When your child isn’t just rare, but probably one of a kind

Savoie at home with 4-year-old Esmé in New York.
Savoie at home with 4-year-old Esmé in New York.

Hillary Savoie, PhD, founder and director of The Cute Syndrome Foundation, is author of Around And Into The Unknown, chronicling her family’s journey to find a diagnosis for Esmé, and Whoosh, about coming to terms with Esmé’s early medical complications.

I think my daughter Esmé is extraordinarily unique—from her tiny pudgy feet that she likes to stuff in her mouth to her beautifully lashed blue eyes and outrageously untamed hair. It’s a mom thing. I guess it is a symptom of loving another person more than life itself.

But my daughter is also unusual in a more scientific way: in her genes. 

The testing conundrum

In November 2011, when Esmé was around 10 months old, we were considering stopping genetic testing. Esmé’s microarray had come back showing nothing by way of genetic changes. We understood that Esmé probably still had a genetic disorder: She was unable to roll over or sit up. She was almost silent, tube-fed and having seizures.

I still had some deep dark hope that she would grow out of all of these challenges—a hope that was threatened by my need to understand Esmé’s health, to find genetic answers. A hope that was complicated by the limits of what genetics might be able to tell us.

A year later, Esmé was in the midst of seizures that were spiraling out of control, not responding well to any of the medications we tried. We found ourselves again wanting to know more. We hoped that any insight into her condition would help us better treat her.

I had no idea how far the following three and a half years would bring me in search of answers. I traveled to Europe and the west coast of the U.S. to meet with researchers from as far away as Australia—geneticists who spend their time at the cutting edge, just beyond what is accepted about genetics.

And we had no idea how many more questions the testing would wind up raising.

A mutation…or two?

Esmé at Boston Children’s Hospital when the Infantile Epilepsy Panel was ordered.
Esmé at Boston Children’s Hospital when the Infantile Epilepsy Panel was ordered.

In the fall of 2012, Esmé’s doctors ordered a newly available Infantile Epilepsy testing panel from the company GeneDx. This panel uses next-generation sequencing to look for changes in the known genes associated with infantile epilepsy, finding even very small genetic changes very quickly. (At the time, the test took approximately 12 weeks and tested for approximately 36 genes; in its current form, the test takes four weeks and tests for 53 genes.)

Esmé at Boston Children’s Hospital when the Infantile Epilepsy Panel was ordered.

In December, we received a call explaining that the test had found a single small mutation in a gene associated with infantile epilepsy and developmental delay almost exclusively in girls. Heather Olson, MD, our neurologist at Boston Children’s Hospital, explained that the gene was called PCDH19 and that Esmé’s specific mutation had never been reported, so it was unknown whether it was expected to be disease-causing. The Epilepsy Genetics group felt it was, more likely than not, at least a partial explanation. So, we took our place somewhere around the 100th documented case of PCDH19 epilepsy.

From what little information I was able to find, there were aspects of this disorder that seemed much like my daughter’s symptoms—drug resistant, cyclical clustering seizures with cyanosis (turning blue) and behavioral differences. However, essentially all the girls I learned about over the coming months lacked the medical fragility, multi-system involvement, extremely low tone and severe developmental delays we saw in Esmé—who, at 2 years old, was still not sitting up, babbling or eating by mouth.

However, this was the only lead we had to explain Esmé—so I took it and ran with it. I became increasingly involved in the PCDH19 community, starting the Cute Syndrome Foundation. During its first 18 months, we funded about $120,000 worth of PCDH19 research and awareness projects, including a project at Boston Children’s modeling PCDH19 mutations in zebrafish.

epilepsy genetics PCDH19
Zebrafish biologist Christian Lawrence gives Hillary and Esmé a tour of the zebrafish facilities at Boston Children’s Hospital. In April 2014, the Cute Syndrome Foundation gave $25,000 to Boston Children’s Ann Poduri, MD, PhD, to support her PCDH19 zebrafish research. Together with Alex Rotenberg, MD, PhD, Poduri is exploring the effects of PCDH19 mutations in zebrafish with the goal of using the fish to screen potential precision treatments.

But as more and more cases of PCDH19 were diagnosed, the gap between Esmé’s symptoms and the others’ became increasingly evident.

So about two years after our infantile epilepsy panel, we dug deeper into Esmé’s genes—this time with whole-exome sequencing—to see if we could come up with more answers… and perhaps find something else we could do to help Esmé. We assumed that she likely had PCDH19 epilepsy and a second disorder that affected her muscles, movement and some of her internal organs.

We didn’t expect to find a second mutation in a gene associated with infantile epilepsy—but that is what we found.

The second mutation

The exome showed that Esmé had a second “mutation of unknown significance” in SCN8A—a recently discovered gene associated with intractable epilepsy, movement disorders and severe developmental delay. The test results also stated that Esmé’s PCDH19 mutation had been reclassified as “unlikely to be pathogenic.”

Fortunately, through the Cute Syndrome Foundation I had the chance to form relationships with a number of clinicians and researchers who work with rare genetic epilepsies. Interestingly, as I started to get in touch with some of these researchers, there seemed to be disagreement about whether one or the other or both mutations were significant in Esmé’s case. There was also a lot of suspicion about what else might be causing her symptoms.

My daughter’s genes are truly putting scientific knowledge to the test. The Cute Syndrome Foundation now also supports SCN8A research and will be co-funding a $20,000 SCN8A grant with two other SCN8A family organizations to improve the pace of research. (Read more on family-driven SCN8A research.)

An answer…or not?

Understanding whether a mutation is disease-causing is a complicated process. It involves theory about what parts of the gene are very similar across different species, what amino acids are interchanged in the mutation and how the mutation might alter the protein produced by the gene. It can also involve functional tests in the laboratory and animal models to measure the effect of the mutation.

Increasingly, it also requires scientists to think bigger than the individual gene—to see how different genes might interact. It also means looking in new places in human DNA for answers that may have been previously overlooked.

So, for now, we will wait while science continues to expand its understanding of the human genome and begin to answer some of the questions we have about Esmé’s life, health and future.

And just as before…only time will tell.

But for now, I suppose, I am content to understand the most important thing of all: Esmé is certainly one of a kind. As we all are.

In that way, I find myself back where I started…beyond wanting to know.

This blog is adapted from a post that originally appeared on Complex Child.