When we started this blog, we believed that today, February 28, 2019, would not come for Katherine.
We’d lost our first child from an early miscarriage. Then, we found ourselves shocked and shattered as we looked into the tear-filled eyes of neurologists telling us to, “Go home and love our daughter.” Our precious Rainbow Baby was slowly dying before our eyes.
As we pushed for answers to the cause of her neurodegenerative disease, we were utterly lost and terrified. Terrified of what they would find, terrified of the pain she might feel, terrified of watching her take her last breath and losing her forever. Amidst our fears, we had to find the strength to face these fears – strength I didn’t believe I had inside of me.
I remember sitting inside a pediatric surgery center and looking around the room into the eyes of a couple dozen frightened parents awaiting news. The look in their eyes still haunts me. I didn’t need a mirror to show me that I had the same terrified look in my eyes. I couldn’t breathe. I felt like I had nowhere to run to make it all go away. I wanted to wake up from this nightmare and go on with my life. All at once I was angry, confused, scared, and sad. I desperately wanted to believe it wasn’t true, but it was really happening. It was real and I could not stop it. Please, I pleaded with the universe, please make this stop. Why, I questioned? Why is life so unfair? My sweet, innocent daughter did not deserve this. It was an incredibly helpless feeling.
I had fallen into utter despair with no light to see me through it. In my very worst moment, I closed my eyes, quieted my thoughts, and had the most incredible vision:
Dave and I were walking on an empty beach. It was a beautiful beach with white sand, blue water, a gentle warm breeze was blowing in our hair and on our faces. We were smiling and content. Peace surrounded us. Ahead, Katherine wore a yellow swimsuit and played in the sand with her back to us. She was looking toward the water, but in my heart I knew she was happy and having fun. We were all together on that beach and we were happy. As we walked in the sand toward Katherine, it felt as though we were walking in paradise.
This vision and feeling has and continues to sustain me through my darkest hours. I found my strength in my lowest place.
Thank you for reading our words and loving our daughter. Just a few short years ago we had little reason to hope that Katherine would live to see February 28, 2019. Yet today, Rare Disease Day 2019, was an average, normal day for us. Katherine got up, ate breakfast, and walked into school with the assistance of her walker and her aide. She asked me if I would paint her nails glittery pink before her tutoring session tonight. As she walked away, I looked back and smiled.
An average day is the most beautiful thing in the world. May you all find the joy in every glorious, average day of your life.
Here’s a brief timeline from 2010-Present of NUBPL as a novel disease discovery to a growing community:
2010: Australian researchers reported “a strategy of focused candidate gene prediction, high-throughput sequencing, and experimental validation to uncover the molecular basis of mitochondrial complex I (CI) disorders.” They created five pools of DNA from a cohort of 103 patients and then performed deep sequencing of 103 candidate genes to spotlight 151 rare variants predicted to impact protein function.
In 2017, I was able to find the boy in this study, Patient 1. He is 18 years old and living in New Zealand with him mom.
2012: Dutch researchers set out to identify the mutated gene in a group of patients with an unclassified white matter disorder that shared the same distinct MRI pattern. They used MRI pattern recognition analysis to select a group of patients with a similar characteristic MRI pattern and then performed whole exome sequencing to identify the mutated gene. They then examined the patients’ fibroblasts for biochemical consequences of the mutant protein. Results: This study identified 6 NUBPL patients from 5 unrelated families with a similar MRI pattern. Two sisters from Canada were diagnosed with NUBPL from this study. We are now in contact. We can tell from this research that Patient 5 has exact same mutations as our daughter, but we are not in contact with them at this time. To read more: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662327/
2013: Ambry Genetics was one of the 1st genetic testing laboratories to offer whole exome sequencing diagnostic services for clinicians, including medical interpretation. At the time a family in California has two daughters undiagnosed, ages 13 and 3, with an unknown white matter disorder. Their doctor recommends whole exome sequencing through Ambry and both girls are diagnosed with NUBPL. A few months after Katherine was diagnosed in 2015, I saw their documentary “The Life We Live: The Spooner Story” on the Global Genes Facebook page. Watch the documentary here.
*That same year (August 2013), at the age of two, our daughter has an MRI after a developmental plateau. Based on her MRI alone, top neurologists thought she had a disease called Infantile Neuroaxonal Dystrophy (INAD). Katherine’s MRI was similar to the patients in the 2012 NUBPL Dutch study, but her grey matter is affected. Doctors never suspected or mentioned NUBPL. Whole exome sequencing confirmed NUBPL in February 2015.
2015: Katherine is diagnosed with NUBPL through whole exome sequencing.
2016: We started a non-profit, NUBPL Foundation, to grow the NUBPL patient community, raise awareness, and fund research into the NUBPL gene.
2016-2019: Whole exome sequencing is becoming more common and affordable; however, there are still barriers. To date, all NUBPL patients have ONLY been diagnosed through whole exome sequencing. As far as the research goes to help clinicians diagnose patients, the 2012 Dutch study, “NUBPL mutations in patients with complex I deficiency and a distinct MRI pattern” is it. We know that Katherine has NUBPL and does not have this “distinct” MRI pattern. As more patients find us from around the world, we believe there may be some other differences that could help clinicians better diagnosis or at least “think” NUBPL as a possibility.
It takes time, awareness, and a larger patient population to see patterns or outliers. The more we talk about it, make noise, and raise awareness as a community (strength and volume in numbers), the better known it becomes to clinicians and researchers around the world.
Personally, I worry about the child getting an MRI today that’s similar to Katherine’s. It’s highly likely the neurologist does not even know about NUBPL because it’s so rare. Depending on the MRI results, there’s a chance they will find that 2012 Dutch research paper, but if the MRI is like Katherine’s, they are likely to keep searching for more common diseases. They may be facing exhaustive testing over the next year or so before whole exome sequencing will give them a definitive diagnosis. There’s also the NUBPL patient with a mild MRI pattern and/or slight developmental delays. These children may also be misdiagnosed.
In the rare disease world, it is our job to make the doctors aware of the disease. As hard as that is believe, that’s the way it flows. The responsibility falls on the parents to find the patients, grow the community, and push for new research (and fund it). It’s hard for a doctor to take on this responsibility unless they make it their sole focus. Realistically, it isn’t feasible for them if they also have a clinical practice. And as a researcher, it doesn’t make much sense to focus all their time on a disease that affects so few patients. If this disease affects a LARGE population? Yes!
For new clinical research to carry weight, you have to have patients, which is one of the biggest challenges with rare diseases. Slowly but surely, patients are getting diagnosed through whole exome sequencing and finding us. If they do not find us, then it’s hard to fit all of these “puzzle pieces” together to see the larger picture. Something most people don’t understand is there’s not a “central” database for doctors to access to find these patients. They really depend on “published” scientific research, and again, it’s our job to find the patients and push this research. Patient registries are helpful. We are getting close to having enough patients for new clinical research and a natural history study of the disease, which is so important for multiple reasons. Again, we have to fund it through our non-profit or find someone who is wants to fund it.
Our job is to be a lighthouse for other NUBPL families. The light has to reach them so everyone can come together on shore, and that light needs to shine bright enough to reach every corner of the world. Some people don’t know to look for a light; others don’t know they are in the NUBPL boat. Some don’t know why it matters or see the benefit of joining a community. As more families join our community, the brighter our light shines around the world. And the brighter we all shine and grow this community, the brighter the light we shine on understanding this disease and helping future patients. As you may have recognized, the silhouette of the girl in the logo is pointing to something. She is pointing ahead to the light and flying toward it. She is hopeful and optimistic as she flies alone to join her community. Together, they will push the needle of science forward.
This is a day you will never forget: The day a doctor tells you your child has a rare disease. I recall doctors using medical terms I’d never heard while showing me MRI images I didn’t want to see.
The initial shock felt like a really bad nightmare. How had I lived 36 years without ever hearing about this horrible disease? It was incomprehensible to me that this disease even existed in the first place, let alone that our precious child has the misfortune of having it. How was this even possible? Why is this happening to my child?
Statistically, we had a better chance of winning the lottery, but the news was the complete opposite. The clinical diagnosis was worse than I ever imagined: I was told that my two-year old had a progressive neurological disease with a life-expectancy of five to seven years.
Every experience is different, but here are a few important things I’ve learned by being the mother of a child with a rare disease:
1) You are the expert when it comes to your child. My daughter’s initial diagnosis was incorrect. That’s right. Turns out she has a completely different disease. We are all conditioned to believe that doctors know all the answers, when in reality they do not. What they do offer is a background of extensive medical training, and perhaps, most importantly, the experience of seeing countless patients with a similar presentation of symptoms, etc. so they can diagnosis and treat you. However, when your child has a very rare disease, most have never seen a patient like your child. An excellent doctor will acknowledge that the parents are the experts when it comes to rare diseases and ask for your input;
2) Instincts are more scientific than a doctor’s best guess. Again, when the diagnosis is rare, parents know more than the professionals;
3) Don’t be afraid to seek counseling. This diagnosis will change your life in an instant and take you on a wild emotional roller coaster ride. Your marriage, family, career, finances, emotional well-being and personal health will suffer from this diagnosis. Seek help;
4) Try, try, try to take care of yourself. You hear it every time you fly on an airplane: Please secure your own oxygen mask first before you try to help others. I constantly fail in this department, but it really is one of the best things you can do for your family;
5) If you don’t advocate for your child, NOBODY else will do it for you. You can do as little or as much as you want, but all of it begins and ends with you. That said, there are many individuals and organizations here to help you navigate your way. Some of my best resources are other parents farther along on this journey. Network with them via social media and ask for their guidance. Rare disease organizations, patients and parents are gaining a stronger presence each day;
6) You are NOT alone. A rare diagnosis can feel really lonely, but there is a community here to support you. They may not live in your community per se, but social media is a powerful tool to unite virtual communities. Although our children may have different diseases, we all share a similar journey. Find a group you feel comfortable with and share your story;
7) Regardless of your faith, don’t rule out science. Our child was diagnosed through Whole Exome Sequencing after being misdiagnosed by two doctors. Advancements in genetics are being made daily. Daily;
8) You will learn to live in the moment, which might be the greatest gift on this journey;
9) Prioritize your daily life. This is tough because everything shifts with this diagnosis. This may take years to figure out what works best for you and your family; and
10) Be kind to yourself. It’s easy to blame yourself for your child’s condition, but none of this has anything to do with fault.
This Friday, February 28, 2014, is “Rare Disease Day.” One in every ten people will suffer from a “rare” disease at some point during his or her life. Why, then, do we call them “rare?”
The National Institute of Health defines a “rare disease” as one that affects fewer than 200,000 people in the United States. This definition of a rare disease was included by Congress in the Orphan Drug Act of 1983. There are approximately 7,000 diseases or disorders that qualify for this designation. Alone, each disease is rare. It is only when counted together that they are not.
Because of the Congressional Orphan Drug Act of 1983, the term “orphan disease” is often used interchangeably with “rare disease.” Anyone who suffers from one or, in our case, has a family member who suffers from one, can understand the harsh poetry of that term. All too often, the sufferers are children. In many ways, they are abandoned by the scientific and medical communities. Few research projects are dedicated to these conditions. Few doctors specialize in treating them. It is difficult to find support groups. It is hard to find people who understand what it is like to watch a child’s symptoms in ignorance of what is causing them and fear of what they may portend. We face life-changing decisions alone and isolated from any sort of community of peers. We are not just facing the possible suffering or death of a beloved child, but all the things that must be changed before we even know what the future holds.
Can both parents work when our child has obstacles to face? Can we enter into daycare or mainstream schools and risk the viruses and illnesses that can so profoundly affect a child with a rare disease? Can they accommodate a child with the issues our child faces? Is our house fit for someone with a disability? Can we afford to go down to one income? Can we afford to make our house accessible? Can we afford to travel to the physicians that specialize in caring for the rare disease patient? All of this is on top of the harsh reality that we or someone we love may be facing death, and while learning that the road to answers will be long and difficult.
When we were told that Katherine likely suffered from Infantile Neuroaxonal Dystrophy or “INAD,” we searched for as much information as we could find on this condition. We had never even heard of it before the neurologist uttered the words. And it is no wonder. We read that there are only nine children in the United States that are confirmed to have that condition right now, and only around 1,000 that have ever been diagnosed with it here. These numbers do not come from scientific sources, so we cannot stand by their accuracy, but the one thing we do know is that it is extremely rare.
Compare this to cancer or heart disease. Most people have been touched by both. Even small towns have more people currently living with cancer or heart disease than have ever had INAD in the history of the United States.
It is understandable that we donate our charitable dollars to studying conditions we know all too well. We race for cures and donate to heart associations. When Congress or state legislatures set aside government research dollars, most of it goes to conditions well-known to voters. On top of this, private corporations spend their money researching new drug therapies and procedures that will make them money. There is not much money to be made from nine INAD children compared to the billions to be made off of each new cancer therapy or even a minor improvement in a heart stint.
Yes, we are orphans. We are alone, with voices too small and too few in number to be heard. This is why awareness matters. If our small choir stands united with the choirs formed by families faced with the other rare diseases, we are not small, we are not few in number, and we are not powerless. Alone we are rare. Together we are strong.
There are concrete things we can change for the better.
One of the things we learned early on in our search for a diagnosis for our daughter is that these conditions are difficult to diagnose. Most “rare diseases” have a genetic cause. Our current neurologist analogized diagnosing a genetic-based condition to editing a book. This particular book consists of detailed chapters on how to build a person. It defines how each cell is constructed, will operate, will replicate, will repair itself and will be stacked to create bones, tissue, brain cells and our whole body. Current estimates are that there are around 26,000 genes in the human body (somewhere between 23,000 and 30,000 by current estimates, excluding a lot of “non-coding DNA,” which is not well understood), translating in this analogy to 26,000 chapters to edit.The genes range from a few thousand DNA bases to over two million bases per gene, translating in this analogy to chapters of a few thousand to a couple million words each. That is a very large book to edit.
Most of these chapters–or genes–come in duplicate. One “chapter” comes from mom and one from dad. You have to know how each duplicate chapter works when the instructions are different (in our family, mom’s instructions usually prevail, but that is not always the case in genetics), and you have to know how these chapters work in unison to know how the construction is to proceed. On top of all of this, environmental factors work into the equation. How does a virus, a toxin or a trauma factor into the blueprint when the body is being constructed? How do the chapters, themselves, define that reaction?
To top it off, we all have hundreds, if not thousands, of typos and omissions. Some typos do not mean much, if anything. Some change the entire meaning of the story. Some we simply do not know.
This editing process ends up taking a lot of time and costing a lot of money. By way of example from our circumstances, for INAD, we know that typos and omissions in the chapter or gene titled “PLA2G6” are known to lead to INAD. However, this is true only 90% of the time. In the other 10% of known cases, no typos exist in these chapters and science just has not discovered another cause. So, we began with a chance that our child has INAD that this test – this edit – would not detect.
There are duplicate PLA2G6 chapters, and the condition is recessive, meaning that you have to have typos in both mom’s PLA2G6 chapter and dad’s PLA2G6 chapter for the child to have INAD.
Each of these chapters is written in script so small that our most advanced machines cannot accurately read them. As far as chapter PLA2G6, the test accurately detects known typos and omissions in a given chapter 85% of the time. In other words, they have used the test against genes that have been confirmed to contain INAD-causing typos, and only find them 85% of the time. The known typos are missed the other 15% of the time; we simply cannot read all the words. Since typos have to exist in both mom’s and dad’s PLA2G6 chapters, however, if no errors are detected in either chapter, the condition is unlikely to be present (there is only a 2.25% likelihood that errors would be present, but missed, in both parents’ PLA2G6 genes).
So, running the INAD test can result in different outcomes: (1) both mom’s and dad’s PLA2G6 have typos of a sort known to cause INAD, in which case the child is diagnosed as having it; (2) either mom’s or dad’s PLA2G6 is detected to have such an error, but not the other one, in which case, the child may be deemed likely to have INAD based on clinical manifestations of INAD and the 15% non-detection error rate in the other “normal” gene; (3) neither parent has PLA2G6 errors that are detected, in which case, the child still may have it because of the 15% error rate in each PLA2G6 editing (a 2.25% chance), or because of the atypical INAD cases where there is some other cause; or (4) errors are detected in the PLA2G6 genes, but not of a sort known to cause INAD, in which case the results are a firm “we don’t know.” The end result is a definite diagnosis of INAD, a “maybe,” a “probably not,” or a “who knows,” but never a “no.”
The cost for these tests can run at around $2,000 each. That’s right, $2,000 to test for just one condition of 7,000. Run the math. At $2,000 per test for 7,000 tests, the cost would be $14 million to edit all of the chapters known to cause “rare diseases.” Truth be told, the math is not that simple. Some tests are cheaper, while others are more expensive. In no case would they run all 7,000, as many conditions can be eliminated based on clinical signs or other blood or urine tests. However, the reality remains that many of these rare diseases share symptoms and it is often necessary to run multiple expensive tests over the course of years to finally reach a diagnosis. At the end of this long and expensive road, the physicians only come up with a definitive diagnosis half of the time. The other half of the time, we know there is some sort of metabolic disease, some rare condition, but we just do not know what it is. Our editing skills have not advanced to the point of knowing where to look for typos or what they mean.
No one can realistically edit all 7,000 chapters associated with these diseases, so doctors look for reasons to pull a particular chapter for editing. To do so, they perform less expensive (but not cheap) tests to try to figure out which chapter to edit. An MRI and MRS result justified the INAD test for Katherine. It turned out negative (but not ruling out INAD, as discussed above). So we move on to look for reasons to pull the next chapter. She had an abnormality in her acylcarnitine profile. We’ve run it again. If it turns out abnormal a second time, we have reason to suspect it may be one of the 30 known fatty acid or organic acid disorders, narrowing it down to 30 new chapters we might have to pull and edit. 30 edits at $2,000 each is still $60,000. It beats $14 million, but is still pretty expensive, particularly when there is a 50% chance that it will result in nothing definitive. We also have a follow up MRI/MRS, a genetic ophthalmologist appointment, and a spinal tap. We also are awaiting results from a skin biopsy. All of these will provide hints at what chapter to pull next for an edit.
Thank goodness for that insurance, right? Wrong.
In most cases, genetic testing is not covered by insurance. In other cases (like our’s) genetic testing is covered under limited circumstances. Insurance companies are in the business of collecting premiums, not paying claims. Therefore, it is rarer than these diseases for an insurance company to find the limited circumstances to be met.
The reason why genetic testing is routinely excluded from insurance policies or claims are rejected is simple: rare disease patients are easy to ignore, and expensive to hear. It costs nothing for the insurance company to let Katherine die, and $60,000 to see why her acylcarnitine profile is high, much less millions to see if she can be saved.
We are literal parents to figurative orphans left to die by harsh economic realities.
Considering she was thought to be the tenth child alive with INAD, she could be rejected without fear of economic backlash. All ten of us could march away in anger and it would help, not hurt, the insurers’ bottom lines. And what is our alternative? Are we to go uninsured? Are we to buy another policy if it, too, has a “let her die” policy toward genetic testing and rare diseases?
We have chosen a different alternative: To join together and be heard. We can change things for the better. We can put economic pressure on insurance companies to cover genetic testing. We can put pressure on politicians to force them to cover it. We can force states to increase newborn screening. We can expand awareness and education of the signs and symptoms of rare diseases. We can expand the flow of money into research of the genetic roots of all disease, including cancer and heart disease, leading to advances in the fight against the rare ones. We can let the lucky 90% know our cause, as many will join our choir if they just know the song.
This is for your benefit. At a 10% overall rare disease rate in the United States, it will affect your family. It is a matter of when, not if. Help us change things for the better before you discover that you or your “Katherine Belle” is among that 10%, an orphan to the medical community and a burden left to die by your insurance company.
With this blog, we stand up to join the chorus. We are singing at the top of our lungs. We contacted our state elected officials. Kentucky Governor Steven Beshear has proclaimed February 28, 2014, as Rare Disease Day in Kentucky; Representative Sannie Overly will read a Rare Disease Day citation in the Kentucky House of Representatives. It may not matter to many of you (yet, but it will affect all of you eventually) but it matters to us. Katherine’s voice matters. Katherine’s life matters. It is worth more than $60,000. It is worth more than $14 million.
And, we will not go quietly. We will be heard.
How can you help? First, you can share this post with everyone you know to help us raise awareness. Second, change your Facebook profile picture (see different examples below) to show your support for Rare Disease Day. Third, encourage your local, state and federal officials to recognize Rare Disease Day. Fourth, wear a denim ribbon on Friday to show your support (jeans for genes) and tell people why you are doing so.