For a medical mystery that defies explanation or diagnosis, the University of Alabama at Birmingham is the court of last resort. Launched in October 2013, the program aims to unravel the most perplexing medical cases in which a diagnosis has not previously been made.

“Undiagnosed diseases present a critical unmet need, with patients often cycling through the medical system with no satisfactory treatment plan,” said Bruce R. Korf, M.D., Ph.D., professor and chair of the UAB Department of Genetics and director of the UDP. “Some of these conditions may be so rare that only a handful of people in the world have them. Others may be more common, but have symptoms that present in an unusual way, making diagnosis difficult.”

The National Institutes of Health Office of Rare Diseases Research says there are about 500 diseases common enough to be in any physician’s repertoire for diagnosis, while another 6,500 are known but are extremely rare.

For patients and their families slogging through the medical system with no answers and no plan, the UDP can be a ray of hope.

During its short lifetime, the UAB program has already diagnosed one patient whose condition had been described in the international medical literature only once before. In other cases, the UDP has produced a diagnosis for conditions that have stymied referring physicians and their patients for years.

Primary team members are Korf, Maria Descartes, M.D., professor in the Department of Genetics, and Martin Rodriguez, M.D., associate professor of medicine in the Division of Infectious Diseases. The core team also includes two nurse practitioners, Carol Dahl, CRNP, and Tammi Skelton, CRNP, who serve as clinical coordinators for adult and pediatric patients, respectively. Meagan Cochran, M.S., is the certified genetic counselor. The program can also draw on a variety of UAB specialists according to the needs of each patient.

Diagnoses are made through a combination of cutting-edge technology allied with more traditional medical strategies such as comprehensive review of records andhistory and time spent listening to the patient or family. Sometimes the team simply engages in contemplation and consultation.

“Each specialist, looking through his or her unique lens, is able to offer differing perspectives,” Korf said. “We have resources and expertise that are unavailable elsewhere in the UAB system, and we often find the best method is an integration of cutting-edge and traditional medicine, leading to a blended, individualized approach. Even then, we sometimes come up empty-handed.”

The program did not come up empty-handed for the Smith siblings, Mandalynn, Aiden and Gage. All three suffered from conditions including severe inflammation of their joints and delayed intellectual development. After countless physician visits spanning more than 20 years in South Carolina, Florida and Washington, the most frequent stab at a diagnosis was “unknown bone disease.”

"We were told that we’d probably never know for sure what had affected three of our children but not the other two,” said the children’s mother, Stephanie Smith. “As a mother, that was not good enough.”

After moving to Alabama, the family began seeing physicians at UAB and were referred to the Undiagnosed Diseases Program.

The team employed a cutting-edge technique known as whole exome sequencing, which identifies the genes responsible for encoding the sequence of proteins. Results revealed that all three siblings had two variants in a gene associated with mucolipidosis III, an inherited disorder classified as a lysosomal storage disease. One variant came from the father and the other variant from the mother.

“With a diagnosis confirmed, we were able to set up a monitoring program to look for issues known to be associated with mucolipidosis III, and to recommend infusions of a bisphosphonate medication, which have shown promise in treating the musculoskeletal symptoms related to this condition,” Korf said.

The Smiths say they are aware of only about 650 cases of mucolipidosis III worldwide, and while there is not a cure for the condition, the family now has answers they did not have before, treatment options they did not know existed and knowledge that will help them plan going forward.

Exome sequencing was employed in another case of a newborn with profound developmental issues at birth. Pope Terry, of Camden, Alabama, is blind and deaf and suffers from multiple seizures. He has never smiled or sat up, and he exists in what can only be described as a vegetative state. Now 3, he lives with his parents, Wesley Ann and Steve, and his healthy older brother, Haas.

“I wanted to know the name of the monster that took Pope’s ability to see, hear, talk, walk, eat, look me in the eye, to chase his big brother around the yard, and to say, ‘I love you, Mommy,’” said Wesley Ann Terry. “I wanted to blame something. I wanted to scream and cry and hate a diagnosis.”

But no diagnosis was forthcoming until Pope and his parents came to the UDP and underwent whole exome sequencing. The results revealed that he had two gene mutations, one associated with seizures and the other involved with impaired cognitive development.

“It would be extremely unlikely that this sort of condition would be recognized in a setting outside a program such as ours — it had been described only once before in the medical literature,” Korf said.

The mutations were categorized as de novo, or new mutations, meaning they spontaneously occurred in Pope. The positive news for the family is that the parents have a very small risk that such mutations would occur again should they have another child. In addition, the risk to older brother Haas for fathering a child with these mutations and their associated conditions is the same as in the general population.  

“We were happy to receive a diagnosis even if it doesn’t change Pope’s future,” said Terry. “I understand Pope’s life is not going to improve by labeling his genetic syndrome, but it may offer hope and potential for future children and families. It also helped us determine if expanding our family was even an option.”

The diagnosis also answered a burning question that troubled Terry.

“For all of Pope’s life, the question consumed me,” she said. “Did one of my genes do this to my child? Am I the one to blame?”

“We all carry genetic variants which can have different effects — or no effect at all — depending on the gene’s location and whether it changes the function of essential proteins,” Korf said. “Genetic variants are commonplace and unpredictable. We try to impress on parents, patients and families that these are naturally occurring variations.”

The UAB program is modeled on a similar program at NIH and is funded by UAB Medicine and patient revenues. It is one of the first undiagnosed diseases programs at an academic medical center.

Patients must be referred to the UAB UDP by their primary care physician or a physician providing ongoing care for the condition under evaluation. The condition should have been present for at least six months.

The program expects to see no more than 40-50 cases per year, and not every patient is guaranteed to receive a diagnosis or treatment plan; in those circumstances, patients will be referred to appropriate UAB specialists for symptom management.

Smith says getting a diagnosis for her three children was comforting, although still a bit overwhelming.

“For us, taking things day by day is too much; we go moment to moment,” she said. “My message to other parents is to be your child’s advocate. Keep searching, and never accept ‘no’ as an answer. Fight for them.”

For the Terrys, the diagnosis brought a bit of closure.

“We had prayed for ‘diagnosis day’ ever since Pope was born,” said Terry. “I wanted to know. I deserved to know. And finally we have a name, which has given us some peace.”