Cardiology Research Profile
LEOPARD Syndrome: A Congenital Disorder
Maria Kontaridis, PhD, a scientist in BIDMC's Division of Cardiovascular Research and Assistant Professor of Medicine at Harvard Medical School, studies a congenital disorder called LEOPARD Syndrome. In the March 2011 issue of the Journal of Clinical Investigation
, a study by Dr. Kontaridis not only identifies the first possible medical treatment for this condition, but also demonstrates the importance of using "personalized therapies" for the treatment of congenital heart diseases. We asked her to describe her work and its broader implications for patient care.
What are congenital heart defects?
These are problems with the structure of the heart that exist from birth. They could affect the heart's walls, its valves or the arteries and veins that carry blood to and from the heart.
Congenital heart defects are the most common type of birth defect in the U.S. and are estimated to affect more than 35,000 newborns each year.
Your research focuses on a specific defect called LEOPARD Syndrome. Can you tell us what this is?
LEOPARD Syndrome is a rare disease that affects about 200 individuals throughout the world. Children born with this condition develop
hypertrophic cardiomyopathy, a thickening of the heart muscle that typically leads to heart failure.
They are also clinically identified by widespread, freckle-like spots on the skin, craniofacial defects, deafness and blood abnormalities that can give rise to pediatric leukemias.
What, specifically, causes LEOPARD Syndrome?
LEOPARD Syndrome is a genetic disorder. Genetic mutations, which can be inherited or developed when DNA is damaged or changed, can alter a molecule's "signaling pathways" during development. (A signaling pathway is a sophisticated system by which cells communicate with one another about basic cellular activities like tissue repair and immunity.) It is estimated that about 30 percent of the defects associated with congenital heart diseases are caused by genetic mutations.
In the case of LEOPARD Syndrome, defects occur in one particular gene called PTPN11, which usually activates the "RAS signaling pathway." Because there are a cluster of congenital diseases caused by defects in other genes along this same pathway, they are collectively called "RASopathy disorders."
What is the premise for studying this disorder?
Our lab focuses on two RASopathies, both primarily caused by differing mutations in gene PTPN11 - LEOPARD Syndrome and Noonan Syndrome. Patients with these two conditions both develop cardiac abnormalities and are similar in outward appearance.
Interestingly, the mutations in PTPN11 that cause Noonan Syndrome are "activating" and increase signaling to the RAS pathway, whereas the mutations causing LEOPARD Syndrome are "inactivating" and therefore decrease signaling to the RAS pathway.
So we were puzzled as to how these two very different genetic scenarios could result in such similar disorders.
What is your discovery?
One way that scientists investigate diseases is by creating "mouse models" which closely reproduce the features of the human disease. This is what we did. By generating and studying the LEOPARD Syndrome mouse model, we learned that the mechanisms of the disease-the signaling pathways affected by the mutations in LEOPARD Syndrome-are quite different from those attributed to causing Noonan Syndrome. Therefore, we reasoned that by targeting the specific molecules in the signaling pathway affected in LEOPARD Syndrome, we could essentially treat the disorder and the cardiac defects associated with it.
We gave the LEOPARD Syndrome mice a drug called rapamycin, which we knew would act specifically on the abnormally regulated pathway that we had just identified. (Rapamycin is best known as a drug used to help prevent the rejection of newly transplanted organs in transplant patients.) The treatment was a success; the hypertrophic cardiomyopathy was actually reversed in our LEOPARD Syndrome mice.
Why is this type of research important?
Not only did our study identify the first possible medical treatment for LEOPARD Syndrome, our research also pointed out the importance of using individualized therapies for treating patients with RASopathy disorders. While the rapamycin treatment was of great benefit to the LEOPARD Syndrome mice, it would likely be of no benefit, or even be detrimental, for the treatment of Noonan Syndrome or other RASopathies that don't affect the same signaling pathways.
By learning more about this rare disease, we get a glimpse of broader implications for treating other, more common congenital heart disorders. This is the rationale behind personalized medicine and targeted therapies: By understanding the biological mechanisms attributed to the specific mutations that cause a disease, we can specifically target those pathways as part of the treatment.
What will be your next steps?
We plan to test rapamycin in a clinical trial to evaluate this treatment in humans with LEOPARD Syndrome. We hope that, ultimately, unlocking the secrets of LEOPARD Syndrome will help us better understand all RASopathies, which as a group may affect as many as one in 2,500 people.
Above content provided by Beth Israel Deaconess Medical Center. For advice about your medical care, consult your doctor.
Posted April 2011