Noonan Syndrome: A Promising New Treatment Discovered

In patients with RIT1-associated Noonan Syndrome, a MEK inhibitor called trametinib was found to reverse hypertrophic cardiomyopathy (HCM) and valvular obstruction. Noonan syndrome is a rare genetic syndrome.

In patients with RIT1-associated Noonan Syndrome, a MEK inhibitor called trametinib was found to reverse hypertrophic cardiomyopathy (HCM) and valvular obstruction, said researchers at Université de Montréal and CHU Sainte-Justine Research Center. //The groundbreaking research is published in the Journal of the American College of Cardiology.

''Up to this finding, our therapeutic options were limited to surgery, including heart transplant, and symptomatic relief with medication," said the study's author, Dr. Gregor Andelfinger, a pediatric cardiologist at CHU Sainte-Justine, a researcher at Sainte-Justine University Hospital Research Center in the fetomaternal and neonatal pathologies axis, and an associate research professor in the pediatrics department of Université de Montréal.

Noonan Syndrome - Causes, Symptoms, Diagnosis and Treatment
Noonan syndrome is a genetic disorder that affects different parts of the body. It is caused by changes in one of various autosomal dominant genes.

‘Noonan Syndrome (NS) is a rare genetic syndrome typically evident at birth and often linked to early-onset severe heart disease. NS is part of a group of diseases termed RASopathies that are caused by activating mutations of proteins belonging to the Ras and mitogen-activated protein kinase families.’

"Trametinib treatment is the first approach specifically targeted to the molecular cause of RASopathies," said Dr. Andelfinger. "While our numbers are still very limited, we report the first patients in whom we were not only able to stabilize, but to reverse the disease of the heart. These results pave the way for larger trials, which are now needed."

Dramatic improvement

Infants less than six months old with NS, HCM and congestive heart failure normally have a poor prognosis, with a one-year survival rate of 34 per cent. In the new study, the Sainte Justine clinical teams used trametinib, an inhibitor targeted specifically against the activating nature of the mutations, to try to treat NS in two patients.

They observed dramatic improvement of clinical and cardiac status in the patients only three months after treatment. Hypertrophy regressed in both patients, with sustained improvement over a total of 17 months of treatment, and normalization of laboratory values. One of the patients, who required ventilation, could be extubated after six weeks of treatment. Both patients showed better overall growth after treatment was started.

"The findings described in this report suggest that a life-threatening form of heart disease affecting young infants might be treatable, which, if true, would be unprecedented and so meaningful for the families whose lives this devastating problem touches," commented Dr. Bruce Gelb, director of the Mindich Child Health and Development Institute at the Icahn School of Medicine at Mount Sinai, in New York City.

Quiz on Genetic Disorders
Genetic disorders include a variety of diseases that are caused by abnormalities or defects in the DNA. Abnormalities in genes are referred to as genetic mutations and these mutations may be small, affecting just one gene or affecting entire chromosomes. Such mutations may develop spontaneously or they may be inherited from either parent. The consequences of such genetic disorders can vary greatly and very often the extent to which a genetic condition affects the person will be influenced by environmental factors as well. Test your knowledge on genetic disorders by taking this quiz.

"Now we need to perform a proper clinical trial to prove that this drug is definitely working for this particular problem," he said.

A promising first

Mouse Model of Noonan Syndrome Created by CNIO Researchers
Noonan syndrome is a rare genetic disease. It presents with a set of pathologies including heart, facial and skeletal alterations, pulmonary stenosis and short stature.

Although the study was limited to two patients, given the promising results these outcomes suggest that MEK inhibition merits further study as a mechanistic treatment option for patients with RASopathies, the researchers believe. The study raises important questions for the treatment of such cases, in particular with respect to long-term efficacy and impact on other RASopathy manifestations.

Because of the role MEK plays in signaling heart growth, Gregor Andelfinger believes studies with a larger number of participants are now required to evaluate long-term side effects, optimal dosing and optimal treatment windows as well as investigate this treatment for other types of heart disease. It is conceivable that MEK inhibition may prove most effective during a fixed time window before the onset of irreversible cardiac remodeling in RASopathies, including those caused by genes other than RIT1.

Source-Eurekalert