It’s human nature to need answers. We don’t like uncertainty.
That includes getting answers about your health. You go to your health care provider; you want to leave with a diagnosis.
But not all health care encounters work out that way. For about 25-30 million Americans, a diagnosis never comes, because the disease is rarely seen, previously undescribed or a rare form of a common disease. So the uncertainty continues. Visit after visit. Year after year.
Now the odds of finding a diagnosis have improved. Vanderbilt University Medical Center is one of seven medical centers around the country in the Undiagnosed Diseases Network (UDN), a clinical research initiative of the National Institutes of Health (NIH).
The Vanderbilt UDN clinical site will have emphases on heritable lung diseases in adults and children, heritable and other heart problems including pharmacogenetics, arrhythmias and autonomic disorders in adults, and metabolic and other genetic problems in children.
Loss of Vision, Muscle Weakness, and No Diagnosis
Maggie Hall, 14, of Cookeville, Tennessee, is one of Vanderbilt’s first UDN patients. She started wearing glasses when she was 5, and then developed weakness, exercise intolerance and worsening vision.
“When she was 8, basically over one day’s time, her vision decreased significantly,” said her father, Mike Hall. “One night we were throwing a football inside, and she wasn’t even getting close to catching it. Then we played a board game and she couldn’t find her piece on the board. We thought ‘oh my gosh, what’s going on?’ and we started to panic.”
There had been signs, Hall said. A couple of months before, Maggie had been working on homework with her mother when she started to stumble over words and became nauseated. Then her vision blacked out. They rushed her to the hospital, but her vision came back. A CT scan failed to show a diagnosis.
Several months later she had what her parents thought was a migraine and loss of vision, and the vision never completely returned. She has some peripheral vision, but her central vision is gone. She was seen at Vanderbilt and then Emory. Steroids that were prescribed didn’t help.
But along with decreasing vision, she also began experiencing intermittent muscle weakness. Although physicians believe her eyesight is an optic nerve issue, they don’t know if the eyesight and muscle weakness are related.
In the summer of 2014, Maggie became very weak. On a trip abroad with her father in Luxembourg, the weakness progressed and she had no appetite. She needed a wheelchair upon her return to the United States, but the weakness improved.
“She had another episode in the fall of 2014. Maggie couldn’t walk at school without getting winded and stopping to rest. She had tingling in her calves and numbness in her toes, was losing weight and needed help standing up.
“That was a very tough year,” Hall said.
Maggie began seeing Tyler Reimschisel, M.D., a Vanderbilt professor of Pediatrics and Neurology and director of the Division of Developmental Medicine. She also visited the Mayo Clinic for help in diagnosing her illness. “We were starting to panic. Her health was going down, down, down,” Hall said. Physicians ruled out multiple sclerosis and muscular dystrophy, and she had a muscle biopsy and a nerve conduction study performed to check muscle and nerve health. “They saw nerve death and muscle death, but also some regrowth,” he said.
Maggie’s B12 levels were also very low—about 90. Normal levels are 110-1,500 picograms per milliliter. Reimschisel’s target for Maggie’s level is 450. She has been getting B12 injections and vitamin cocktails, and her level is now approaching 400.
For the Halls, not having a diagnosis hasn’t been so much frustrating as “sad.” “As long as she keeps doing fine, that’s all that matters, but if having a diagnosis would help us treat it, then sure,” Hall said. “We’re very happy to be in this (UDN) program and see what comes up. I just want her to get better. But also, I’m scared to find out what it is. I just want her to have a good life.”
Maggie, a high school freshman, attends Cookeville High School on an abbreviated schedule. She is assigned a helper to aid in getting from class to class. Hall said that Maggie has kept a positive attitude as her health has waxed and waned. She has a larger iPhone with enlarged type so she can see to text, and a device called a Merlin that electronically magnifies books on her computer monitor. “She can get around the house fine and she doesn’t complain about her vision,” he said.
For the past six years, prior to the formation of the UDN, hundreds of patients were evaluated in the Undiagnosed Diseases Program (UDP) at the NIH in Bethesda, Maryland. They have come from nearly every state, the District of Columbia and seven foreign countries.
With the seven centers now accepting patients, the NIH has opened an online patient application portal called the UDN Gateway. Those ages 1 month to 99 years are eligible to be considered, and a doctor’s recommendation is required. The Gateway replaces what had previously been a paper-and-mail application process.
“These are patients with mysteries that we are trying to solve,” said John Phillips III, M.D., David T. Karzon Professor of Pediatrics and director of the Division of Medical Genetics and Genomic Medicine, who is co-principal investigator of the Vanderbilt UDN with John Newman, M.D., Elsa S. Hanigan Professor of Pulmonary Medicine. “The NIH’s goal in this is to discover new diseases,” Phillips said.
“A lot of these people haven’t been diagnosed, not because they don’t have something, but because nobody has seen what they have before. The demand has outgrown what NIH can offer (alone), and there’s the convenience issue—patients have to come from California to Bethesda. This network of clinical sites will serve that same role, but will be more geographically dispersed.”
Phillips said each clinical site in the UDN will offer studies that go beyond what is routinely done, such as whole exome sequencing (sequencing all genes).
Newman said Vanderbilt was an ideal choice because of its structure and strengths in bioinformatics, its BioVU program (Vanderbilt’s bank of de-identified DNA samples), the REDCap (Research Electronic Data Capture) developed at Vanderbilt, and the Clinical Research
Center where patients will be seen.
“We’re very well positioned for this kind of work at Vanderbilt. This is what we do,” he said.
The six clinical sites (excluding the NIH site) in the UDN will receive $43 million over four years and will contribute local medical expertise and conduct clinical evaluation and scientific investigation in cases that involve patients with prolonged undiagnosed conditions.
Since its 2008 launch, the UDN has reviewed more than 3,100 applications from patients around the world. More than 800 patients have been enrolled for a one-week evaluation.
While approximately 25 percent of those have received some level of clinical, molecular or biochemical diagnosis, many patients remain undiagnosed.
By including an additional six clinical sites, the UDN will both draw upon the unique expertise of new clinical research groups and cultivate opportunities for collaboration among a larger group of expert laboratory and clinical investigators. Physicians within the network will collect and share data. They will also benefit from common protocols designed to improve the level of diagnosis and care for patients with undiagnosed diseases.
By the summer of 2017, each new clinical site will accept about 50 patients per year. The network has also brought on board two DNA sequencing facilities, one is at the Baylor College of Medicine, and the other is at the HudsonAlpha Institute for Biotechnology in Huntsville, Alabama, partnering with Illumina in San Diego.
Putting a Name With a Disease
Between the launch of the UDN network in September 2015 and the end of January, 354 applications had been received and 41 of those were assigned to Vanderbilt. By early February, nine patients had been seen at Vanderbilt.
Eighteen-year-old Rachel Barnett of Springfield, Tennessee, was one of them.
Baye Barnett, Rachel’s mother, doesn’t know the cause of a complex set of physical problems that her daughter, Rachel, has battled since birth—a heart defect, a low blood count that caused anemia, one kidney that doesn’t function, high blood pressure, scoliosis and glaucoma. It seems like each doctor’s visit uncovers a new problem, but no real answers for her puzzled family.
Barnett said she is hoping to finally be able to put a name with Rachel’s disease.
The teenager was initially diagnosed with Diamond-Blackfan anemia, a disorder of the bone marrow, but that was later ruled out by her medical team at Vanderbilt.
“It seems like something new turns up every time we take her to the doctor,” Barnett said. “We’ve just decided this is just Rachel. Every time we bring her to the doctor, we leave thinking ‘maybe this is it.’ But we may have to accept that we may not ever know.”