As far as rare diseases go, Noonan syndrome is not all that rare. A genetic condition that affects development in one baby in every 2,500 births, it’s the most common incurable rare disease. It usually appears in features of the face, but more dangerously affects the anatomy of the heart, growth and nutrition, and triggers developmental delays.
Hypertrophic cardiomyopathy is the most lethal symptom of Noonan syndrome. It’s an unusual thickening of the heart that, in its most severe form, kills 70 percent of babies before their first birthday.
Pediatric cardiologists Gregor Andelfinger (Université de Montréal and Saint-Justine Hospital) and Bruce Gelb (New York City’s Mount Sinai Hospital) reversed this lethal symptom for the first time by repurposing a cancer drug.
Left unchecked, the thickening walls of the heart make the heart stiffen. Unable to relax, it gets harder and harder for the heart to fill up and pump blood.
Lyana Deslauriers was born with a particularly severe case of heart defects due to Noonan syndrome. She had severe heart thickening that affected both sides of her heart, and all four of her heart valves were improperly formed. Her hands and feet were blue as her heart struggled to deliver blood.
At first, doctors started her on the standard treatment to try to stop her heart from growing even thicker; propranolol is a drug that reduces the force of the heart’s contractions when it pumps, but even at the highest dose it wasn’t enough. Her heart continued to grow.
The other possibilities for standard interventions were risky. Implanting a mechanical pump to help take some strain off her heart would be difficult given its tiny size, and surgically shaving off some of the heart muscle would come with a high complication rate.
Instead, her dire condition meant she was eligible to try something experimental. She would become one of the first to successfully try trametinib, a targeted anti-cancer drug that inhibits pathways that are hyperactivated in Noonan syndrome and other related genetic mutations called RASopathies.
The same genes can also be affected in about a third of solid cancers, like breast cancer or lung cancer, which is why the same drug can have benefit for such diverse conditions.
“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,” said Gelb in a statement.
Deslauriers and a German patient with a mutation on the same gene were both treated with trametinib, and the normalization of their heart tissue is remarkable. Three months in, both their hearts were shrinking. Now, after 17 months of treatment, their improvement has been sustained, their cardiac hypertrophy has regressed, and both are still alive.
The results are still limited to only two patients, but the team plans to expand to a larger trial. For now, this is very promising news for two young toddlers who are beating the odds.