What’s wrong with me?
For many years and dozens of doctor visits, Amy and her older sister have battled an undiagnosed genetic muscle disease.
Since adolescence, when they overexert themselves with exercise, their muscles start to break down, leaving them with significant muscle weakness, soreness and twitching, full body fatigue, headaches and nausea.
With the soreness and pain comes a high risk of rhabdomyolysis, which occurs when damaged muscle tissue releases its proteins and electrolytes into the blood. These substances can damage the heart and kidneys and cause permanent disability or even death.
“When I have an episode of full-blown rhabdomyolysis, it feels terrible — like every ounce of my body is extremely fatigued. It’s like nothing else I can compare it to or describe. Walking across a room feels daunting and exhausting, at least until I can semi-recover,” said Amy, 30, who has asked that her last name not be used.
She is one of thousands of patients in the United States looking for a diagnosis for something so rare they may never find the answer.
“After a while, because there wasn’t a test that hadn’t been done, we just kind of let it go (finding a name for their disease). There were some suspicions of certain muscle diseases that were rare and genetic, but our levels for those were either a little too high or too low, so nothing ever fit a diagnosis,” Amy said.
But in May, after being referred to the National Institutes of Health’s Undiagnosed Diseases Network (UDN) at Vanderbilt University Medical Center, Amy and her sister received the answer they had been searching for — a diagnosis.
At VUMC their genomes were sequenced, and a mutation was found. They were diagnosed with a rare form of Limb-girdle muscular dystrophy (LGMD), a group of disorders that affect the voluntary muscles around the hips and shoulders. The condition can be progressive, leading to loss of muscle strength and bulk over years. At present, there is no cure or treatment.
In April, VUMC, an original member institution of the NIH program, announced it is launching its own program, the Vanderbilt Undiagnosed Diseases Program (VUDP), which will operate alongside the NIH program. The VUDP goal is to expand services to many more patients who are living with the often-dire consequences of an undiagnosed disease.
The new program, which has begun reviewing and accepting patients, will allow VUMC, already a national leader in assisting adults and children with undiagnosed diseases, to help more patients and families who are struggling to find answers.
According to the NIH, there are an estimated 30 million people in the United States with rare diseases, and as many as 1 in 10 are without a diagnosis. An undiagnosed disease can include a rare or newly described disease or a rare presentation of a more common disease. Between 70 and 80% of undiagnosed diseases are due to rare genetic disorders.
“The remarkable collaboration of our clinicians, geneticists, biostatisticians and others, and their amazing success with the NIH’s Undiagnosed Diseases Network fueled the desire to expand these efforts for patients and families. Many have lived in anguish while not knowing the true nature of their health problems or a way forward regarding possible treatments. Our mission with VUDP is to give these patients answers, hope and peace of mind,” said Jeff Balser, MD, PhD, President and Chief Executive Officer of VUMC and Dean of Vanderbilt University School of Medicine.
Patients who have not been diagnosed have often been on a lengthy journey through the U.S. health system. Because nobody has seen their diseases before, or through lack of access to expertise and advanced diagnostic modalities, they can remain undiagnosed for life.
“This program is driven by a passion to help patients coming to us in search of an answer. Many adult patients with undiagnosed diseases have been looking for answers for 10-20 years, and pediatric patients, all their lives. Emotionally, as you can imagine, it’s very tiring, and there’s often a sense of hopelessness,” said Rizwan Hamid, MD, PhD, Dorothy O. Wells Professor of Pediatrics, director of Pediatric Medical Genetics and Genomic Medicine and director of the VUDP.
The VUDP will use Vanderbilt’s unique capabilities for analyzing genetic results, including its BioVU databank that allows for searches for genes and gene variants, Hamid said. “Leveraging resources like BioVU, the UDN program at VUMC has been extraordinarily successful. But we are very limited through the NIH program,” he said. “We can only evaluate 30 patients a year — 15 adults and 15 children. On average, 10 patients are rejected or not evaluated for each patient who is accepted. At Vanderbilt we have incomparable expertise — an amazing collection of genomic resources, physicians and scientists. Why not make it available to more people?”
The new program will be a partnership between the Department of Pediatrics at Monroe Carell Jr. Children’s Hospital at Vanderbilt and the Department of Medicine at the Vanderbilt University Hospital. “Our participation in the NIH program has been a wonderful example of this great collaborative spirit we have in our institution. The new program is another example of that,” Hamid said.
Since 2015, when the NIH-funded UDN program began enrolling patients, 202 patients from nine states have been accepted into Vanderbilt’s UDN, one of 12 clinical sites around the country working with four core labs to solve medical mysteries. Among all sites, the UDN has received 5,045 applications and 2,004 participants have been accepted. Of those, 1,563 have been evaluated and 479 participants have been diagnosed.
Hamid said the VUDP will begin with about one patient a week — the initial plan is to see 45-50 patients a year, with further expansion in the future. Like the NIH-funded program, medical records are submitted prior to the patient being seen, then it’s determined whether it’s likely the patient can be helped. The review starts with an initial medical records review, then those accepted consent to clinical testing and genomic sequencing (whole exome or whole genome), as well as an extensive inpatient clinical evaluation, which can often take up to five days.
“Since these are difficult cases, most will not be solved in that one-week period. The diagnostic odyssey from the time we see a patient until we get some sort of conclusion can sometimes take many months or longer,” Hamid said.
“The NIH-funded UDN program has been an enormous success at VUMC, with many patients receiving a definitive diagnosis and treatment plan after years in a diagnostic odyssey,” said Steven Webber, MBChB, MRCP, James C. Overall Professor, chair of the Department of Pediatrics and Pediatrician-in-Chief. “However, the number of patients that the program has been able to help has been limited based on the restrictions inherent to the program. This new clinical UDN program gives us the opportunity to offer VUMC’s expertise to many more patients who remain with chronic, debilitating illness but without a clear diagnosis.”
Kimryn Rathmell, MD, PhD, Hugh J. Morgan Professor and Chair of the Department of Medicine and Physician-in-Chief for the Vanderbilt University Hospital and Clinics, said she is excited that this resource can be shared with a broader group of patients.
“This multidisciplinary, collaborative team is ready to take on the most challenging cases,” she said. “Our unity of clinical acumen with curiosity, and our depth in the cross-cutting fields of immunology, genetics and data science, make VUMC the place for diagnosis of complex diseases.”
The VUDP team consists of Hamid; John Phillips, MD, David T. Karzon Professor of Pediatrics and professor of Medicine and Pathology, Microbiology and Immunology; Joy Cogan, PhD, professor of Pediatrics; John Newman, MD, Elsa S. Hanigan Professor of Pulmonary Medicine; John Fahrenholz, MD, assistant professor of Medicine; Kevin Byram, MD, assistant professor of Medicine; Lisa Bastarache, MS, research assistant professor of Biomedical Informatics; Mary Koziura, DNP, FNP-BC; Anna Bican; and Jennifer Kennedy, CGC.
Digging Through the Weeds
The group focused on undiagnosed diseases is made up of members of seven teams of scientists and data scientists from VUMC and Vanderbilt University — from areas including biostatistics, precision medicine, structural biology and genetics. They meet weekly to look at some of the analyzed data on patients to see if they can trim a list of thousands of possible candidate genes to a shorter list of six to 15 candidates.
“It’s an agnostic kind of review with a goal of narrowing down the list of what genes could be causing the problem,” said Anna Bican, Vanderbilt’s site coordinator of the NIH program. “The goal is to determine if the patient has a new disease, an atypical presentation of a known disease or possibly two or more diseases. To do this, the group combines the patient’s medical history, in-depth analysis of DNA sequencing data, and additional input from the BioVU, GTEx and structural biology analyses. These diseases cannot be identified by genomic analysis or by an extensive medical evaluation alone. It is only in the pairing of the two together that the diagnosis can be made.
“Every UDN site starts the review in the same way — with the initial lab report — but beyond that, each site goes about evaluating patients in a different way,” Bican said. “It’s important to have everyone in the same room. We start digging through the weeds, and it’s all the minds in this group that bring us to a diagnosis.”
Jacob Hall, 19, from Sevierville, Tennessee, is another patient who has received a diagnosis through Vanderbilt and the UDN.
Hall, his sister, Sarah, and his mother, April, who died in 2014, all began having symptoms including progressive muscular weakness and impaired sensory function in the legs and arms and hearing loss. Although a link was never established, the family initially believed some of the trio’s declining health issues might have been related to receiving a flu shot that protected against the H1N1 virus in 2010. April’s health steadily declined, and she died in May 2014.
In Knoxville, Jacob began receiving intravenous immunoglobulin therapy to help people with weakened immune symptoms, but an insurance issue led the family to bring him to VUMC. Hamid was called in for a consultation, and he referred them to the UDN.
“Dr. Hamid said that with all three of them coming down with the same symptoms, it didn’t seem right,” said Allen Hall, Jacob’s grandfather. Allen and his wife, Judith, April’s mother, are the legal guardians for Jacob and Sarah.
After extensive genetic testing, Jacob was diagnosed with a rare neuromuscular disorder that results from a genetic mutation.
The disease is so rare it didn’t even have a name until 12-year-old Mitchell Herndon, of Missouri, was diagnosed with the disorder in 2012. He died in 2019, and the disease has been named Mitchell disease. His remains were donated to Washington University in St. Louis to be analyzed for neuromuscular diseases research.
“There’s currently no treatment, although they’re trying to come up with a treatment plan,” Allen said. “We’re hopeful to an extent, but I’m afraid the damage that has been done is nonreversible. It would be great if it was, because Jacob has a smart mind. But he has no feeling from the waist down and can’t walk. We’re thankful for the (UDN) program. If we hadn’t come to Vanderbilt, we never would have known about the program and gotten a diagnosis.”
A Diagnosis Doesn’t Mean a Treatment
Hamid said patients are told from the beginning that they might not end up with an answer. “We tell them the success rate at Vanderbilt is very high, but they need to prepare themselves that even with all we can do, we may not find an answer for them, but we will do our best using the most cutting-edge informatics technology resources, some that are unique to Vanderbilt,” he said.
And patients are also told that having a diagnosis doesn’t always lead to a treatment.
“If we find the answer, that’s fantastic, and sometimes, but not always, the answer allows us to treat their condition,” Hamid said.
Amy, who recently moved from Nashville to Richmond, Virginia, with her husband, and two children, ages 3 and 1, said “knowing isn’t necessarily good news. There’s no treatment. But not having a diagnosis for so long just felt like an ongoing question mark in my life and for my health. I definitely assumed I would never have an accurate diagnosis, so it felt like a relief when it happened,” she said. “We don’t have a lot of answers about how this will affect us long term, but that’s the nature with most muscular dystrophies.”
Her diagnosis also led to some reassuring news about whether her children can inherit the disease. Her husband was tested to see if he carried the recessive gene, and he didn’t, so it’s impossible for her children to inherit the disease.
So, for now, Amy and her sister will let their bodies tell them when they need to slow down and rest. “Over the years, we’ve both learned to understand our bodies more, when to slow down and when to stop,” she said.
Physicians believe that she has a mild type of limb girdle disease. Her strength tests are normal, and she has no permanent muscle damage. “For that I’m very thankful,” she said.
Visit www.vanderbilthealth.com/service/undiagnosed-diseases-program for more information on the Vanderbilt Undiagnosed Diseases program, including how to apply.