A Michigan State University pediatric researcher and a Spectrum Health physician have identified a new genetic syndrome in a 3-year-old girl who, for more than two years, has gone undiagnosed.
The discovery is the first to link a particular gene, known as ODC1, or ornithine decarboxylase, to developmental problems in a human, something that up until now, has been only seen in mice.
Their findings, published in the American Journal of Medical Genetics, could help other doctors formally diagnose patients who have similar symptoms.
“It’s likely that other cases will be discovered now,” said André Bachmann, a professor of pediatrics in the MSU College of Human Medicine, who co-authored the study with Caleb Bupp, a medical geneticist at Spectrum’s Helen DeVos Children’s Hospital in Grand Rapids, Michigan.
Symptoms of the currently unnamed syndrome — although both authors have submitted a proposed name — include large body mass and head size, developmental delay, hair loss, muscle tightness affecting movement and speech, low muscle tone, birthmarks, as well as visual and hearing problems.
“The ODC1 gene plays an important role in a number of physiological and cell developmental processes including embryo and organ development,” Bupp said.
Bachmann, who has studied the ODC1 gene and protein it produces for more than 25 years, was contacted to help with the undiagnosed case by Bupp, who, after sequencing the patient’s entire DNA, found that the gene had a mutation.
“After reviewing the DNA data, I noticed that this gene mutation could have higher activity levels, accumulating too much of the ODC protein in the body,” Bachmann said. “Excessive accumulation of the protein generally leads to an imbalance in the body and a bad outcome.”
An overactive gene is referred to as having gain-of-function characteristics, which in cases of gene mutations, is uncommon. In fact, the opposite is seen more often. Bachmann said that most mutations are categorized as loss-of-function, meaning they are less active or completely deficient.
To confirm his gain-of-function theory, Bachmann tested the patient’s blood and compared it to samples from two healthy children who were the same gender and age. He found larger quantities of the ODC proteins in the patient sample, as well as increased levels of positively charged molecules, called polyamines, that when over produced, may contribute to cancer in some situations.
“While this patient doesn’t have cancer, it appears that the accumulation of ODC proteins and higher levels of polyamines are linked to the observed symptoms, including developmental delays and hair loss,” Bachmann said. “We also think that this increased ODC activity can be reduced to normal levels with DFMO, a well-known, already established drug.”
Bachmann has spent 17 years studying DFMO, or difluoromethylornithine, in his preclinical research. While it's been widely understood that the drug blocks the activity of the ODC protein, his work has shown that it can do the same in cases of neuroblastoma, a pediatric cancer.
“DFMO might be a new way to help children with the syndrome,” Bachmann said. “Since some developmental delays are not likely reversible after the child has reached a certain age, future newborn screenings for the ODC1 mutation could be very useful, so we can intervene as early as possible.”
Both Bachmann and Bupp plan to conduct further testing to confirm their findings and eventually, may consider getting appropriate approvals to validate the effectiveness of the DFMO drug in fighting the syndrome’s effects.
MSU research assistants Chad Schultz and Katie Uhl, along with Helen DeVos Children’s Hospital critical care physician Surender Rajasekaran, also helped conduct the study.
