The University of Alabama at Birmingham (UAB) continues to prove itself as an international juggernaut in scientific and medical research, with the results having profound effects for people across Alabama and the world.
In a press release this week, UAB detailed that its Undiagnosed Diseases Program (UDP) recently found a previously unknown genetic variant that is believed to account for a debilitating disorder in a young woman.
A case study published in the Monday issue of Neurology, the journal of the American Academy of Neurology, outlined the UAB research team’s report on the discovery of the variant and described the incredible steps taken to unlock this medical mystery.
The patient, a woman in her 20s, first began to develop impairment of her lower limbs at age five. By adulthood, she could no longer walk and had hand tremors, large spasms of her legs in the evenings, intermittent slurred speech and occasional tingling in her fingers and toes.
The woman underwent evaluation at UDP, housed in UAB’s Department of Genetics, which is a court of last resort for cases in which a diagnosis has not been made despite exhaustive efforts by medical professionals.
“We have resources and expertise that can be brought to bear in these cases,” explained Dr. Bruce Korf, UAB’s chief genomics officer and director of the UDP. “Our hope is to be able to provide answers that have eluded the best efforts employed to date.”
After an exhaustive review of symptoms and family history, along with various tests to rule out other options, the patient underwent whole genome sequencing and variant analysis at Huntsville’s HudsonAlpha Institute for Biotechnology.
This genome sequencing revealed a never-before described mutation in the ADCY5 gene.
Other variants of that gene have been associated with childhood movement disorders. Testing of the parents indicated that the variant was not present in either, indicating it was a spontaneous mutation in the woman.
“For these combined reasons, the variant was predicted to be the likely cause of the woman’s condition according to the guidelines of the American College of Medical Genetics and Genomics,” advised Dr. Marissa Dean, assistant professor in UAB’s Department of Neurology and the first author of the case study. “We were ultimately able to give the family of diagnosis of dystonia with spastic paraparesis, likely due to the variant in the ADCY5 gene.”
Dean outlined that while there is no known treatment to reverse the condition, simply having a diagnosis often gives patients and families closure and relief. She is also overseeing supportive therapy for this patient, including physical and occupational therapy and medications to treat muscle spasms and stiffness.
“The conditions seen by the UDP are rare, so the discovery of a new variant of a gene is extremely important,” Korf added. “Every piece of information that we can decipher sheds a bit more light on our understanding of genetic disease.”
The UAB UDP is comprised of a team that includes a designated certified genetic counselor and a clinical nurse coordinator. Physicians from various subspecialties, in such areas as radiology, rheumatology and neurology, serve as consultants and provide their expertise as needed.
The program, one of the only such efforts based at an academic medical center, is modeled on a similar one at the National Institutes of Health.
In this case, now that the gene mutation has been identified, a pathway to a cure or treatment is more realistic.
“It’s important to understand all we can about these types of conditions,” Dean emphasized. “How many people are affected? Are there environmental or other factors that contribute? Until we better understand the basis of the disease, we cannot begin to understand what might work as cure or treatment.”
She also spoke to the unique importance of Alabama’s HudsonAlpha in cases like this, concluding, “Whole genome sequencing may be a helpful tool to identify rare disorders.”
Because of the discovery of this novel mutation, the case study also called for the addition of ADCY5 to gene sequencing test panels for spastic paraparesis, which could lead to future diagnoses.
Co-authors on the case study from UAB were Korf; Ludwine Messiaen, Ph.D., Dept. of Genetics; Salman Rashid, M.D., Dept. of Pediatrics; and David Standaert, M.D., Ph.D., Dept. of Neurology. Co-authors from HudsonAlpha Institute for Biotechnology were Gregory M. Cooper, Ph.D.; and Michelle D. Amaral, Ph.D.
Sean Ross is the editor of Yellowhammer News. You can follow him on Twitter @sean_yhn
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