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Maria Escolar, M.D.
Associate Professor of Pediatrics
University of Pittsburgh School of Medicine
Director, Program for the Study of Neurodevelopment in Rare Disorders
Children’s Hospital of Pittsburgh of UPMC
Dana Foundation Grantee 2007-2012
You are in the midst of a multi-year study, funded by the National Institutes of Health with Dana Foundation support, to compare how a crucial white-matter tract in the brain (cortico-spinal tract) develops in normal babies vs. babies with Krabbe disease, a rare, often fatal neurodevelopmental disorder affecting the motor system. Why the interest in this particular bundle of myelinated nerve fibers?
Maria Escolar: Over the last 13 years we have been treating babies diagnosed with Krabbe disease with transplanted unrelated umbilical cord blood. We learned very quickly that by the time a baby has symptoms, it’s really too late to benefit from transplantation. So we began treating babies as newborns in the hope that we could treat successfully if we started early enough. Even then, the results were inconsistent; some babies still had significant disability while others went on to walk and function almost normally. We knew the treatment was working, but we didn’t understand why it was working in some babies and not in others.
Our hypothesis is that maybe those babies who don’t do well after transplantation already have impairment in the myelination of their cortico-spinal tracts, the major motor pathway in the brain. To see if that is true, we have used Diffusion Tensor Imaging (DTI, a noninvasive MRI technique for assessing white matter in the brain) and developed a methodology to calculate how much myelination those tracts have at birth. With that data, we reasoned, we could predict which newborn babies could benefit from transplantation.
In August 2006, New York State began implementing population-wide screening of newborns for Krabbe disease. We viewed this as an opportunity to use DTI to try to predict, based solely on the degree of impairment seen in the myelination of these cortical tracts, which babies would have more disability.
Devastating as it is, Krabbe disease is quite rare, affecting about one in 100,000 children. What relevance might this work have to other, more common disorders of early brain development?
We have many potential uses for the future. I think the most significant impact this work will have is in understanding more prevalent motor diseases like cerebral palsy (the leading cause of childhood motor disability in the United States). It will also help determine if transplantation therapy is going to help babies with Krabbe disease who are diagnosed through newborn screening. Once we establish what the normal range of myelination is in the cortico-spinal tracts, we can apply the same methodology to any child, whether their injury is due to a genetic disease or a stroke, and compare them to that normal range. If we see a lot of problems in the tracts, that child most likely will have more motor disability. This information would help families decide what kinds of interventions to undertake.
In the future, there will be treatments for these conditions. Already, there are clinical trials trying to repair damaged myelin with stem cells, for example. My question is: How are clinicians going to know if they’re actually helping these kids? Maybe the children would have gotten better without the treatment. You’ve got to be able to really quantify the damage and understand the effect of treatments for injuries to the brain.
What have you found so far in your study?
We have a large database of about 400 normal babies who we have followed for more than two years, in addition to data on about 20 babies with Krabbe. The data show that babies who had the most damage to the cortico-spinal tract—less myelination as measured by DTI—ended up doing much worse even after transplantation.
Imagine the cortico-spinal tract as a tree with branches and leaves. A normal baby has a robust trunk with a lot of branches and leaves. Babies with Krabbe have a tree with very few branches and few leaves. If you see that pattern at birth, you know that baby is already too sick for transplantation to be beneficial; by the time the transplanted cells begin to engraft—typically about two months—the child is deteriorating rapidly. On the other hand, a baby who has been diagnosed with Krabbe disease from genetic testing or low levels of galactocerebrosidase enzyme (a marker of Krabbe) but is born with a pretty robust trunk will probably do well with transplantation. The timing of treatment in these patients is extremely important.
It’s important that we have a tool that is able to predict outcomes, because this information is going to be very critical as more states consider newborn screening for Krabbe disease and other genetic disorders.
Some have criticized these screening programs in part because there may be little that can be done for newborns diagnosed with certain conditions, leaving parents and healthcare providers with hard choices.
When you do population screening, some of the babies who are identified as having low enzyme levels are not going to develop the disease until they are older. Krabbe disease has been linked to more than 100 genetic mutations, and there is wide variability in how and when the symptoms present. With the most severe infantile form, babies present symptoms by two to three months of age and die by one to three years. But a lot of babies have a late-infantile form where symptoms present between six months to three years. Other forms may have symptoms that present later in childhood (early-juvenile or late-juvenile forms) or even in adulthood.
Because of this, it is very difficult to advise parents whether to transplant. We’ve learned that if you wait until a child has symptoms, transplantation is not going to work. But what if the child will not have symptoms until they are adults, by which time there could be a better treatment? How do you figure out which babies to treat? We are in that situation where you have babies who are identified through screening but we don’t know if they should be treated. The mortality of transplantation can be as high as 30 percent; that is not something you want to give to a baby who may not present any symptoms until adulthood.
Right now this DTI method is the only tool that we can really use to predict how much damage these babies are going to have.
I’m trying to imagine what it must be like for a parent whose child has no symptoms but has been diagnosed with Krabbe disease, and who now has to make a decision about whether to put the child through a stem cell transplant.
This is exactly what we face in clinic all the time. Parents who have had a previous child with Krabbe know exactly what we’re talking about, so they want to do something about it right away. But the ones who have no family history of the disease, who have this baby who looks perfectly normal, they think we’re crazy when we tell them their baby needs a procedure that carries a 30 percent chance of death.
That’s why using this MRI tool also makes such a huge difference—to show the parent: “This is how normal looks and this is how your child looks.” Being able to visualize that helps them understand that, even if we’re not seeing outward symptoms yet, the disease is there.
What are the next steps in your research?
The next step is to do the same study with kids who have more common disabilities, such as cerebral palsy (CP). In CP, as in Krabbe disease, cortico-spinal tracts are often compromised. We want to see if this DTI methodology can predict those kids’ prognoses as well.
We are hoping to recruit babies at risk for CP and see how well we can predict which ones develop motor disability and which do not. This would be important as stem cell therapy develops. A few trials are already being planned to investigate these therapies in kids with motor disability and it will be critical to understand what the treatment is doing. In all these diseases, you have to treat very early to have an effect. If there is a lot of damage, the treatment doesn’t work well.
Why has there been so little research to understand white matter changes in the developing brain?
Brain development, especially over the first three years of life, is a much unexplored area in terms of how to measure it. People have tried, but nobody has been able to actually quantify how the cortico-spinal and other tracts change over time in normal development. It’s not an easy thing to do; these tracts cross over and are difficult to measure. We have a statistician and a mathematician to help us solve these issues.
Myelination occurs very quickly in the newborn brain, which makes sense if you consider that a baby goes from being unable to lift its head to being able to walk in a matter of months. The cortico-spinal tract controls all of that. The change in that area is so huge from birth to two years, and so little is known about it, I think that anything we learn is going to be extremely important in terms of understanding how childhood diseases affect movement.
As the brain develops, other white-matter tracts myelinate very quickly as well. We are doing an exploratory study looking at other tracts to determine how they change over time. We have collected all the data and we can now go back and quantify all the tracts that myelinate in the first two years. It will be new information in the sense that we are describing how myelination progresses over the first years of life both in normal kids as well as in kids with Krabbe and other motor diseases.