Genetic Testing, Precision Medicine, and Research: Advice From Veteran Caregivers

I received this note from Charlie’s genetic counselor just last week.

“Hi Danielle,

Results did just come back, and there was no definitive diagnosis- a copy of the report is attached for your records.  Therefore, we will move forward with getting Charlie’s information enrolled in EGI.  There was one variant identified in a gene called MTOR- changes in this gene have been identified in some children with autism spectrum disorders, epilepsy, and differences in brain formation, however these are typically de novo (only in the child), whereas Charlie’s variant was inherited from his father.  This makes it much less likely that this is the cause of Charlie’s differences.”

And with that, the mystery of why my Charlie had infantile spasms, a rare and devastating form of pediatric-onset epilepsy, deepened.

How did I feel at that moment?

Heartbroken: I knew in my head that the odds of getting an answer were slim, but my heart hoped we would find out anyway.

Discouraged: I put a lot of work into getting this test approved by insurance and scheduled, only to have my hopes dashed.

Relieved: At least they didn’t find anything, well, more awful than I already know he has.

Angry: I am so, so, so sick of all of this. Sick, sick, sick, sick of epilepsy.

Self-pity: Why is this happening to me and my child? Why can’t we get SOMETHING to go right for us?

Denial: is it possible they just don’t know everything? Could they be wrong? Could it be this MTOR, or perhaps, GABRG2, the mutation that they found on the last test that he inherited from me? How could it NOT be inherited, since my uncle died in childhood from epilepsy?

Curious: Why is Charlie like this? Is it genetic? There must be an answer.

HOPEFUL: thanks to the Epilepsy Genetics Initiative , Global Genetic Variants Registry, and other research opportunities happening for kids with epilepsy right now.

When we first embarked on our journey with infantile spasms, I turned to online caregiver support groups for advice. The known causes of infantile spasms are numerous and range from genetic mutations to stroke to brain malformation. Some parents know the cause at the time of diagnosis, but many of us do not. Every parent’s first question is, “Why?” What did I do to cause my child to be so sick? Is it something I did when I was pregnant? Some environmental exposure or medication that I took? Could it be the glass of wine I had before I found out that I was pregnant, or all the diet soda that I drank?”

We are almost relieved to find out that very often, a completely random and unpreventable genetic mutation is the culprit, but then we start to worry about what genetic testing might discover. “If I have other children, will I pass it on to them? Does the genetic mutation cause problems in other organs? How long do children with this mutation usually live?“

Again and again, the subject of genetic testing came up in the discussion forums, but I didn’t understand any of it. Up to that point, I had limited academic coursework in genetics required of my Master’s in Public Health program. Indeed, many of the current hot topics in genetics were in their infancy fifteen years ago when I started graduate school. In my professional life as a clinical research data analyst, I often work on research projects involving patients with rare diseases that have genetic causes, but always AFTER their mutations were identified, not before.

I knew nothing about genetics or mystery diseases. I was just like many of you reading this right now.

My fellow “cryptogenic” (mystery cause) parents repeatedly discussed the different genetic “panels” to request from our neurologist. At that time, there was one that looked at 53 genes commonly linked to infantile spasms. Since those days more than six years ago, the “epilepsy gene panel” has expanded. Back then, most of the parents I know who received positive results from genetic testing then went on to one of a few wonderful, large patient support communities. A terrific group that comes to mind is the Tuberous Sclerosis Alliance (for people with TSC1 or TSC2 mutations).

These smaller, narrow panels leave many of us with no idea why our child is having seizures, and therefore, what other medical conditions they are at risk to develop, which medicines to avoid, and no support group to help us care for our children throughout their lifespan.

Take heart.

There is hope.

The whole exome looks at a lot more than the smaller epilepsy panels.  However, when scientists analyze your child’s whole exome, they are looking for KNOWN mutations. New mutations are constantly being discovered and added to the list that they check for during testing. Mutations become known when people with epilepsy get their whole exome analyzed and sent to researchers who can dig deeper and identify new mutations.

That’s why it’s really, really important for all of us “unknowns” to get our kids’ whole exomes into the big genetic data pipeline, so scientists can have more people to look at, compare, and discover what’s wrong with our kids.

Some other caregivers, and even people in my own life, have asked me, “Why do you want to know? Isn’t it best to leave well enough alone? He’s already experienced years of brain damage from thousands of seizures, and has lost a big part of his brain to brain surgery. Knowing his mutation won’t change Charlie’s outcome, so why put yourself through this pain?”

Here are my own personal reasons for pursuing a genetic cause for Charlie’s epilepsy:

Precision medicine: knowing the exact mutation(s) can lead to targeted therapies for Charlie, therapies that could significantly improve his health, quality of life, and development. It is inaccurate to state that knowing his mutation now, after years of brain-damaging seizures and two brain surgeries, will not change his outcome. We just don’t know what a targeted therapy might do for Charlie.

Currently, most epilepsy treatment protocols for mystery kids like Charlie involve throwing medication after medication at them, in random order or at the preference of the physician, and hoping something works. In fact, most parents are told early on that if three medications are tried and fail, the odds of any pharmaceutical working at that point are slim. Something that works for one kid doesn’t work for the other, and nobody knows why, because we don’t understand the underlying issue that made our kids sick in the first place. It’s like not knowing that there’s a connection between glucose and diabetes. How would they ever have come up with insulin as a treatment without that basic understanding of the functions of the body that regulate glucose? It’s pretty much a crap shoot, and it’s always hard to say which med is helping or hurting, especially when the child is on two, three, four, or even more anti-epileptic treatments at a time. All of the medications have side effects, some worse than others, and the medications themselves can trigger seizures when they are withdrawn.

Knowing a mutation would allow scientists to target the specific problem, kid by kid, so that we can avoid trial-and-error crap shoot mystery diagnosis epilepsy care. This is madness, and we, as parents, have the power to make a HUGE contribution to the solution by participating in genetic studies like the Epilepsy Genetics Initiative.

Research: knowing his mutation(s) puts Charlie first in line for any study of those mutation(s), including clinical trials of new drugs that could lead to a targeted therapy for him. I don’t want a study to pass us by because, as a mystery kid, we don’t meet the inclusion criteria of a specific mutation.  For example, as soon as I find out his mutation, I can enroll in the Global Genetic Variants Registry, and receive notification whenever we are eligible to participate in a study.

Support: If there are other kids out their like Charlie, with the same combination of symptoms, I want to meet them. Maybe it won’t be until our kids’ data are roommates in the same research database that it is discovered that there is more than one Charlie out there.

Imagine if your kid had diabetes, but you didn’t know it was called diabetes. How would you meet other parents online who also had kids with the same symptoms, if you couldn’t Google ‘diabetes?’ The diagnosis makes all the difference in finding support. This is especially true for those kids who were never diagnosed with a syndrome or condition like infantile spasms (IS) or Lennox-Gastaut Syndrome (LGS). While the associated organizations do not represent specific genetic causes, there is strong support in the general IS and LGS communities that is not available to mystery kids without these diagnoses.

Access to services: Understanding and documenting the severity of his mutation(s) will help me to justify therapy and education services.

Medication safety: knowing his mutation(s) would also tell us which medications he SHOULD NOT HAVE, as some medications can make seizures worse in kids with certain mutations.

Overall health: Certain mutations that cause epilepsy also cause problems in the eyes, heart, kidneys, and/or skeletal systems, just to name a few. These problems might not become clinically apparent until long after the epilepsy presents itself. Knowing Charlie’s mutation(s) can help me to be proactive and start relationships with specialists who can follow Charlie and prevent complications that may arise.

Another “bonus” that often comes with genetic testing for epilepsy is the opportunity to learn about additional genetic mutations that you or your child might have that could cause diseases.  For example, sometimes the tests will also reveal if you have the most common mutations that are implicated in breast cancer.

Family history: Knowing his mutation(s) allows me to make other family members aware, especially if this is an inherited condition. And if it’s not an inherited condition, this information will give us all a sense of relief.

Closure: because I’m his mother, and I deserve to know.

So how do we go about getting the whole exome done and sent to researchers? I will give it to you straight:  most of the time, the burden is on you, the caregiver, to initiate this process, and the system does not make it easy for us.  It is a battle worth fighting, for so many reasons.

You will almost certainly hit roadblocks early on, most likely with the insurance company. In addition, it might be difficult to schedule the tests, especially if both parents need to have blood drawn on the same day.  Sometimes, you can arrange in advance to have the tests scheduled with clinical blood draws at your next visit, but this can be a challenge to arrange, or when you get to the lab, they might not know what you are talking about, your husband’s name isn’t in the system so he has to wait for his blood draw, your kid is hungry, you still have to drive an hour to get home and pick up your other kid at school…I know, I know, believe me!

By the time you hit your first genetics testing obstacle,  you have put so much time and effort into it that you will feel overwhelmed, frustrated, and very sick of pushing for something that will not provide immediate seizure relief for your child.  You will want to throw in the towel and say to heck with the whole thing. You may feel like you don’t have it in you to fight for this on top of everything else. I hear you. I have been there. PLEASE don’t give up, for all the reasons I listed above. Luckily, you have me and many other experienced parents who are ready and able to help you through it.

The first step is to ask your child’s neurologist if a gene panel or whole exome testing is right for you.

I will be blunt. Insurance companies can be total jerks about covering genetic testing, and it can be cost prohibitive to pay for the whole thing out of pocket. Parents often complain to me that they feel “priced out“ of genetic testing. That is absolutely shameful. I hate to hear that. Have no fear, I have found some ways around insurance rejections.

After our first brain surgery but before our whole exome testing, our brilliant neurogenetics doctor wanted to see if Charlie had a certain mutation because the next drug on our list was contraindicated for that particular mutation. In other words, if he had the mutation, that drug could make his seizures a lot worse. The insurance company rejected our request for coverage of the test, citing that it wasn’t “medically necessary.”

That particular rejection really got to me.  I had lost all faith in humanity.

Fortunately, the doctor and dedicated genetic counselor at our hospital spent a lot of time and effort educating the health insurance company and, eventually, getting the decision overturned. If you get rejected, ask your genetics counselor to get involved and advocate for a reversal.

Something else parents need to know is that many genetic testing companies offer patient assistance programs to people whose insurance won’t cover genetic testing, usually limiting your out-of-pocket expense to $100 or less. Check with the company and your genetics department about this option if your genetic testing is rejected by insurance.  If you need some advice on this, send me an e-mail:  danielle@neurologyparent.org.

Once your genetic testing is completed, you should explore research studies. Usually, it’s just a matter of consenting to let your doctor or lab send the test results, medical history, and/or blood sample to the study team.  Start by asking your neurologist about studies. If your mutation has a support group or nonprofit organization associated with it, reach out to them. Look up any clinical trial through clinicaltrials.gov. As I mentioned before, for epilepsy, I highly recommend the Epilepsy Genetics Initiative (EGI). Note that you don’t need to have a known mutation to participate. In fact, one of the goals of EGI is to make those discoveries!

For those of you with KNOWN mutations, you can join up with researchers around the world. Our friends at the Global Genetic Variants Registry have just launched their website here. The purpose of their site is to link families with genetic epilepsies with researchers, possibly on the other side of the world, to understand the genes of epilepsy and find new treatments.

Finally, I reached out to my own network, Neurology Parent Professionals, for advice for families who are facing the prospect — or aftermath — of genetic testing.  Here is some of their advice:

“Make an in-person appointment with a genetic counselor and make sure they explain the mutation in a way that you can understand.  Ask a few key questions at the appointment, such as:

  • Is this definitely a pathogenic mutation?
  • How does it affect or potentially affect the child? This way you get set up with the right specialists right away such as cardiologist, ophthalmologist, physical medicine, etc.
  • Is gene therapy an option for this specific mutation, either now or in the future?

Research away, education is power, learn as much as you can- read it even if it doesn’t make sense right now, it will eventually as you continue to learn. Google it often, as there’s constant updates in genetic research right now

I know everyone is in a different place in their journey and some may not be able to jump right into advocacy but as soon as you are ready, get involved!”

–Leah

“Starting the process to access services if applicable is necessary to learn and initiate even though it is a stressful time. Every State has different case loads, waiting lists, evaluations etc.  Become proficient on the ins and outs of your insurance. Do you need referrals? What quality and quantity of services are provided by the plan? Does your State bill for services or do they bill your insurance? Know that pharma offers services to absorb medical costs. Last, try not to become overwhelmed. It’s a lot that has to be accomplished but just stay calm. It’s a marathon, not a sprint (most of the time but not always).”

–Andrea

“Just because they find other kids with that same mutation doesn’t mean they are “Apple to Apple.” They may have other mutations that play into it, a larger mutation, and other factors play in. So, just because you find like families you may not find like kids.”

–Holly

I hope that you find this post useful as you navigate your own genetic testing odyssey. The goal of my blog is always to write posts that I wish were available to me when Charlie and I were just starting out. As always, please don’t hesitate to contact me or comment below, with any questions or suggestions.

Helpful resources

How to Research Your Child’s Medical Condition Like A Pro

Genetic and Rare Disease Information Center: Support for Patients and Families

Epilepsy Genetics Initiative

YouTube Course:  Useful Genetics from University of British Columbia

Global Genetic Variants Registry

Rare Epilepsy Network

Clinicaltrials.gov  Look up clinical research studies in the US

How to create Google news alerts (put your mutation name or syndrome in and get an alert every time it is mentioned online)

NIH Precision Medicine Initiative Cohort Program  This is a very educational website for people interested in learning more about precision medicine.

Who was Tommy Boyce?

Tommy Boyce was my uncle, my father’s brother.  Here’s what I know about him:

He had “terrible epilepsy” with “seizures every day.”

He was “blind from birth,” something that was blamed on a “birth injury.”

He “was like a baby all his life.”

He died around age 8? 10? in the early 1950’s? from something related to epilepsy.

That’s all I know.

I found out about Tommy when I was about ten years old.  My brother and I were on the floor of my grandmother’s living room, sifting through a box of old photographs.  I came across a black-and-white photo of a beautiful boy I had never seen before.  There was something…different…about him, but I didn’t know how to put it into words.

“Who is this, Grandma?”

“Oh, that’s just a little boy I used to take care of.”

Grandma was a retired nurse, so that answer rang true.

When I got home, my brother, who already knew about Tommy, must have told my mother what I saw.  She sat me down and told me what little she knew about Tommy.

She described my Grandmother’s anguish, the wife of an alcoholic, who would not accept Tommy as his son.  She described her devotion to Tommy, the amount of work required to care for him.

She shared a few sweet stories of my father’s relationship with his brother.  He would ask their grandma for an extra cookie “for Tommy,” knowing Tommy didn’t eat cookies, and was saving the cookie for himself.

But that’s it.  It was never discussed after that, and I didn’t think much about Tommy until that night in the Johns Hopkins emergency room in February of 2011, when I was told infantile spasms, a “catastrophic” form of epilepsy, was suspected as the cause of my Charlie’s strange movements.

“Tommy!” I gasped, as I crumpled to the floor.

Tommy died in childhood, presumably as a result of his epilepsy, but I know very little about the circumstances.  I want to change that.  I want to shine a light on the stigma of epilepsy and the mystery of SUDEP.  I want to explore any possible genetics that tie Tommy’s epilepsy to Charlie’s.  I want to tell my grandmother’s story, as it is my story, and the story of so many women throughout the world.

Please join me in my multi-part series as I try to solve the mystery of Tommy’s death.