Do We Know More About the Cause of Moebius Syndrome Than We Think?

I’m not a doctor and I don’t play one on TV or on the internet. I’m just an ordinary person who has lived with Moebius syndrome for 63 years. But sometimes I think medicine can benefit from a set of untrained eyes looking at something and asking a question that may have been overlooked simply because everyone has gotten used to looking at it the same way.

So here is my observation. It isn’t a medical conclusion, and I’m certainly not suggesting that I have figured out something doctors and researchers have been trying to understand for more than 100 years. It is simply my 63-year-old intuition telling me that something about the way we talk about the “unknown cause” of Moebius syndrome doesn’t quite add up.

Maybe We Are Asking the Wrong Question

Doctors have known the basic neurological pattern of Moebius syndrome since the late 1800s. Paul Julius Möbius recognized the connection between congenital facial weakness and the inability to move the eyes normally from side to side. More than a century later, those same two things remain at the center of how classic Moebius syndrome is identified.

We normally associate those problems with the sixth and seventh cranial nerves. The sixth cranial nerve helps move the eye outward, while the seventh controls much of the movement of the face. That doesn’t necessarily mean every person with Moebius has exactly the same damage to exactly the same place. Research has shown that the problem can involve the nerves themselves, the part of the brainstem where those nerves originate, or the way those systems developed before birth.

But we know where the problem shows up.

That is what got me thinking.

Maybe the biggest unanswered question isn’t simply, “What is Moebius syndrome?” Maybe the real question is, what happens during development that causes these particular systems to develop differently?

In other words, maybe what we still haven’t found is the trigger.

Then I Started Reading About Misoprostol

This is where things became interesting to me.

In 1993, researchers reported on seven children in Brazil whose mothers had taken a medication called misoprostol during the first trimester of pregnancy. Some of those children had Moebius sequence along with limb abnormalities.

That could have been an interesting little study that disappeared into a medical journal and was never heard from again.

But it didn’t.

In 1998, a much larger study was published in the New England Journal of Medicine. Researchers looked at 96 Brazilian babies with Moebius syndrome and compared them with babies who did not have Moebius. They found a strong connection between prenatal exposure to misoprostol and Moebius syndrome.

Other studies followed. Researchers continued to find an association between early pregnancy exposure to misoprostol and a pattern that could include Moebius syndrome, limb differences, clubfoot and other abnormalities.

Let me be very clear about something before we go any further. This does not mean misoprostol causes every case of Moebius syndrome. It obviously doesn’t. Moebius syndrome was described long before misoprostol ever existed, and most people with Moebius have no known history of prenatal misoprostol exposure.

That isn’t what caught my attention anyway.

What caught my attention was the explanation researchers proposed for why misoprostol might sometimes result in Moebius syndrome.

What If Misoprostol Is a Clue?

Misoprostol causes uterine contractions. Researchers proposed that powerful contractions during a very important stage of early development might temporarily interrupt or reduce blood flow to the developing baby. If that happens at just the wrong time, it could interfere with the development of parts of the brainstem, including the areas involved with the sixth and seventh cranial nerves.

This is sometimes called a vascular disruption theory. Put much more simply, something may temporarily interfere with the blood supply while these parts of the nervous system are being formed.

That idea has continued to appear in Moebius research.

A 2003 study looked at the brains of children with Moebius sequence who had been exposed to misoprostol before birth. The findings were consistent with something disrupting normal brainstem development very early in pregnancy.

In 2006, researchers went back through several previous studies and found that prenatal misoprostol exposure was strongly associated with both Moebius sequence and certain limb defects. Later studies continued to find a recognizable pattern connected with early misoprostol exposure.

So we aren't talking about one study from 30 years ago that was never followed up. There is a body of research behind this connection.

But here is where my untrained eyes start asking questions.

If misoprostol can create the circumstances that sometimes result in Moebius syndrome, what exactly happened?

And if we can answer that question, then the next question becomes even more important:

What else could make the same thing happen?

Maybe There Is More Than One Road to Moebius Syndrome

This is where I think the word “cause” might sometimes get in our way.

We keep looking for the cause of Moebius syndrome as though there has to be one thing responsible for every person who has it.

Maybe there isn't.

Imagine several different roads all leading to the same destination.

In one pregnancy, there could be some kind of temporary disruption of the blood supply during a critical point in development. Misoprostol might be one thing capable of creating that situation.

In another person, a genetic change could interfere with the development of the same nervous system.

In another case, maybe something completely different happens that we haven't identified yet.

Different beginning. Similar result.

There is some research that makes this possibility worth considering. Scientists have identified genetic changes associated with Moebius syndrome in a small number of people. One study involving the genes PLXND1 and REV3L showed that two very different genetic problems could eventually affect development of the facial motor system.

That caught my attention for the same reason the misoprostol research did.

Different things appear capable of interfering with the development of the same general neurological system.

So maybe there isn't one road to Moebius syndrome.

Maybe there are several.

Cause or Trigger?

When we say, “The cause of Moebius syndrome is unknown,” most people probably take that to mean doctors have no idea why Moebius happens.

But that isn't completely true.

We know quite a bit.

We know the basic neurological systems involved. We know that problems involving development of the sixth- and seventh-cranial-nerve systems are central to classic Moebius syndrome. We know that certain genetic changes have been found in a small number of cases. We know there is a well-documented connection between prenatal misoprostol exposure and Moebius sequence. And researchers have spent decades looking at vascular disruption as one possible explanation for how some cases develop.

What we don't have is one explanation that works for everybody.

Maybe that's because there isn't one.

Instead of asking only, “What causes Moebius syndrome?” maybe we should also be asking, “What triggers the developmental event that becomes Moebius syndrome?”

What happens during those first few weeks of development? What affects that particular area of the developing nervous system? Can several completely different events produce the same outcome?

And why are the sixth and seventh cranial nerve systems so often involved?

There is another question that I think is just as important. If some people with Moebius have mainly facial movement and eye movement differences, while others also have feeding problems, speech differences, limb differences, chest wall differences and other conditions, could the timing or location of that early developmental disruption help explain some of those differences?

I don't know.

But I think it is worth asking.

Misoprostol Isn't the Answer. It May Be a Clue.

I am not suggesting that misoprostol caused my Moebius syndrome. I have absolutely no reason to believe that it did. I am not suggesting that it caused your Moebius syndrome or your child's. I am also not suggesting that vascular disruption explains every case.

And I certainly don't believe that I sat down at my computer one afternoon and solved something medical researchers haven't been able to solve.

What I am suggesting is much simpler.

We have a medication that has repeatedly been associated with the development of a Moebius-like pattern. Researchers have even proposed a biological reason why that might happen.

Instead of looking at that research and saying, “Well, misoprostol can't explain everyone with Moebius, so it isn't the answer,” maybe we should look at it differently.

Maybe misoprostol isn't the answer.

Maybe it is a clue.

If researchers can determine exactly what happens during development when misoprostol exposure results in Moebius syndrome, perhaps that could help us understand what happened in people who were never exposed to misoprostol.

Maybe the question we have been asking for more than 100 years needs to be changed slightly.

Instead of only asking:

What causes Moebius syndrome?

Maybe we should also ask:

What biological event creates the Moebius pattern, and how many different things can trigger that event?

Again, I'm not a doctor. These aren't medical conclusions. They're questions from a 63-year-old guy who has spent his entire life looking through eyes that don't move normally and speaking through a face that doesn't work like everyone else's.

Living with something for 63 years makes you curious.

Sometimes curiosity begins by looking at what we already know and asking a very simple question:

What are we missing?