A recent University of Iowa study has provided insight to an enzyme that contributes to the irregular heartbeats in an extremely rare disease—Timothy syndrome—and how restraining that one enzyme prevents the irregular heartbeat.
Mark Anderson, MD,PhD, cardiac electrophysiologist, and Potter-Lambert Chair in Cardiology at University of Iowa Hospitals and Clinics, talks about this enzyme’s role in arrhythmias:
What is Timothy syndrome?
Timothy syndrome is a rare disease of a gene that encodes a calcium channel. A calcium channel is a special protein that serves as the main doorway for calcium entry into electrically excitable tissue like heart and brain. The Timothy syndrome has multiple manifestations, including autism, developmental disorders with limbs, but most notably—cardiac arrhythmias. Cardiac arrhythmias are the reason that these persons, on average, die between age 2 and 3.
How many people are affected with Timothy syndrome?
We don't know precisely, but all indications are that Timothy syndrome by itself is an extremely rare disease and somewhere between 20 and 30 cases have been reported.
If so few are affected, what prompted research into the irregular heartbeats in patients with Timothy syndrome?
That's a great question. These rare genetic diseases give us an opportunity to study mechanisms at a singular molecular level. We've already learned that other rare diseases, like long QT syndromes, provided wonderful insight into more common arrhythmias; for instance, those that occur in people that have heart failure or who have had a heart attack. I think the same thing will happen with Timothy syndrome. The models created around these defects in the calcium channel teach us a lot about how calcium pathways that lead to arrhythmias are interconnected within the cells. This gives us better ideas about where we could target them for—not just Timothy syndrome, but for common disorders that affect millions of Americans.
What enzyme causes the arrhythmias?
This is an enzyme called calmodulin kinase II. It's one our laboratory has studied for over a decade.
What does the identification of this enzyme mean beyond the potential treatment of people with Timothy syndrome?
The role of this enzyme in arrhythmias in Timothy syndrome supports experiments from other kinds of animal models of heart failure and myocardial infarction, suggesting that it probably has a broad role in determining disease outcomes, both for arrhythmias and for worsening muscle function that leads to heart failure. We think that it may also have a role in other disease types. One of the most intriguing would be to think if it had a role in some of the multisystem manifestations of Timothy syndrome, like autism.
What are the next steps in looking at calmodulin kinase II enzyme with regard to other possible medical advancements in treatment?
The next steps involve creating cellular in animal—and this is mostly mouse models—to understand disease in each of these separate areas. And also to develop small molecules or drugs that could target this enzyme to test if they would be beneficial for treating these patients.
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