Category Archives: David and Glenda

Today is Kentucky Gives Day 2018

TODAY is Kentucky Gives Day, an online 24-hour annual fundraising event bringing charities and Kentuckians—near and far—together for a powerful day of action.

Last year, the NUBPL Foundation won 2nd place overall for most funds raised in 24 hours. Impressive! With your donation TODAY, we aim to win 1st place and win an additional $1,500 for research. In case you missed it, here’s an in-depth article from The Pennsylvania Gazette about the critical research you are supporting.

Research dollars are difficult to come by for rare diseases, and your generous donation goes a long way toward helping us meet our goals. NUBPL is a progressive disease with zero FDA approved treatments. Once the brain cells have died, there is no bringing them back.

We are racing against time to save our children. 

As the parents of a six-year old affected by this devastating disease, we cannot thank you enough for supporting our cause and helping keep hope alive for her future. Thank you!

Click here to make your tax-deductible donation. 

The Pennsylvania Gazette #Hope4KB Cover Story

A special thank you to The Pennsylvania Gazette for the feature cover story about how our family’s journey through the realm of rare disease led us to the newest frontier of precision genetic medicine at the Children’s Hospital of Philadelphia.

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#GivingTuesday

Today, Tuesday, November 28, 2017, is #GivingTuesday, a global day of giving fueled by the power of social media and collaboration. Celebrated on the Tuesday following Thanksgiving (in the U.S.) and the widely recognized shopping events Black Friday and Cyber Monday, #GivingTuesday kicks off the charitable season, when many focus on their holiday and end-of-year giving.

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NUBPL.org

We need your support

We want to take a moment to give you an update on Katherine Belle.

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Katherine Belle, age 6

You can see from the photos that she’s happy and growing. She’s loving first grade and changing so fast (as is typical at this age). Although she did not have a third MRI, her latest round of testing this fall was mostly “normal,” which is what every parent wants to hear. The only thing that was slightly abnormal was a mild curvature of her spine (neuromuscular scoliosis) – something that is common with disorders of the brain. At this time, all organs other than her brain remain unaffected. This is indeed a blessing.

She continues on the clinical trial drug EPI-743 and her “Mito Cocktail,” both of which have been very helpful for her. She is growing stronger and walking more and more. She is mostly walking upright around our house – still holding on to surfaces the majority of the time, but taking more independent steps in between. It’s amazing to watch this process as her brain rewires itself, opens new pathways, and creates muscle memory. At this point, we can see how the repetition is building on itself and beginning to accelerate.

This experience is hard in many ways because nobody wants to watch their child struggle, but at the same time it’s mind-blowing to watch the process of how the human brain has the ability to reorganize itself when pushed by a resilient human spirit. It’s incredible. Again, this is a blessing.

We don’t want her to fight this alone. We know enough about this disease to know that even the toughest fighters cannot beat a failing human body. She needs our help.

When we first started on this rare disease journey, I recall feeling like we were stuck in the past, medically speaking. Nobody knew what was wrong with our child, let alone how to treat her. Science was on our side for getting a fairly quick diagnosis through whole exome sequencing. We continue to exhaust all possible avenues to help her as quickly as possible, from a clinical trial, to vitamins and supplements, best therapies, educational environment, and now research.

On the days when the fight seems too hard and the fundraising has slowed to a halt, the sound of a ticking clock fills our heads. This part is the hardest of all for us as her parents – wanting to do everything we can to help our daughter while being constrained by a short timeframe to stop the disease progression. It’s easy to look at a smiling, happy, healthy looking photograph of a vibrant six-year old and not think about her future. As her parents, though, it’s all we think about.

Timing is critical. Science was on our side for getting a NUBPL diagnosis; now we hope we can push science to discover a treatment she needs NOW to increase her odds of not regressing cognitively and physically. It’s been 55 years since this first patient was diagnosed with mitochondrial disease and there’s still no FDA approved treatment to help patients like Katherine. We say the time is now and we will do everything in our power to advance the needle of research.

It’s like knowing in advance that your child is going to die in a car crash and having the opportunity to stop them from getting in the car that day. Just as we watch Katherine slowly rewire her brain to overcome her physical obstacles, she inspires us to keep pushing for a treatment that will hopefully come sooner rather than later.

There’s an upcoming article coming out soon that will go more in-depth about the research we’re funding, but we want to tell you a little here today. Researchers at the Children’s Hospital of Philadelphia are using cutting-edge Crispr technology to study zebrafish with Katherine’s NUBPL mutations to learn about the natural history of the disease and test currently available therapies.

Donations made today on #GivingTuesday will help us fund this critical research.

There are two places you can make a donation today to support the NUBPL Foundation:

1) Facebook

2) Children’s Hospital of Philadelphia (Hope for Katherine Belle Mitochondrial Disease Research Fund)

Also, please consider voting for Katherine’s #GivingStory here. Entries with the most votes are eligible to win up to $10,000.

Thank you very much for your consideration.

Sincerely,

Dave & Glenda

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The Liebster Award

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We are excited to share with you that our blog, Hope for Katherine Belle, has been nominated for the Liebster Award, an award created to give recognition to new bloggers. 

We would like to thank Modified Mamas for your support and for nominating us for this fantastic award.

Here’s how the process works: Bloggers are nominated by their peers. Once they are nominated, they look for blogs that speak to them and have less than 200 readers per month, and then they nominate those bloggers – paying it forward.

Upon nomination, The Liebster Award Nominees are asked to answer 10 questions.

Here are the 10 questions Brandy and Nicole at Modified Mamas asked us:

Q: What made you decide to start a blog?
A: When we received the soul-crushing news that our then two-year old daughter, Katherine Belle, had a progressive, neurodegenerative disease in 2013, we were utterly devastated. We needed an outlet to express what we were feeling, but also on a practical level, we needed a way to give community updates to friends and family at once so we didn’t have to keep repeating very complicated, painful information. 

Q: What is the number one way you market your blog?
A: Over time, our blog has become more than just a place for community updates, although that is still very much an important component. As we’ve moved through our rare disease journey, this blog provides a way to get our story out into the world to help us find other patients like our daughter, which is especially important now that we founded a non-profit to research her mitochondrial disease and grow the patient population. The number one way we market our blog is through a companion Facebook page, Hope for Katherine Belle

Q: Where do you see your blog in 5 years?
A: We see this blog as an ever-evolving public journal of our rare disease journey. When we started blogging, we sat down together and discussed what this blog meant to us. Given the grim odds our daughter faces, coupled with our immense grief over learning that she’s slowly dying from a rare mitochondrial disease, we understood that our family had a long, rough road ahead. In the beginning, we were told there was no hope for Katherine. Together, we decided to reject this opinion – both medically and spiritually – because we believe there’s always hope. Excerpts from our first blog posts established the tone of our blog (and journey):

Dave:

But this is not a blog about hopelessness. Far from it.  It is a blog about hope. It is about faith.  Above all, it is about love. While we have faced many hard days in the wake of this news — and will face more in the days to come — we have also felt and seen the redeeming power of hope, have been buoyed by the love given us by family, friends and complete strangers and have been astounded by the ability of faith to change things for the better, whether it is faith in a benevolent God, faith in each other or faith in a miraculous child.

Glenda:

Each day I share my photographs with friends and family and tell them a story that does not always require words, and that sometimes cannot be expressed with them. It is a story of faith, hope, love, and determination.  As we continue ahead on our journey toward a diagnosis, I see a brave and thriving girl who is progressing, not regressing.  I see a happy and joyful child who meets every obstacle or challenge with the biggest smile and the most positive attitude. I see a future with many more photographs of accomplishments, milestones, and laughter. In all of my pictures, I see faith, hope and love.  Above all, I see an abundance of love.

Three years later and we still feel the same way. Where do we see this blog in five years? Ideally, in five years (even sooner) we hope we’re sharing groundbreaking research about cures/treatments for mitochondrial disease, along with photos of a happy and thriving 11-year-old Katherine Belle. We hope that people will understand that when we received devastating news in 2013 that we didn’t just sit down and hope for the best; instead, we stood up and looked mitochondrial disease squarely in the eyes and fought with everything we had – we pushed for a diagnosis, treatments, and cures, and advocated for our child every single day. Our greatest hope is that five years from now our hopes and hard work to fund treatments and cures will be a reality, not just for our own child, but for all those affected by mitochondrial disease.

Q: What do you do in your downtime/do you have a hobby other than blogging?
A: In our downtime we run a non-profit, the NUBPL Foundation, to raise awareness and fund research to cure mitochondrial disease. We try our best to carve out time for self-care (so very important!), which usually involves reading, biking, gardening, and home projects. 

Q: What one piece of advice would you give other new bloggers?
A: Keep writing and searching for your authentic voice and purpose. 

Q: What is your favorite book?
A: Angle of Repose (Glenda); I, Claudius (Dave)

Q: Do you have a phrase (or code) you live by?
A: “It is not the critic who counts; not the man who points out how the strong man stumbles, or where the doer of deeds could have done them better. The credit belongs to the man who is actually in the arena, whose face is marred by dust and sweat and blood; who strives valiantly; who errs, who comes short again and again, because there is no effort without error and shortcoming; but who does actually strive to do the deeds; who knows great enthusiasms, the great devotions; who spends himself in a worthy cause; who at the best knows in the end the triumph of high achievement, and who at the worst, if he fails, at least fails while daring greatly, so that his place shall never be with those cold and timid souls who neither know victory nor defeat.” (Glenda)

“Don’t let the perfect be the enemy of the good.” (Dave)

Q: What is your favorite drink?
A: Coffee (Glenda), Diet Coke (Dave)

Q: What gets you out of bed in the morning?
A: During the week our iPhone alarm clock. On the weekends, a chipper six-year old saying “Rise and shine!”

Q: What is the last thing you do at night before you close your eyes?
A: Kiss one another and say goodnight.

Now it’s our turn to nominate some fellow bloggers.

Our 6 nominees for the Liebster Award 2017:

Upon accepting this nomination, it becomes your turn to write your Liebster Award 2017 acceptance and nominate some fellow deserving blogs. In your post you’ll need to follow these Liebster Award rules:

  • Thank the blogger who nominated you for the Liebster Award (www.hopeforkatherinebelle.com)
  • Link back to the blogger who awarded you – that would be us – www.hopeforkatherinebelle.com 
  • Upload the award to your blog. It can be done as a blog or on the sidebar.
  • Answer the questions you have been asked. (see below)
  • Nominate 5 blogs with followers less than 200 that you believe deserve to receive the award. If you feel others deserve the award, then you are welcome to nominate more.
  • Notify the nominated bloggers so that they can accept the award. Bloggers can be nominated more than once, giving their readers more chances to learn more about them.

Our Questions for Our Nominees Are:

  1. Can you tell readers about yourself and your blog?
  2. Something surprising you’ve learned from starting your own blog?
  3. Do you have periods when you want to abandon your blog, and if so, what brings you back?
  4. Where would you go if you could travel anywhere in the world?
  5. Do you have a blogging mentor?
  6. What was your proudest achievement (life in general)?
  7. What is your favorite quote?
  8. What do you think your blog says about you?
  9. Where do you see your blog in five years?
  10. How do you relieve stress and unwind?

We are inspired by each of you and look forward to your responses!

xo,

Glenda & Dave

Kentucky Gives Day 2017: Support NUBPL Foundation

“Never doubt that a small group of thoughtful, committed citizens can change the world. Indeed, it is the only thing that ever has.”
Margaret Mead

In 2015, our (now) 5-year old daughter, Katherine Belle, was diagnosed with an extremely rare Mitochondrial Complex 1 disease caused by mutations in the NUBPL gene.

The harsh reality is we have a vibrant and amazing five-year old daughter who fights daily with everything she has, but because NUBPL is a recently discovered disease without any available treatments, we do not know what the future holds in terms of her health and disease progression.

As tireless advocates for our daughter, we decided to do more. We founded the NUBPL Foundation to fund research for NUBPL, which causes progressive atrophy in our daughter’s cerebellum, as well as speech and developmental delays.

Katherine is just one of 11 patients in the WORLD identified in scientific research, although we believe the number of confirmed NUBPL patients is likely closer to between 25 to 50. All patients have been diagnosed through Whole Exome Sequencing (WES), and we have no doubt that the NUBPL patient population will continue to increase as more families use WES to diagnosis their children. We have been very public about our story so that we can help clinicians and families better diagnose NUBPL in the future.

Because orphan diseases are rare, they lack support groups and national organizations. And, 95% of rare diseases do not have any FDA approved treatments, including NUBPL. Orphan diseases don’t attract as many research dollars because few people are affected, and for pharmaceutical companies, there’s less incentive to fund the research for a treatment that will not produce a good return on their investment.

Our daughter and other affected children deserve better.

NUBPL Foundation

We have carefully listened to proposals from top researchers from around the country and have decided to fund the promising research of Dr. Marni Falk at the University of Pennsylvania. The Mitochondrial-Genetic Disease Clinic at Children’s Hospital of Philadelphia (CHOP) is one of the top research centers in the nation for Mitochondrial related diseases. This research gives us hope that therapies will soon be developed to help treat the mitochondrial dysfunction of Katherine and other NUBPL patients.

100% of your tax-deductible donation will directly fund the research of Dr. Marni Falk and her team at CHOP to research the NUBPL gene and to develop life-enhancing treatments for the mitochondrial dysfunction of Katherine and other NUBPL patients. 

Our matching gift pool from our Double The Hope partners will match every donation – DOLLAR FOR DOLLAR – we receive from you on April 18, 2017, to ensure we reach our $25,000 goal.

Click on the picture to donate to the NUBPL Foundation:

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Mitochondrial Disease Awareness Week (September 18-24)

In honor of Mitochondrial Disease Awareness week, we would like to help you better understand Mitochondrial Disease, especially as it relates to our daughter. There are families that do not like to discuss their child’s disorder, and although we can respect that decision and honor their wishes, we have a very different perspective when it comes to our own daughter.

For starters, we cannot hide the fact that Katherine cannot walk, has a mild tremor, and an irregular speech pattern.  Knowing our child is a wonderful opportunity to learn about rare diseases as you get to know her personally, and since she is unable to fully articulate the ins and outs of her disorder, we are her voice. No, we do not think her disorder defines her, but it is as much a part of her as anything else. Second, we are not embarrassed by her disorder and do not want her to feel that it should only be discussed behind closed doors. Third, knowledge is powerful. We don’t want people to guess why our child cannot walk – we want to educate you with the facts so you can help spread awareness just by being informed.

This is the way we understand or think about our daughter’s condition: Katherine has a very rare genetic disorder known as Mitochondrial Complex I (or 1) Deficiency caused by mutations in her NUBPL gene. There are dozens of types of “Mitochondrial Complex I Deficiencies” but her particular type is very rare. To date, only 6 people have been diagnosed with it in the United States and approximately 25 in the world. That said, it has only been known about since 2010, and can only be diagnosed through Whole Exome Sequencing – a complex and often expensive genetic test. We expect many more to be diagnosed with it in the future.

One of the patients (residing in the U.S.) has identical mutations to Katherine. We know a little about her through research papers.

Because there are so many types of Mitochondrial Complex I disorders and each is different, we sometimes refer to Katherine’s type as “NUBPL,” the name of the gene affected.

So what is NUBPL/Mitochondrial Complex I Deficiency?

When people think of “mitochondria,” many think of DNA from just the mother. This is true only with respect to some of the DNA making up the mitochondria. In fact, they are put together mostly from gene pairs with one gene from each parent (nuclear DNA), plus just a handful involving just one gene coming from the mom (mitochondrial DNA).

All of our cells (except red blood cells) contain mitochondria. The mitochondria produce the energy our cells need to function, to replicate, and to repair themselves. They are the “powerhouses” of the cell.

This “power” is produced through a series of chemical reactions taking place in 5 different physical structures. These are called complexes I through V (or 1 through 5). They work together like an assembly line. If a problem exists in one “complex,” it can harm production down the line in another, ultimately resulting in too little “energy” being produced.

Like an actual power plant, the process of producing usable energy also produces chemical byproducts that can be toxic. Our bodies clean these byproducts through, among other things, “anti-oxidants.” However, sometimes a person with a mitochondrial disease produces too many toxic byproducts for the anti-oxidants to work, leading to a build-up of toxins. This process is called “oxidative stress.”

Thus, a good analogy is a power plant with five buildings, each producing products that are sent down the line, ultimately producing energy from the final building, Complex V, while also producing polluted water that is filtered and cleaned by another facility before being released into a stream. A person with a mitochondrial disease has a problem in at least one building of the five. As a result, she may not produce enough product to be passed along and ultimately turned into energy to meet the needs of the cell (not enough energy is coming out of Complex V) or may be spitting out too much pollutant to be filtered and the water in the stream is getting polluted.

Either of these can result in premature cell death or impaired function.

The nature of these diseases is that they often cause damage over time — again, like pollution from a factory. Similarly, illness can increase energy needs of the body, and cells can become damaged because of their inability to meet the needs in times of higher demand. Both of these things occurs in all of us as we age (mitochondrial dysfunction is a significant contributor to the symptoms of old age, including wrinkles, loss of muscle, loss of brain function, clumsiness, and heart disease). Patients with a primary mitochondrial disease just suffer this fate differently, earlier, and in different parts of their bodies. Note, however, that this is not the “premature aging” disease. Regardless, by their very nature, these diseases often progress.

The extent to which Katherine’s particular condition, NUBPL, is progressive is not yet known. In most cases, it progresses to a degree – it has with Katherine. Fortunately, many of the patients have long periods without any advancement of the disease and many are thought to have become stable. The reasons are not clear, nor has the disease been known about long enough to determine if this is typical.

The patient with Katherine’s identical mutations is now 13. Our information is now 5 years out of date (it was in a 2010 research paper). As of 2010, she could walk with a walker and had normal intelligence. She had not had much regression after an initial period of regression experienced when she was a toddler.

Different cell types have different energy needs. Skin cells, for example, need little energy, so contain few mitochondria. Heart, kidney, liver, and brain cells, on the other hand, have high energy needs, so contain the most mitochondria. Liver cells, for example, may contain as many as 2,000 mitochondria per cell. As a result, these parts of the body are susceptible to “mitochondrial diseases,” either because the energy needs are not being met, or in meeting them too much “pollution” is being produced. Some of these diseases affect only one of these parts of the body, while others may affect multiple systems.

Katherine’s disorder is a problem in “Complex I,” thus the name “Mitochondrial Complex I Deficiency.” This is the largest of the five complexes, the one involving the most genes for its assembly and function. It is the most common place for these diseases to arise.

Knowing that Katherine has a disorder in Complex I tells you very little. Returning to the power plant analogy, it is like telling you there is some sort of problem in “building one” of a five building complex, but not knowing what that problem is; it could be something small, like a clogged toilet, or it could be something large, like the complete collapse of the building. The devil is in the details.

Some Complex I deficiencies are quickly fatal. Others are far more benign. Indeed, it is likely that many are so benign that a person can live a long healthy life without knowing they have a disorder. Still others may suffer problems only late in life, such as developing Parkinson’s or heart disease.

Thus, Mitochondrial Complex I Disorders can range from quickly fatal to unnoticed and insignificant. No known patient has died from the disease and only one has died at all (from what is not clear, nor is it entirely clear that NUBPL was the only condition he had, as he was the first NUBPL patient and died before current testing methods were developed).

In Katherine’s case, the gene affected, NUBPL, is “nuclear,” meaning she inherited one gene from each of us. In order to manifest as a disease, Katherine had to receive one mutated gene from both of us – one mutated gene and one normal one will not result in disease, but only “carrier” status (Glenda and I are both carriers, each having one mutated gene, but not two). Having a single mutation of this gene is rare. Having parents who each have one mutation of the gene, rarer still. Having both pass one mutated gene to the child is extremely rare (there is only a 25% chance that two carriers will have a child with two mutations) – lottery-level odds (more people win the Powerball each year than are known to have NUBPL, worldwide).

Because it is so rare and so newly-discovered (discovered in 2010), not a lot is known about Katherine’s form of Mitochondrial Complex I Disorder. What is known or suspected is as follows:

The NUBPL gene is known as an “assembly gene.” This means that it is not part of the physical design or structure of Complex I, but is a gene that contributes to its assembly. In particular, it is involved in the assembly of “iron-sulfur clusters” that transfer electrons during the chemical reactions in Complex I.

Think of it as Katherine having an accurate blueprint for “building one” of her power plant, but someone used defective wiring or put the wiring in it the wrong way. What this means is not fully understood. One possible result of this is that the electrons that are supposed to be carried by this “wiring” may leak out and be transferred to chemicals other than those intended, producing the toxins referred to above (known as “Reactive Oxygen Species” or “ROS”).

While it would seem like this defect would affect the mitochondria throughout the body (and NUBPL patients must monitor all systems to make sure problems do not crop up), to date, NUBPL mutations seem concentrated in the brain of patients. While some NUBPL patients have issues throughout the brain, most are concentrated in the cerebellum.

Katherine is fortunate in that her brain appears to be spared except for the cerebellum and one very small inflammation in her corpus callosum that has not changed and may well resolve or never affect her in any way.

As far as energy production, Katherine’s Complex I residual function appears to be low normal in fibroblasts grown from her skin cells. No brain cells have been tested due to dangers from brain surgery. This is where it is likely to be most affected, so low normal residual function does not tell us much about her brain issues. She does not appear to lack energy, in general (a common issue in “mito kids”) – and exercise is likely good for her.

The cerebellum is not the part of the brain primarily involved in “higher” brain functions, nor is it involved in the autonomic functions (like breathing and heartbeat). That said, there are connections between the cerebellum and cognition in many cases (the role of the cerebellum in cognition is not fully understood). Some NUBPL patients have lower than normal cognitive abilities, while others (including the person with the same mutations as Katherine) have little to no cognitive impairment at all. This may depend on whether other areas of the brain are affected and to what extent, or it may be happenstance of what part of the cerebellum is or may come to be affected. We just don’t know.

We do know that the cerebellum helps regulate and direct the signals coming into and out of your brain. For example, the cerebellum does not initiate the signal from your brain telling your legs to move. However, that signal passes through the cerebellum before it is sent to the legs, and the cerebellum helps direct it and tell it how much pressure, strength and speed to use. The leg then sends the signal back the brain to tell it what has happened. That signal also passes through the cerebellum before being sent to the part of the brain in control of the leg. With a damaged/abnormal cerebellum, those signals can get mixed up, amplified, muted, or misdirected. This results in clumsiness, difficulty controlling the force or pressure of one’s muscles, difficulty writing, poor articulation of speech, poor motor planning, and a lack of coordination when walking, clapping, playing patty-cake, etc.

Because these signals travel through the cerebellum thousands of times per second from all parts of our bodies, significant problems can occur. As an example, the simple (to most of us) act of standing, alone, requires thousands of these signals to pass through the cerebellum each second; nerves of the ankles, feet, knees, thighs, torso, arms, neck, and head signal the brain about what they are doing, the inner ear tells it up from down, the eyes tell it what is going on around us, etc. These signals pass through the cerebellum, are regulated, and passed on to the higher brain for interpretation. That higher brain then decides what to do, and signals back how the body needs to adjust given all the signals coming in from all of these body parts. Maintaining balance while standing is a coordinated and complex function—one that modern computers could not hope to replicate – that we take for granted and do not even think about. That is not the case for Katherine. Katherine’s entire “balance center” of her cerebellum is the most affected, making balance a daunting task, requiring a great deal of concentration. It is like a normal person trying to walk a tight-rope in windy conditions. Add to that trying to coordinate all of these body parts to walk, and the task is beyond her current abilities.

The brain is remarkably adaptable, however. People suffering from significant brain injuries can re-learn to walk, talk, and function. Repetition and rehabilitation allow the brain to make new pathways and connections to do what it once did elsewhere.

Sensory input is hard for Katherine to process. She can be overwhelmed by chaotic environments, as her brain is not telling her what is going on in the same way as the rest of us. She processes things more slowly. This probably is not so much of a function of her higher intelligence, as her body’s way of communicating between her senses and her higher brain.

You can expect Katherine to be off balance. She will have trouble with writing. She may become overwhelmed or confused by sensory input. She will have trouble articulating her words. She will have difficulty controlling the volume and pitch of her speech. She will be clumsy and uncoordinated. She does not yet have a good grasp of the body’s “potty” warning signals — she is better at telling you she has gone, than telling you she is about to go. All of these things can frustrate her, cause her to withdraw from others at times, or become anxious. That said, she has a very good vocabulary and understanding of things.

Children with Mitochondrial disease have some difficulty controlling their body temperature, can become fatigued, need to stay hydrated, and can suffer more when ill than other children. So far, these do not appear to be problems with NUBPL patients, other than some worries when they become ill. However, there are things to be aware of in case they occur.

Katherine is currently on an experimental medication called EPI-743 (or is on a placebo. She will receive 6 months of both over a 14 month double-blind clinical trial). It is part of a clinical trial run by the National Institutes of Health. This is essentially a very potent anti-oxidant, thousands of times more powerful at the cellular level than any anti-oxidant you can get in food or supplements.  While administration and action of the medication in the body is a far more complicated thing, in a laboratory setting fibroblasts grown from her cells demonstrated susceptibility to oxidative stress (discussed above) and an 80% or higher return to viability from administration of the medication. We hope that predicts that the EPI-743 will clean up the toxins she may be producing and will help her cells produce energy, and arrest any progression of the disease. It could do more.  While it cannot revive dead cells, it may save those that were damaged and dying, and allow them to function better, improving her condition (along with physical and occupational therapy), not just arresting its decline.

She also is on a compounded medication commonly called a “mitochondrial cocktail” that does many of the same things in different ways, as well as supplement one of the chemical products of Complex I, being a substance called Ubiquinol, a form of CoQ10.

We lived with a misdiagnosis that guaranteed us that Katherine was going to die in the next few years. The NUBPL diagnosis is serious and full of unknowns, but “serious and unknown” is better than “known and hopeless.”

We want to stress that we think it is important for other children and their families to understand Katherine. This provides insight into the rare disease community in general, mitochondrial disease patients, in particular, and Katherine, individually. It will help them get to know Katherine (and others like her) and explain why she cannot walk or do other things they take for granted.

Mitochondrial Disease Explained for Non-Scientists

There are families that do not like to discuss their child’s disorder, and although we can respect that decision and honor their wishes, we have a very different perspective when it comes to our own daughter.

For starters, we cannot hide the fact that Katherine cannot walk, has a mild tremor, and an irregular speech pattern.  Knowing our child is a wonderful opportunity to learn about rare diseases as you get to know her personally, and since she is unable to fully articulate the ins and outs of her disorder, we are her voice. No, we do not think her disorder defines her, but it is as much a part of her as anything else. Second, we are not embarrassed by her disorder and do not want her to feel that it should only be discussed behind closed doors. Third, knowledge is powerful. We don’t want people to guess why our child cannot walk – we want to educate you with the facts so you can help spread awareness just by being informed.

This is the way we understand or think about our daughter’s condition: Katherine has a very rare genetic disorder known as Mitochondrial Complex I (or 1) Deficiency caused by mutations in her NUBPL gene. There are dozens of types of “Mitochondrial Complex I Deficiencies” but her particular type is very rare. To date, only 6 people have been diagnosed with it in the United States and approximately 25 in the world. That said, it has only been known about since 2010, and can only be diagnosed through Whole Exome Sequencing – a complex and often expensive genetic test. We expect many more to be diagnosed with it in the future.

One of the patients (residing in the U.S.) has identical mutations to Katherine. We know a little about her through research papers.

Because there are so many types of Mitochondrial Complex I disorders and each is different, we sometimes refer to Katherine’s type as “NUBPL,” the name of the gene affected.

So what is NUBPL/Mitochondrial Complex I Deficiency?

When people think of “mitochondria,” many think of DNA from just the mother. This is true only with respect to some of the DNA making up the mitochondria. In fact, they are put together mostly from gene pairs with one gene from each parent (nuclear DNA), plus just a handful involving just one gene coming from the mom (mitochondrial DNA).

All of our cells (except red blood cells) contain mitochondria. The mitochondria produce the energy our cells need to function, to replicate, and to repair themselves. They are the “powerhouses” of the cell.

This “power” is produced through a series of chemical reactions taking place in 5 different physical structures. These are called complexes I through V (or 1 through 5). They work together like an assembly line. If a problem exists in one “complex,” it can harm production down the line in another, ultimately resulting in too little “energy” being produced.

Like an actual power plant, the process of producing usable energy also produces chemical byproducts that can be toxic. Our bodies clean these byproducts through, among other things, “anti-oxidants.” However, sometimes a person with a mitochondrial disease produces too many toxic byproducts for the anti-oxidants to work, leading to a build-up of toxins. This process is called “oxidative stress.”

Thus, a good analogy is a power plant with five buildings, each producing products that are sent down the line, ultimately producing energy from the final building, Complex V, while also producing polluted water that is filtered and cleaned by another facility before being released into a stream. A person with a mitochondrial disease has a problem in at least one building of the five. As a result, she may not produce enough product to be passed along and ultimately turned into energy to meet the needs of the cell (not enough energy is coming out of Complex V) or may be spitting out too much pollutant to be filtered and the water in the stream is getting polluted.

Either of these can result in premature cell death or impaired function.

The nature of these diseases is that they often cause damage over time — again, like pollution from a factory. Similarly, illness can increase energy needs of the body, and cells can become damaged because of their inability to meet the needs in times of higher demand. Both of these things occurs in all of us as we age (mitochondrial dysfunction is a significant contributor to the symptoms of old age, including wrinkles, loss of muscle, loss of brain function, clumsiness, and heart disease). Patients with a primary mitochondrial disease just suffer this fate differently, earlier, and in different parts of their bodies. Note, however, that this is not the “premature aging” disease. Regardless, by their very nature, these diseases often progress.

The extent to which Katherine’s particular condition, NUBPL, is progressive is not yet known. In most cases, it progresses to a degree – it has with Katherine. Fortunately, many of the patients have long periods without any advancement of the disease and many are thought to have become stable. The reasons are not clear, nor has the disease been known about long enough to determine if this is typical.

The patient with Katherine’s identical mutations is now 13. Our information is now 5 years out of date (it was in a 2010 research paper). As of 2010, she could walk with a walker and had normal intelligence. She had not had much regression after an initial period of regression experienced when she was a toddler.

Different cell types have different energy needs. Skin cells, for example, need little energy, so contain few mitochondria. Heart, kidney, liver, and brain cells, on the other hand, have high energy needs, so contain the most mitochondria. Liver cells, for example, may contain as many as 2,000 mitochondria per cell. As a result, these parts of the body are susceptible to “mitochondrial diseases,” either because the energy needs are not being met, or in meeting them too much “pollution” is being produced. Some of these diseases affect only one of these parts of the body, while others may affect multiple systems.

Katherine’s disorder is a problem in “Complex I,” thus the name “Mitochondrial Complex I Deficiency.” This is the largest of the five complexes, the one involving the most genes for its assembly and function. It is the most common place for these diseases to arise.

Knowing that Katherine has a disorder in Complex I tells you very little. Returning to the power plant analogy, it is like telling you there is some sort of problem in “building one” of a five building complex, but not knowing what that problem is; it could be something small, like a clogged toilet, or it could be something large, like the complete collapse of the building. The devil is in the details.

Some Complex I deficiencies are quickly fatal. Others are far more benign. Indeed, it is likely that many are so benign that a person can live a long healthy life without knowing they have a disorder. Still others may suffer problems only late in life, such as developing Parkinson’s or heart disease.

Thus, Mitochondrial Complex I Disorders can range from quickly fatal to unnoticed and insignificant. No known patient has died from the disease and only one has died at all (from what is not clear, nor is it entirely clear that NUBPL was the only condition he had, as he was the first NUBPL patient and died before current testing methods were developed).

In Katherine’s case, the gene affected, NUBPL, is “nuclear,” meaning she inherited one gene from each of us. In order to manifest as a disease, Katherine had to receive one mutated gene from both of us – one mutated gene and one normal one will not result in disease, but only “carrier” status (Glenda and I are both carriers, each having one mutated gene, but not two). Having a single mutation of this gene is rare. Having parents who each have one mutation of the gene, rarer still. Having both pass one mutated gene to the child is extremely rare (there is only a 25% chance that two carriers will have a child with two mutations) – lottery-level odds (more people win the Powerball each year than are known to have NUBPL, worldwide).

Because it is so rare and so newly-discovered (discovered in 2010), not a lot is known about Katherine’s form of Mitochondrial Complex I Disorder. What is known or suspected is as follows:

The NUBPL gene is known as an “assembly gene.” This means that it is not part of the physical design or structure of Complex I, but is a gene that contributes to its assembly. In particular, it is involved in the assembly of “iron-sulfur clusters” that transfer electrons during the chemical reactions in Complex I.

Think of it as Katherine having an accurate blueprint for “building one” of her power plant, but someone used defective wiring or put the wiring in it the wrong way. What this means is not fully understood. One possible result of this is that the electrons that are supposed to be carried by this “wiring” may leak out and be transferred to chemicals other than those intended, producing the toxins referred to above (known as “Reactive Oxygen Species” or “ROS”).

While it would seem like this defect would affect the mitochondria throughout the body (and NUBPL patients must monitor all systems to make sure problems do not crop up), to date, NUBPL mutations seem concentrated in the brain of patients. While some NUBPL patients have issues throughout the brain, most are concentrated in the cerebellum.

Katherine is fortunate in that her brain appears to be spared except for the cerebellum and one very small inflammation in her corpus callosum that has not changed and may well resolve or never affect her in any way.

As far as energy production, Katherine’s Complex I residual function appears to be low normal in fibroblasts grown from her skin cells. No brain cells have been tested due to dangers from brain surgery. This is where it is likely to be most affected, so low normal residual function does not tell us much about her brain issues. She does not appear to lack energy, in general (a common issue in “mito kids”) – and exercise is likely good for her.

The cerebellum is not the part of the brain primarily involved in “higher” brain functions, nor is it involved in the autonomic functions (like breathing and heartbeat). That said, there are connections between the cerebellum and cognition in many cases (the role of the cerebellum in cognition is not fully understood). Some NUBPL patients have lower than normal cognitive abilities, while others (including the person with the same mutations as Katherine) have little to no cognitive impairment at all. This may depend on whether other areas of the brain are affected and to what extent, or it may be happenstance of what part of the cerebellum is or may come to be affected. We just don’t know.

We do know that the cerebellum helps regulate and direct the signals coming into and out of your brain. For example, the cerebellum does not initiate the signal from your brain telling your legs to move. However, that signal passes through the cerebellum before it is sent to the legs, and the cerebellum helps direct it and tell it how much pressure, strength and speed to use. The leg then sends the signal back the brain to tell it what has happened. That signal also passes through the cerebellum before being sent to the part of the brain in control of the leg. With a damaged/abnormal cerebellum, those signals can get mixed up, amplified, muted, or misdirected. This results in clumsiness, difficulty controlling the force or pressure of one’s muscles, difficulty writing, poor articulation of speech, poor motor planning, and a lack of coordination when walking, clapping, playing patty-cake, etc.

Because these signals travel through the cerebellum thousands of times per second from all parts of our bodies, significant problems can occur. As an example, the simple (to most of us) act of standing, alone, requires thousands of these signals to pass through the cerebellum each second; nerves of the ankles, feet, knees, thighs, torso, arms, neck, and head signal the brain about what they are doing, the inner ear tells it up from down, the eyes tell it what is going on around us, etc. These signals pass through the cerebellum, are regulated, and passed on to the higher brain for interpretation. That higher brain then decides what to do, and signals back how the body needs to adjust given all the signals coming in from all of these body parts. Maintaining balance while standing is a coordinated and complex function—one that modern computers could not hope to replicate – that we take for granted and do not even think about. That is not the case for Katherine. Katherine’s entire “balance center” of her cerebellum is the most affected, making balance a daunting task, requiring a great deal of concentration. It is like a normal person trying to walk a tight-rope in windy conditions. Add to that trying to coordinate all of these body parts to walk, and the task is beyond her current abilities.

The brain is remarkably adaptable, however. People suffering from significant brain injuries can re-learn to walk, talk, and function. Repetition and rehabilitation allow the brain to make new pathways and connections to do what it once did elsewhere.

Sensory input is hard for Katherine to process. She can be overwhelmed by chaotic environments, as her brain is not telling her what is going on in the same way as the rest of us. She processes things more slowly. This probably is not so much of a function of her higher intelligence, as her body’s way of communicating between her senses and her higher brain.

You can expect Katherine to be off balance. She will have trouble with writing. She may become overwhelmed or confused by sensory input. She will have trouble articulating her words. She will have difficulty controlling the volume and pitch of her speech. She will be clumsy and uncoordinated. She does not yet have a good grasp of the body’s “potty” warning signals — she is better at telling you she has gone, than telling you she is about to go. All of these things can frustrate her, cause her to withdraw from others at times, or become anxious. That said, she has a very good vocabulary and understanding of things.

Children with Mitochondrial disease have some difficulty controlling their body temperature, can become fatigued, need to stay hydrated, and can suffer more when ill than other children. So far, these do not appear to be problems with NUBPL patients, other than some worries when they become ill. However, there are things to be aware of in case they occur.

Katherine is currently on an experimental medication called EPI-743 (or is on a placebo. She will receive 6 months of both over a 14 month double-blind clinical trial). It is part of a clinical trial run by the National Institutes of Health. This is essentially a very potent anti-oxidant, thousands of times more powerful at the cellular level than any anti-oxidant you can get in food or supplements.  While administration and action of the medication in the body is a far more complicated thing, in a laboratory setting fibroblasts grown from her cells demonstrated susceptibility to oxidative stress (discussed above) and an 80% or higher return to viability from administration of the medication. We hope that predicts that the EPI-743 will clean up the toxins she may be producing and will help her cells produce energy, and arrest any progression of the disease. It could do more.  While it cannot revive dead cells, it may save those that were damaged and dying, and allow them to function better, improving her condition (along with physical and occupational therapy), not just arresting its decline.

She also is on a compounded medication commonly called a “mitochondrial cocktail” that does many of the same things in different ways, as well as supplement one of the chemical products of Complex I, being a substance called Ubiquinol, a form of CoQ10.

We lived with a misdiagnosis that guaranteed us that Katherine was going to die in the next few years. The NUBPL diagnosis is serious and full of unknowns, but “serious and unknown” is better than “known and hopeless.”

We want to stress that we think it is important for other children and their families to understand Katherine. This provides insight into the rare disease community in general, mitochondrial disease patients, in particular, and Katherine, individually. It will help them get to know Katherine (and others like her) and explain why she cannot walk or do other things they take for granted.

Four

Today, our beautiful Katherine Belle turns four years old.
IMG_4102_2Looking back, we realize that every prior birthday has greeted us with worries. By her first birthday, we knew something was wrong; our expectation that she would walk prior to turning one proved untrue and her motor development had stalled. Our nagging worry at one was a gut wrenching terror by two; she still was not walking. On her third birthday, we were living under a death sentence and the day was a bittersweet reminder that we probably had few such occasions left.
IMG_2674IMG_8819Today, we have a new – an accurate – diagnosis, NUBPL, Mitochondrial Complex 1, and a new hope. This is a happy day and one of many more to come.IMG_4122_2 IMG_4073_2

Happy 4th birthday, Katherine Belle.  We love you baby girl!

Xoxo,
Mama & Daddy

NUBPL – Mitochondrial Complex 1

IMG_6825As many of you have already heard, KB was recently diagnosed with NUBPL – a rare form of Mitochondrial Complex 1 disorder. We cannot say enough good things about the genetic testing company, GeneDx, that provided the Whole Exome Sequencing. They have a very generous financial assistance policy (FAP) that allows them to work with patients on their out-of-pocket-costs, which is such a blessing on this financially strenuous journey.

We are pleased to let you know that since being diagnosed with NUBPL we have found another family with two daughters, Cali and Ryaan, with this same disorder. From the moment we watched their video, The Life We Live, and saw their photographs, we knew we found our community. What’s more is they are a wonderful family who shares the same passion for their family and drive to find a cure. They introduced us to their doctor, Virginia Kimonis, University of California Irvine, who has discussed her research with us. Here’s a wonderful article about Dr. Kimonis and The Spooner Family. We have spoken at length with Dr. Kimonis and are planning a trip to California to meet with her team and The Spooners.

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The Spooner Family

At this time, we have just three patients from the United States – Cali, Ryaan, and Katherine Belle. We are very hopeful we will find others in time. For now, together we face the monumental task of privately funding NUBPL research. Both families agree we will not let financial obstacles stand in the way of helping our children. We have created a NUBPL.org site and Facebook page to facilitate the search for other NUBPL patients and raise funds. Please take a moment to view our new site and Facebook page and share with your networks. A special thanks to Matt Might for the shout out in his informative post, Discovering new diseases with the internet: How to find a matching patient.

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Cali, 16

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Ryaan, 6

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Katherine Belle, 3

Last week we learned the wonderful news that KB has been accepted for the U.S. National Institutes of Health EPI 743 clinical study. We feel very blessed to be in this study and are quite hopeful this drug will greatly improve her mitochondrial function. We are hopeful that Cali and Ryaan will be admitted to this trial in the future.

NUBPL Gene – Mito Complex 1 (Diagnosed)

February 2015 – Katherine Belle was DIAGNOSED through Whole Exome Sequencing: Mitochondrial Complex 1 – NUBPL Gene.

We want to introduce you to the Spooner Family and their daughters Cali and Ryann, both of whom have mutated NUBPL genes like Katherine. We were undiagnosed for only two years…their oldest daughter was undiagnosed for thirteen years.

Although not identical, I can tell you that after seeing this video I immediately saw similarities between our daughters. After being misdiagnosed for so long with something that didn’t feel right in our hearts, it is so comforting to know and accept the correct diagnosis.

Please watch this video when you get some time. It’s lengthy, but very important and inspiring: The Life We Live

We are all interested in finding others with the same diagnosis.  They may contact me at gcmccoy1@aol.com.

Be Mine

IMG_4835Earlier this week I pulled out a few Valentine’s Day decorations and found Katherine’s mail bag from her daycare days.  I saved the few cards she received (she was only there for two years).  Looking through them made me sad because she isn’t currently in school (we are planning to send her next year) and doesn’t have a peer group.  She makes cards for her therapists and relatives, but she really doesn’t receive any.  IMG_4746IMG_7537Who wouldn’t want this girl to be their Valentine?
IMG_4940Let’s show Katherine Belle how much she’s loved.  She LOVES Valentine’s Day.  Let’s shower her with love.

IMG_4758Xoxo,

Glenda & Dave

#Hope4KB

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I like a challenge, especially when the challenge is for a good cause. What is #Hope4KB?

  1. #Hope4KB is a T-shirt campaign designed to raise awareness for rare diseases around the world through social media (KB is our daughter, Katherine Belle, a three-year-old from Lexington, KY, who is battling an unknown, progressive rare disease);
  2. You purchase your #HopeforKB shirt from Print My Threads here;
  3. Orders will be collected through March 1st. Wear on Rare Disease Day on February 28, 2015 (only orders placed by February 18th will arrive for Rare Disease Day, but we want you to wear this shirt all the time!) ;
  4. Take a picture of yourself and/or family and friends wearing your #Hope4KB shirt and share it on your social media accounts, i.e. Facebook, Instagram, Twitter, etc. with #Hope4KB; and
  5. The goal is to BREAK. THE. INTERNET.

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Ellen did it.  Kim Kardashian did it. It happened with the ALS #IceBucketChallenge – Let’s do it with #Hope4KB! Not to mention these are the softest, most comfortable American Apparel tri-blend short sleeve track shirts.  Trust me, you’ll be wearing this shirt LONG after February 28, 2015. (Psst…you can still help even if you don’t have any social media accounts – this campaign is for everybody!  Simply take a picture and send it to me at gcmccoy1@aol.com and I’ll make sure it’s shared!) *Proceeds will benefit Katherine Belle and Katie Webb Kneisley. (Click here to read her story.)

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A Magical Vacation

Laughter is timeless, imagination has no age, and dreams are forever.  
Walt Disney

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IMG_7348After working hard on a brief from December through early January, the time came for a much-needed break. Fortunately, this aligned with availability at our friends’ condo in Sarasota and while Glenda’s mom was in Wildwood, Florida.

Sandwiched between these two locations is Disney World. We are “wish-eligible” at Make-a-Wish and similar wish-granting organizations and have wondered whether Disney would be a good place to use our one wish for Katherine. With her sensory processing issues, we did not know if she would enjoy the experience. So, we decided to splurge for two park days to see in between Sarasota and Wildwood. I’m glad we did. Katherine really enjoyed the trip.

Glenda and I have decided to give you our top 10 moments on our Sarasota-Disney-Wildwood trip. We are not looking at one another’s list, so these may overlap. They may not. Here are mine, in chronological order:

  1. Walking from Sarasota to St. Armand’s key on our first day, in the beautiful 70-degree weather (leaving behind frost at home), eating lunch and gelato outside, and then walking back;IMG_4654IMG_4134IMG_4138IMG_5331IMG_5342IMG_5279IMG_5270
  2. Building Katherine a “bouncy castle” out of blow-up mattresses at the condo in Sarasota, and her laughter playing inside of it;IMG_5606
  3. Putting on a “puppet show” with Katherine’s stuffed animals from outside the “bouncy castle”;IMG_4246
  4. After learning of Katherine’s diagnosis, the concierge at the Disney resort booking reservation times for us at the rides we wanted to do, and then bringing her a stuffed Minnie Mouse doll. Well-played Disney, well-played;IMG_4403
  5. After running out to get something from the gift shop, returning to the room our first night at Disney to hear Katherine exclaim “Look Daddy, I can walk!” Followed by her letting go of the sides of her pack-and-play and taking a very good step by herself. She then showed mommy another step. While she cannot walk on her own, these steps are the best I’ve ever seen her take and her excitement at “being able to walk” was priceless. Magic Kingdom, indeed;
  6. Taking her on Dumbo as her first ride, then tentatively waiting to hear whether she liked it. Her exclamation, “play another game,” meant “yes”;IMG_6351IMG_6335
  7. Watching her slowly come to love the characters. She met Cinderella, Rapunzel, Belle, Ariel, Donald Duck, Goofy, Mickey, Daisy, Minnie (from a distance), Chip and Dale and some monkey-thing from the Lion King. Goofy and the monkey-thing frightened her – though she has a Goofy obsession. After being tentative, she grew to like them. She still held Glenda’s hand while meeting the animal characters, a separate favorite thing for me;IMG_6569IMG_6524
  8. Dancing with her in her princess dress while waiting for a table at a restaurant, while she made her dress puff out while jumping and twirling (with my assistance) only to realize that the entire restaurant was set up to look out the large windows over the lake behind us. We were the floor show;IMG_7392
  9. Looking at all the sleeping children and zombie-fied adults waiting for the bus back to the hotel after the fireworks, with the only spark of life in the entire line being our little KB, after 12 hours in two parks and no nap, still jumping up and down, screaming “Jump! Jump! Fireworks! Jump!” Boy were my arms tired; IMG_4557
  10. Listening to Katherine sing along with her Mickey’s Clubhouse DVDs on the ride home.
    (Ok, I have to give a couple more, sorry Glenda):
  1. Watching Katherine crawl-chase Glenda’s mom’s dog, Joey, to pet, kiss and play with him. Only last year, she was still physically shaking in fear at the sight of a dog;
  2. During a silly spat with Glenda on our last night in Wildwood, having Katherine say, in her best Glenda voice, “Calm down, Dave. Just calm down” – I honestly wasn’t “not calm” just a little animated – after laughing and sitting down and re-assuring her that I was ok and it was silly, and reminding her to always call me daddy (she only calls me “Dave” when she is imitating mommy), having her hug and kiss me and ask “does that make you not mad, daddy?” After answering “yes,” having her sit thinking for a minute, grin and then ram her toy rabbit, Bibi, in my face, then ask “Does that make you mad again?”;
  3. Watching KB bounce around singing “hot dog, hot dog, hot diggety dog”;
  4. After leaving our meeting with mermaid Ariel, hearing her remark that she was wearing the mermaid’s dress; andIMG_7297
  5. Being covered in glitter from carrying my little princess all over the park. Who knew I look fantastic in green glitter?

    Glenda’s top 10 moments, in no particular order:

  1. Our friends’ condo in Sarasota is a pink Spanish style built in the 1920s.  When we arrived, Katherine excitedly pointed to the condo, exclaiming, “We’re staying in a pink hotel!”  She talked about the ‘pink hotel’ the entire time;IMG_4149IMG_5594IMG_4109
  2. Katherine watching Mickey Mouse Clubhouse DVDs on the trip and knowing all the songs by the time we got home.  This was really a first for her in terms of trying to sing along. Hearing her sing, “hot dog, hot dog, hot diggity dog” is priceless;
  3. Riding “It’s a Small World” at Disney. It took me back to my own first Disney experience as a child.  I loved watching her eyes light up with delight.  When it ended she exclaimed,  “ride again!”  We did.  She loved it;IMG_6431IMG_6451IMG_6459
  4. Shortly after arriving at our Disney hotel, Dave asked the concierge about getting a handicap pass for our stroller.  Not only did he proceed to book everything we wanted to do in advance and give us guidance on everything we needed, but he showed up at our door 30 minutes later with a Minnie Mouse doll for KB.  As he handed it to me he said, “we hope your daughter has a magical stay at Disney”; IMG_4267
  5. I knew that I wanted her visit with Ariel to be extra-special.  We decided to take her to a shop to pick out a new dress and have glitter sprinkled in her hair.  Ariel was so excited to see that KB was dressed like her and made the visit memorable for all of us.  As I was taking photographs I saw the look of pure joy on KB’s face .  That moment brought tears to my eyes and a smile to my face.  Yes, this was where we needed to be at this moment.  As we pushed her away in her stroller, she looked at her dress and said, “This dress is really cute. I am a mermaid”;  IMG_7253IMG_7202IMG_7246
  6. Bibi was with us everywhere we went and got to enjoy all the sights and sounds, even getting a little glitter on her head;IMG_6801
  7. Seeing Dave covered in glitter from head to toe from carrying and dancing with his princess;IMG_6779
  8. Seeing Dave and KB dancing together in her beautiful princess gowns;IMG_4563IMG_6488
  9. We took her to a character breakfast even though we knew she might be afraid of life-size characters.  She was scared but we told them she just wanted to wave so they didn’t get too close.  By the time Daisy Duck came by she was less afraid and would reach out to hold my hand for reassurance.  It was very sweet how she held my hand and also very brave for someone who was completely over-stimulated; andIMG_4575
  10. Seeing Disney through the eyes of my daughter. Sometimes it’s best to jump in the car and drive to Florida, in the direction of Disney, with no particular plans but to feel sunshine on your face, eat ice cream, and laugh. As Disney himself said, “Adults are only kids grown up, anyway.”  After a very tough year of being more grown-up than I’ve ever imagined, it was fun to feel like a child again, if only for a few days.IMG_6478IMG_6372IMG_6378IMG_7273IMG_7179IMG_5836IMG_5436IMG_4434IMG_4576IMG_6130IMG_6156IMG_4164

Back Where We Started

On June 19th and 20th, 2014, Katherine had several different appointments and procedures at the Cleveland Clinic. These included a follow-up MRI, a spinal tap to draw spinal fluid for testing, an appointment with a genetic ophthalmologist to look for signs of metabolic disease that commonly appear in the eyes, an appointment with our neurologist, Dr. Parikh, and with a geneticist. As will be discussed below, an EEG was added at the last minute.

The MRI and spinal tap occurred on the morning of the 19th. The ophthalmologist was that afternoon. Our appointment with Dr. Parikh was set for the 20th, but we received a call a little while after the MRI that they needed to schedule it for later that afternoon. At that moment, we feared the MRI showed that something was wrong.

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Unfortunately, we were correct. The MRI showed that the damage to her cerebellum had spread since her original MRI in August of 2013 and now impacted her “entire balance center.” Dr. Parikh then uttered the dreaded acronym: INAD (short for Infantile Neuroaxonal Dystrophy). For additional information, go to:

http://www.ninds.nih.gov/disorders/neuroaxonal_dystrophy/neuroaxonal_dystrophy.htm

The appointment with Dr. Parikh immediately turned to chaos. Glenda started crying very hard, Katherine got upset and kept asking “mommy, you ok?” and I felt like I was falling into a hole. Dr. Parikh wanted to discuss our reaction and the MRI some more, including showing us the images, but it just wasn’t really possible to focus. I remember he kept putting his hand on Glenda’s shoulder to give comfort and reassure her, but she was inconsolable.  I did manage to explain to him that we had hoped that her MRI had not changed and that we hoped it was not INAD based on the prior negative tests. I also said that we felt like this was a death sentence.

Dr. Parikh said that the other tests were not definitive. The genetic test that was normal is normal in 20% of the cases where other tests shows that the patient has INAD, the nerve testing (EMG) is sometimes normal in the early stages of the disease, as is the skin biopsy, and the eye test (done earlier that day and showed no abnormalities and that she has better eye-sight right now than either mommy or daddy) was often normal throughout the course of the disorder. While the MRI was also not definitive, he knew of no other medical condition that shows her particular MRI findings. He asked if we wanted to look at the images, but we did not have the strength. We may regret this, but we just couldn’t right then.

He went on to say that he is 90% certain that she has INAD. I guess that means there is still a 10% chance that she has something else. He wants to follow up with the genetic testing to see if that “something else” comes up.  Dr. Parikh also tried to reassure us that even if it is INAD, there is still hope. He said these cases are so very rare, that we cannot assume that our daughter will follow the same course as those that went before her; they are constantly learning that these rare disorders have different types, different outcomes and different time frames. I replied, “but her MRI is showing that her condition is advancing.” He answered “yes.” I do not remember anything that followed during that appointment except for Katherine’s repeated question “mommy, you ok?” Glenda later told me that Dr. Parikh said, “I was hoping the MRI result was going to be different, but it is not.”

Based on the MRI, an EEG was added to Katherine’s appointments. Abnormalities in the EEG are an early sign of INAD. We got up early the next morning to put Katherine through this test. A few days later we received a call from the Dr. Parikh’s office. The EEG showed “no signs of concern.” Yet another typical finding for INAD is missing. Only her MRI appears in any way like this dreaded disorder.

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Yet, it is the MRI that really matters. Regardless of the label or acronym put on the disorder, the bottom line is that it is damaging Katherine’s brain. Her higher functioning remains normal for now, but her ability to control her movements is becoming increasingly impaired.

For example, her intelligence seems unaffected. Her vocabulary is growing. Her sentences are becoming more complex. She understands ideas that we thought beyond her age, including a pun the other day on Bubble Guppies, which she proved was no fluke by immediately telling a related joke (though not a pun) of her own. Her memory is better than ours. In fact, we use her as our shopping list, telling her what we need to get at the grocery, sometimes a day in advance, and she invariably remembers to tell us to get it when we go to the store. Yet, she struggles with movement. She cannot walk. Standing without aid is rare now. Standing with aid is unsteady. She falls often when sitting or crawling. Her right foot is becoming tighter when manipulated and drags when she walks with aid. She is clumsy when using her hands to reach for something or feed herself.  She is unable to hold a large popsicle.

While her language content and structure is getting better, her ability to communicate the words is becoming more of a struggle; she is slipping back into that stage that all parents know well when mommy and daddy can understand most of what she says, but other people have trouble understanding her. In short, she is a happy, smart and funny little girl, slowly (for now) losing her ability to control her movements. This is slow enough that we have been able to convince ourselves that we see no regression, only the result of someone trying to do more and to do it quickly, but with a problem in her cerebellum. We now know that this is not true. In the end, what we learned is that her condition is spreading damage through her cerebellum, leading to increased balance and motor problems; she is regressing.

We can continue to hope. We are re-involving a physician from Oregon who ceased to be part of the picture after PLA2G6 testing appeared to indicate that INAD was unlikely, but who is an expert in this family of disorders. She may offer additional opinions or ideas of how to proceed. Dr. Parikh mentioned something about consulting with INAD experts in other countries, but what he said is lost in the haze of that appointment. We are going to perform whole exome sequencing at the Cleveland Clinic to see if “something else” pops up – assuming that insurance agrees to pay for it to be done, which is far from given. We will discuss this testing in a future post. Whether it shows a known mutation that leads to a different diagnosis, a mutation that becomes part of the body of knowledge about the causes of INAD in those 20% of cases where there is no PLA2G6 mutation, or a new mutation and a new rare disease, the answer matters to us. It gives us our only chance, however slim, to find something treatable. It also may add to advancements in the science behind these rare diseases that one day may save someone else’s child, even if not our own beloved Katherine. Soon, we may be left with nothing that current science can offer and no more battles we can fight.

Following the devastating appointment with Dr. Parikh, we made a tear-filled, defeated walk across the Cleveland Clinic campus. We decided that a trip to the beach with Katherine would be good for all of us, which it was.

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On our drive to South Carolina, we discussed our options, which are very few, and realized we were right back where we started last September.

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And then THIS happened.  Celebrities, friends, family, strangers, and even a few mermaids started sharing their “Hope for KB” images, reminding us more than ever there is always hope and we are never alone on this journey.

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Courtney Cox

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Thanks to all for sending us your photos and messages during our darkest hours, and for your constant prayers, love and support.  To view more photos of Hope for KB, please click below or follow us on Facebook: https://www.facebook.com/media/set/?set=a.308673892635515.1073741834.250763271759911&type=3

Rare Diseases: Together We Are Strong

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?”

globalgenes-1.orgThe 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.globalgenes.org

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.

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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.

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What’s in your genes?

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.

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And, we will not go quietly.  We will be heard.

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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.

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The steps of the Kentucky State Capitol, House of Representatives.

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wp-filebase_thumb.phpClick links below for additional information:

The Global Genes Project

Rare Disease Day

Rare Disease Day USA

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