds of IVF and all resulted in eventual miscarriage. … It had taken such an emotional, physical and mental toll on me that I couldn’t do it again. We had our son, Jason, who is now 8 months old, naturally.”
Ward hopes that by the time her children grow up, there will be treatments or even a cure for RVCL, should they turn out to have the mutation. She has decided to wait on testing them so that they can make the choice together when they are older.
“I take things more seriously and live more for the moment because at any point I could have the onset or my mom’s could get worse,” she said. “This morning we went to get a dozen specialty doughnuts, and, why not! You’ve got to live life.”
Her big sister, Kimberly, was relieved to find out that she doesn’t have the gene, and so neither do her four children. Yet her joy for them is tempered by grief. “I’m happy that I’m negative but I’m sad that my other family members aren’t,” said Antonelli, who lives near Pittsburgh. “My sister and I are very close.”
Another source of stress is the fact that few people can really understand what it’s like to have such a rare condition.
“You can sympathize with people who have cancer because you understand it,” Antonelli said. “My mom has a death sentence but people can’t appreciate how dangerous and unknown these rare diseases are. There are very few visible symptoms.”
Miner, who came to Philadelphia from St. Louis in 2021 to lead Penn Medicine’s research center, is among numerous experts seeking answers to RVCL.
“What motivates me is knowing that this is a solvable problem because it’s a disease caused by a single gene mutation,” he said. “This disease is going to be eventually treatable and hopefully cured, but we don’t know how long it’s going to take, five years or 15 years.”
“Unlike many other diseases, RVCL is due to one protein encoded by one gene,” said Miner. “Now that we know the genetic cause, we’re hoping to be able to develop personalized medicines for these patients and their families. Understanding this particular gene and protein is about far, far more than this specific disease. The drugs that are being developed to target the TREX 1 protein are very likely to become useful for other diseases, as well.”
Small has some weakness on her left side, which causes a slight limp; her vision is impaired; and she tires easily. She left her nursing job in October 2019.
Now that her husband, Dave, is retired, they are enjoying travel and spending time with their family. She maintains an optimistic outlook, hopeful that progress will be made in unlocking the mysteries of RVCL, if not for her then for her children, grandchildren and future generations.
“My outlook is good,” she said. “My husband tells me I’m going to live until I’m 80. I’m not going to live until I’m 80 but that’s OK. I’m much more likely not to make it out of my 60s but that doesn’t depress me. It’s just the way it’s working out.”