Three rare genetic conditions, including Krabbe disease, are the focus of the $3.8 million grant
BUFFALO, NY — “Your baby has a genetic disease.” It’s one of the most terrifying things new parents can hear. However, it often turns out not to be true because while newborn screening is extremely accurate for many common conditions, screening accuracy rates for rare and even fatal conditions can be abysmal, according to genetics experts.
The extraordinarily high rate of false positives can subject newborns to unnecessary, often painful, interventions and parents to unnecessary anxiety.
The National Institutes of Health awarded a researcher at the University at Buffalo an extremely competitive grant known as the R01 grant to lead an international effort to dramatically improve the accuracy of newborn screening for three rare, often fatal, genetic diseases. The five-year, $3.8 million grant is funded by the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.
The diseases are Krabbe’s disease, also called globoid cell leukodystrophy, a neurological disease that is almost always fatal and affects 1 child in every 250,000 births; mucopolysaccharidosis type I (MPSI), also known as Hurler’s Syndrome, which causes damage to major organs in the body, usually results in death by age 10 and affects 1 in 100,000 births; and Pompe Disease, which disables the heart and skeletal muscles, is often fatal and affects 1 child in every 40,000 births.
“These are terrible childhood conditions, and while they are not yet curable, there are treatments that can halt their progression,” said Thomas J. Langan, MD, grant principal investigator, associate professor of neurology and pediatrics at the Jacobs School. of Medicine and Biomedical Sciences at the UB and a doctor with Neurology at the UBMD. “The sooner an intervention occurs, the better the child’s quality of life will be.”
At the same time, he explained, an extraordinarily high rate of false positives can subject parents to unnecessary anxiety and children to wholly unnecessary interventions.
“Screening tests for these diseases are not accurate enough,” Langan said.
For decades, Langan, who is director of clinical research at UB’s Institute for Myelin and Glia Exploration, has been on a mission to correct this. In addition to providing clinical care for children with neurological disorders, he conducts research on genetic disorders. He expanded the World Krabbe Disease Registry, a database maintained by the institute, which now has clinical and genetic information on more than 190 affected patients.
A key focus, now funded by the current grant, has been its investigation to develop the most accurate biomarkers for rare genetic diseases. Their new approach to Krabbe disease and MPSI screening is called the bivariate-based analysis approach, which increases accuracy by tracking two biomarkers for each disease.
“In our preliminary studies on Krabbe disease, our newborn screening test using this approach has proven to be between 90 and 92% accurate,” Langan said, a tremendous improvement over current screening for the disease that, at best, is only 10-20% accurate. “Furthermore, our approach was able to predict which child would start to develop Krabbe symptoms before they occur, allowing interventions as early as possible. Our studies indicate that similar outcomes should be possible with Pompe disease and Hurler syndrome,” he said.
For all three diseases, Langan said, it should be possible to reach a positive predictive value, the probability that a patient who tests positive actually has the disease, of nearly 100%.
The test will be done on all babies born in Buffalo at John R. Oishei Children’s Hospital and other US locations; in addition, testing for MPSI will be done at three locations in Japan, where the disease is most prevalent.
At the end of the five-year lease, approximately 20% of newborns born in the US will have passed this test developed at the UB.
Langan’s collaborators at UB will analyze biomarker results from samples from all sites, which consist of a single spot of blood routinely taken from the heel of a newborn, now used to detect up to 50 genetic conditions.
Newborn screening using the single blood point originated at UB with Robert Guthrie, who first used it in the 1960s to screen for the genetic disorder called phenylketonuria (PKU). Today, dozens of genetic diseases are detected from that single drop of blood.
“It is entirely appropriate for Dr. Langan is doing this critical work here at UB, where his team is expanding the power of newborn screening, leveraging the tremendous public health contribution that Dr. Guthrie did at UB decades ago,” said Allison Brashear, MD, vice president of health sciences at UB and dean of the Jacobs School.
UB is the lead institution. US contributors include the Albert Einstein College of Medicine; Icahn College of Medicine; Syracuse University/Upstate Medical Center; Montefiore School of Medicine; Stony Brook University; National Children’s Hospital; University of Cincinnati School of Medicine; University of Missouri; Northwestern University/Lurie Medical Center; University of Illinois Chicago; Wadsworth Center, New York State Department of Health; Nemours Child Health; and the University of Washington School of Medicine. Japanese collaborators include reference centers in the Japanese prefectures of Osaka, Gifu, and Shimane.
This multinational consortium was established by Langan and is known by the acronym BANS Network for Ban Adverse Results in Newborn Screening.