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The Next Chapters for Marfan Syndrome

The Next Chapters for Marfan Syndrome

When Harry “Hal” Dietz was training in pediatric cardiology at Johns Hopkins in the mid-1980s, he found himself increasingly frustrated about how little medicine had to offer for children with Marfan syndrome. The puzzling condition caused his young patients to grow significantly taller than their peers, have defects in organs, ranging from the lungs to the eyes, and—most disconcerting—problems in the heart valves and aorta.

“Many of these children were going on to need multiple cardiac surgeries and experiencing early death,” recalls Dietz. “We didn’t seem to be making that much of a difference.”

That’s why Dietz decided to switch his focus, training in genetics to better understand Marfan syndrome. He worked alongside Clair Francomano and Victor McKusick, who launched the nation’s first medical genetics division and was among the first to describe the connective tissue disorder.

Dietz’s career change has proven fruitful: Over the next 30 years, he and his colleagues discovered the genetic mutation that caused this condition, the regulatory role that the protein produced by this gene provided and that an existing blood pressure medication acts on this pathway, with the potential to slow the rate of aortic enlargement in these patients.

“There’s a sense of progress,” he says, “but there’s also a sense that there’s so much more to do.”

Between seeing patients with genetic cardiovascular conditions once a week and researching other disorders that fall under this umbrella in his lab—including Loeys-Dietz syndrome, a condition Dietz co-discovered, which shares many of the same features as Marfan syndrome—he has continued adding to the Marfan story.

Dietz’s lab is now working to identify the optimal drugs, combination of drugs and doses for the care of Marfan patients.

He and his colleagues are also determined to better understand what happens at every step in the pathway between the gene defect that causes Marfan syndrome and the devastating aortic enlargement that eventually leads to aortic dissection. Part of their research relies heavily on investigating the biochemical events that occur in mouse models for this condition, developed in their lab. However, the team is also exploring this question in human families that carry the Marfan mutation.

“You see striking differences in the severity of disease among family members, despite the fact that they all have the same underlying gene defect,” says Dietz—perhaps, he explains, because other genes are modifying the effect of the original mutation.

The team’s analysis identifies several points along the pathway that appear to be vulnerable to these genetic modifiers. In time, Dietz says, his and other labs hope to develop new treatments that could sway the course of this disease by targeting these vulnerable events.

Eventually, he says, Marfan patients may be able to live free of the fear that their bodies could fail them, while still avoiding multiple life-changing surgeries.

“The Marfan story is far from over,” adds Dietz. “Our lab continues to add to this aggressive research domain.”

 

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