Life-altering first-degree relative study aims at changing course of disabling disease worldwide
Two things happen when Teri Schreiner, MD, MPH, diagnoses a 10-year-old with multiple sclerosis (MS): It breaks her heart and inspires her research.
The pediatric neurologist focuses studies on the immune-mediated disorder, which can jumble patients' thoughts, steal their ability to walk and cause many other life-long symptoms by disrupting nerve cells and short-circuiting the body's messaging system.
In a recent study, Schreiner and colleagues are looking at first-degree relatives of pediatric and young adult patients with MS, in hopes of pinpointing genetic and environmental factors and predicting risk. Although early in their study, these researchers are already affecting lives.
"We are helping people maintain their level of functioning by identifying them at the earliest possible minute, even before they actually know they have MS," said Schreiner, a researcher and provider with the Rocky Mountain MS Center at the University of Colorado Anschutz Medical Campus (RMMSC at CU). First-degree relatives (parents, children and siblings) of people with MS have a 10- to 20-fold increased risk of developing the disorder.
The aim: changing the course of MS
As part of the study, asymptomatic, first-degree relatives undergo MRI scans in search of telltale markers of MS in the brain- plaques or lesions left from the immune system's mistaken attacks on the nerve-protecting myelin sheath.
"And we're actually finding both kids and adults who have these spots," said Schreiner, an associate professor in the Department of Neurology at the CU School of Medicine.
Next, researchers analyze other risk factors among the MRI-positive group, seeking a composite score for predicting who will go on to likely develop MS. Providers can then guide the susceptible participants in lifestyle changes and drug therapies if needed, potentially warding off disabilities.
"We are helping people maintain their level of functioning by identifying them at the earliest possible minute, even before they actually know they have MS." - Teri Schreiner, MD, MPH
Scientists hope they can create a standardized risk-stratification score for screening, changing the course of MS worldwide, said John Corboy, MD, MA, neurology professor and co-director of the RMMSC at CU.
As many as 235 genetic changes play role
While both cause and cure remain a mystery for MS, researchers believe an interplay of genetic and environmental factors likely triggers the disorder that affects as many as 1 million Americans, according to a recent National Multiple Sclerosis Society study.
Thankfully, pediatric cases of the progressive disease - which often results in flareups of symptoms in its most common relapsing-remitting form throughout life - are rare, at 5% of all cases, Schreiner said.
Targeting both genetic and environmental aspects of the disease is critical to the study, said Corboy, whose center combines patient care and research, treating over 4,000 patients a year and conducting multiple basic and translational studies.
"Some genes interact with certain environmental factors, potentially becoming a trigger through that interaction. So having or not having a gene may have an impact that we are completely unaware of," Corboy said. The RMMSC at CU conducts about 30 clinical trials at any given time.
Signs and Symptoms
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Solving the MS puzzle remains challenging, with scientists associating about 235 genetic changes with the disease along with numerous environmental factors, including low vitamin D levels, living in northern latitudes and having a history of Epstein-Barr virus infection, among many others.
Potential environmental links abound
On the environmental side, researchers use a questionnaire, developed with the help of Professor Jill Norris, chair of the Department of Epidemiology at the Colorado School of Public Health (ColoradoSPH), to reveal potential triggers in study subjects.
Questions cover identified risk factors, such as age, sex, Body Mass Index and where the participants grew up.
"We ask about a multitude of factors," Schreiner said. "For example, we ask about smoking in the home, family members with other autoimmune diseases, vitamins, medications, whether or not they've had any unusual hobbies like welding or other unusual exposures that may help us to understand what these environmental triggers are."
Studying children with MS can more readily offer insights, Schreiner said.
"An adult diagnosed at 28 has 28 years of exposures to consider and assess which ones really matter," she said. "When a 14-year-old is diagnosed, there are half that many exposures to consider. We suspect that when kids are diagnosed, the genetic burden may be higher, possibly offering more genetic clues."
Taking a data-driven, personalized look
On the genetic side, researchers collaborate with informatics and genetic experts across campus, such as Christopher Gignoux, PhD, associate professor in the Division of Biomedical Informatics and Personalized Medicine, and his colleagues with the Colorado Anschutz Research Genetics Organization (CARGO), Schreiner said.
First-degree relatives share 50% of a MS patient's genetic makeup.
"We are comparing the genetic data of our first-degree relatives in the study to MS patients and to healthy controls to see if we can detect within our first-degree relatives a preponderance of those 235 genetic changes."
"Some genes interact with certain environmental factors, potentially becoming a trigger through that interaction. So having or not having a gene may have an impact that we are completely unaware of." - John Corboy, MD, MA
A recent grant from the National MS Society will extend the observation period of the first-degree relatives, taking the study to the next level, Schreiner said.
'It is a very hopeful time'
MS, which most often strikes women and men in their prime (average age of onset is 30), does not shorten life expectancy but can dramatically affect quality of life, costing them jobs or leaving them wheelchair-bound.
"That is what we are trying to effect," Schreiner said. "If I can provide a personalized estimate of risk, taking into account multiple factors, then a first-degree relative can say, 'OK, I'm going to do everything in my power to lower that risk,'" Schreiner said, such as monitoring vitamin D levels, exercising and not smoking.
Combined with today's MS-targeting drug therapies, disabling symptoms can be slowed, if not prevented, Corboy said. "Our options now for treatment are broad," said Corboy, who finished his fellowship in 1992, when there was not a single beneficial treatment for MS.
The next year, in 1993, the first drug was approved, and doctors now have about 20 medications, most targeting the inflammatory process in some way, to choose from. "And they do have a significant impact on people's lives," Corboy said. "So it is a very hopeful time."
