Category Archives: David and Glenda

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:

KY-gives-day-logo

 

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.

INAD: Our First Rare Disease Community

From August of 2013 until February of 2015, we lived with the diagnosis that Katherine had Infantile Neuroaxonal Dystrophy (“INAD”), a rare and progressive neurological disease. We were first given this diagnosis by Pediatric Neurologists at the Cincinnati Children’s Hospital. It was supported later by a Pediatric Neurologist at the Cleveland Clinic. We lived longer as an INAD family than we have yet lived as a NUBPL Mito Complex 1 family.

During the year and a half as an INAD family, we made connections with and began following other INAD families online. This was our community, our support group, and the only people in the world who knew what we were living through.

One family we learned about, but have never spoken to, are the Martins of Middleton, Ohio. Katherine falls between the Martin girls, Layla and Angel, in age. Layla was born three months before Katherine and Angel was born the next year.

We learned of the Martins through newspaper articles about the family. Just recently we found out that they have a Facebook group page and joined it this week. This was a missed opportunity to connect to another INAD family near us while we were still an INAD family.

Layla and Angel also were diagnosed with INAD at the Cincinnati Children’s Hospital. We did not know this at the time we were going there. The physicians gave no hint that they had another INAD family. One of the Neurologists did state that Katherine’s MRI was very very rare and that he had never seen one like it in all of his years of practice, but the oldest Neurologist at the hospital had seen one like it one other time. I now wonder if this was Layla’s or Angel’s MRI.

It is strange to think that we travelled the same roads, both literally and metaphorically, as the Martin family; we were given the same diagnosis and the same “road map” of our daughters’ futures by the same doctors, at the same facility, at almost the same ages, and roughly the same time.

Having been an INAD family for so long, we will always feel a part of that community and their stories will resonate with us. They are the stories of the daughter we thought we had. Katherine was bracketed by her future and past selves in Layla and Angel.

Layla will be laid to rest today at the Hoskins Funeral Home in Lebanon, Ohio. Rest in peace little one. Live in peace, Martin family.

Hope for Katherine Belle Contributions

We sincerely thank each of you for your generous donations. Each contribution was so helpful in helping us get an accurate diagnosis for Katherine. Future donations will help to further research for NUBPL.

$5 – $20
Anonymous
Lisa Auge
Donald Kirby
John Shouse
Daniel Egbers
Tania Zivkovic
Anonymous
Lisa Gabbard
Anonymous
Anonymous
Jackie Slone
Jodi Miller
Lindsey Davison
Miriam
Anonymous
Anonymous
Deborah Drury
Janet Lensing
Marla Blair
David Helmers
Pete Palmer
David Longenecker

$25 – $50
Anonymous
Anonymous
Anonymous
Anonymous
David Smith
Michelle Eviston
Robert Johnson
Just Aces2x
Ann Leslie Jones
Ingrid & Joe Jordan
Sara Kinslow
Anonymous
Anonymous
Anonymous
Kelly Bradley
Tonya Nuckolls Smith
Danielle G.
Jeffrey Burdette
Dena Wilson
Katie Irwin
Patrick Conley
Caroline Winston
Marisa Aull
Susan Nalley
Amanda Crawford
Jenny A.
Anonymous
Anonymous
Claudine Aldon
Anonymous
Sandy Auge
Joan Gregory
Piper Plummer Mehigan
Kathryn Belle Allen
Polly Helm
Rae Ann and Aragon Caldwell
Cheryl Gayhart
Anonymous
Anastasia Turner
Jared Hughes
Anonymous
Dave Daniel
Mindy Timberlake Sunderland
Anonymous
Lisa Simonds
Tammy Downard
Natalie Ballash
Anonymous
Ken and Jane Kerns
Melissa Davis
Laura Reynolds
Amelia & Garret Lewis
Terry Lennie
Anonymous
Beth Kleykamp
Anonymous
Myra Hughes
Anonymous
Morgan & Bradley Turner
Brandi Sharkey
Mary Beth Richard
Ron Gray
Bertrand Might
Matt Hudson
Anna Dominick
Laura Timberlake

$60 – $100
Anonymous
Matthew Ryan
Brian Humphrey
Anonymous
Courtney McGair
Allie Townsend
Lori Daniel
Julia Burnett Armstrong
Isabel Ladd
Anonymous
Anonymous
Ruth Castle
Laura Hagan
John Stapleton
Doug Richards
Stacey & Charles Magee
Julie Bell
Joanne Hall
Christina O’Brien
Chris Chase
Laura Zucker
David Wheeler
Pam Stith
Ann Aldridge
Anonymous
Stuart Family
Scott Weigel
Sara Charles
Anonymous
Anonymous
Anonymous
Julie & Jim Smith
Anonymous
Susan Sears/Bill Rambicure
Owen McMasters
Terri Sue
Elizabeth Taylor
David Oakes
Anonymous
Ashley Soriano
Dan Cauley
Sheila Hiestand
Vanessa Cantley
Hal Helmers
Jenny Scott
Mary Page Platerink
Stephanie Morrison
Sheila Bottoms Gerkin
Paula Holbrook
Laura Vincent

$150 – $250
Mark Hillard
Anonymous
Patrick Gault
LaDonna Koebel
Mark King
Anonymous
Ninfa Floyd
Chris Woods
Anonymous
Marian Hayden
Shannon Ragland
Nyoka Hawkins & Gurney Norman

$500 – $1000
Anonymous
Hannah & Mike Duffy
Alvah McCoy
Anonymous
Cole Preston
Kathy Lancaster
Jill & Craig Schroeder
Anonymous

$3,000
Michelle Lerach

Also, a very special thanks to Pem and Kevin Ausbrook, Patricia Madden, Jerry and Mary Ann Faughn, Kathy Cowden, Alvah McCoy, Stephanie Preston and Mike Meuser, Print My Threads (Ashland, KY), and everyone who purchased a #Hope4KB T-shirt.

To make a donation for NUBPL research, please click here.

A Response To Our Naysayers: Rare Disease Statistics Are Absurd Because They Are Accurate

On the Home Page  of our blog, we state that “Rare diseases affect more people than all cancers plus HIV combined, yet half of the patients do not know what is wrong.” In a recent Reddit string (we were not part of this conversation, but merely stumbled on it), this statistic raised a particular person’s ire, but not for the right reasons, in our opinion.  He/she stated:

“‘Rare diseases affect more people than all cancers plus HIV combined, yet half of the patients do not know what is wrong’…I’m calling BS on this. Well yeah, because … No.”

This person went on in another post to call us “pretty absurd,” following up with the following statement: “It’s pretty basic statistics that researchers do. From this document, we can infer that cancer prevalence is about 4.5% (14.5 million / 318.9 million). It’s pretty absurd to claim that these rare diseases, each of which 50 people have in the whole world, add up to more than 4.5%.”

When someone else stated that it might be feasible, he/she then stated: “No, it’s not really plausible. Given that the source is some layperson’s blog post on the internet, I don’t understand why you’re trying to find a way to give it credence… To give a bit of perspective, how many people have you known who have had cancer? How many have you known with one of these ultra-rare diseases? To broaden this a little bit, in my two clinical years of med school, I saw exactly one case of a rare disease while nearly all of my peers saw none. We all saw hundreds of patients with cancer.”

When someone finally pointed out that this response relied on anecdotal experience, he/she ended with:

“No kidding. And yet it’s stronger evidence than what she [Glenda] gave.”

We will bite our tongues on the lack of civility and arrogance in the tone of these posts, particularly when one considers that it is in response to efforts to raise awareness about rare diseases in general, and to share with the world our story. Others were also skeptical – though none were quite so arrogant. Therefore, we feel it merits a response and to provide the support for our statement. And, for the record, we are trying to make our blog readable, not a series of medical journal articles. Therefore, we are not loading it up with footnotes and citations. That does not mean we do not try to make sure our factual comments are accurate.

Let us clarify this prior statement. … It is correct exactly as worded, “Rare diseases affect more people than all cancers plus HIV combined, yet half of the patients do not know what is wrong.”

To use the words of the commenter, who goes by the user name uicucengineer, “well, yeah, because… yes.”

We “lay” “bloggers” did not originate this statement. You need not give us “credence” to believe it. We first heard it from a neurologist speaking as part of a panel of neurologists and geneticists at the United Mitochondrial Disease Symposium in DC.

Before we repeated it, we actually did some research. This statement is repeated on the Global Genes website  – go to the bottom, under “care about rare” you will see it come up as part of the rolling information. It and the statistics we set forth below, are repeated in many reports and studies. They are simple to find for anyone caring to look before they speak or post – Dear uicucengineer, Google is your friend.

One problem with uicucengineer is that he/she did not bother to educate himself/herself on the definition of “rare disease” before sounding forth. “Rare disease” has an actual definition. It is not just a disease “50 people have in the whole world” as uicucengineer (who claims to have two clinical years of med school) believes. While it is true that such a disease would qualify, in the United States, a condition is considered “rare” if it affects fewer than 200,000 persons (in the US) combined in a particular rare disease group.

Don’t want to take the word of a “lay blogger?” How about Federal law? Forty-two United States Code section 287a-1(c), provides as follows: “For purposes of this section, the term ‘rare disease’ means any disease or condition that affects less than 200,000 persons in the United States.”

There are over 7,000 diseases that qualify. See Globalgenes.org.

The numbers add up.  According to the Global Genes’ website:

  1. 30 million people in the United States are living with rare diseases (this number is supported by the NIH);
  2. This equates to 1 in 10 Americans or 10% of the U.S. population;
  3. Similar to the United States, Europe has approximately 30 million people living with rare diseases;
  4. It is estimated that 350 million people worldwide suffer from rare diseases; and
  5. If all of the people with rare diseases lived in one country, it would be the world’s 3rd most populous country.

By contrast, according to SEER.cancer.gov, there are currently a little under 13.8 million cancer patients and survivors in the United States as of 2015. That’s right, 30 million versus 13.8 (rounding up).

HIV totals do not make up the 16.2 million difference. The global total of HIV infections is estimated at 34 million, with 1.4 million in all of North America (according to AVERT).

While cancer and HIV rates vary somewhat from country to country, these prevalence rates generally carry through. Cancer and HIV patients and survivors add up to far fewer than rare disease patients. Alone we are rare, together we are common.

Sorry you did not see more of us in your two clinical years at med school, uicucengineer, but we are out there. We are all around you. Please open your eyes and learn about us, what we suffer through, and what we need. Please do not go into medicine if you are not willing to learn and to research before you speak – unknowledgeable medical professionals are already a significant problem to the rare disease world.

Another commenter on this string (was far more civil) and stated:

“I do have a bit of an issue with this statement: ‘Rare diseases affect more people than all cancers plus HIV combined, yet half of the patients do not know what is wrong.’ Well yeah, because cancers and HIV are specific diseases whereas ‘rare’ diseases can be any number of undiagnosable things. I’m not sure what their point is.”

When someone chimed in with some points about funding (thank you 88Wolves, whoever you are), the original poster responded:

“But funding for cancer can be applied across a finite number of diseases, whereas for rare diseases it’s literally anything. It does seem the funding would support increased genetic research which I suppose can only be a good thing, but a ‘rare’ disease is never going to be able to receive the funding that cancer or HIV do because they’re rare.”

This comment makes some valid points, and deserves a response. Here are a few additional facts:

  1. (From Global Genes) 80% of rare diseases are genetic in origin;
  2. (not from Global Genes, but carrying through on the math contained therein) That means of the approximately 30 million people in the U.S. with a rare disease, approximately 24 million have a genetic origin;
  3. (Global Genes) Approximately 50% of the people affected by rare diseases are children;
  4. (Id.) 30% of children with rare disease will not live to see their 5th birthday;
  5. (Id.) Rare diseases are responsible for 35% of deaths in the first year of life;
  6. (Id.) The prevalence distribution of rare diseases is skewed – 80% of all rare disease patients are affected by approximately 350 rare diseases;
  7. (According to the Kakkis EveryLife Foundation) 95% of rare diseases have not one single FDA approved drug treatment;
  8. (Global Genes) During the first 25 years of the Orphan Drug Act (passed in 1983), only 326 new drugs were approved by the FDA and brought to market for all rare disease patients combined;
  9. (According to the National Institutes of Health Office of Rare Disease Research) Approximately 6% of the inquiries made to the Genetic and Rare Disease Information Center (GARD) are in reference to an undiagnosed disease;
  10. (Id.) Approximately 50% of rare diseases do not have a disease specific foundation supporting or researching their rare disease;
  11. (According to the Rare Disease Impact Report) The average time to diagnosis for a rare disease is about 7.6 years in the U.S., and 5.6 in the U.K.;
  12. (Id.) The typical patient goes through 8 physicians before getting a diagnosis;
  13. (Id.) The average patient is misdiagnosed between 2 and 3 times before getting an accurate diagnosis;
  14. Few insurance policies will cover the genetic tests necessary to diagnose these diseases; and
  15. (Id.) While over 90% of rare disease patients/families surveyed had insurance, 55% had uncovered expenses related to the disease, 53% had to spend their savings to reach a diagnosis, 34% had to obtain charitable or public assistance, and 23% had to use their retirement accounts.

While it is true that research into one disease might not benefit another, this is not invariably true and there are many common issues across diseases.

For example, since most of these diseases have a genetic cause, it is important to all of the disease population to have easier, cheaper, and faster access to genetic testing. Insurance companies need to stop refusing to cover these tests and should drop requirements that all non-genetic tests be exhausted before genetic tests are considered. In our case, our daughter went through numerous tests before Whole Exome Sequencing, all because we had no prayer for insurance approval until we did so. These included two MRIs, two skin biopsies, a spinal tap, an EMG, an EEG, an EKG, a genetic ophthalmologist appointment, dozens of blood tests and numerous urine tests. These required our daughter to be anesthetized several times, and some were invasive (EMG, spinal tap, and biopsies). None led to answers, only a misdiagnosis of Infantile Neuroaxonal Dystrophy. The Whole Exome Test required a mere blood draw and gave us a correct diagnosis – a year and a half later and after two insurance denials and appeals and having to live with a misdiagnosis that gave our child a life-expectancy of 7 to 10 years of age. No patient should go through this. With progressive diseases, as many of these are, delays can cause irreversible damage as possible treatments (like EPI-743 and Mitochondrial Cocktails) are not given.  Patients need to be allowed access to the best diagnostic tools available, to have access to the less invasive and better test first, and to the insurance coverage they thought they were paying for, not to have insurance companies delay diagnosis, dictate care, and refuse coverage. With expanded knowledge, with coordination and a gathering of our voices, pressure can be put on insurance companies (or legislation when necessary) to stop these practices.

With expanded genetic testing comes expanded understanding of our genetic code. This may lead to the next generation of medicine, including the genetic bases or susceptibilities toward all diseases.

Government initiatives like the Undiagnosed Disease Program at the NIH and the Precision Medicine Initiative can help spur research and diagnosis.

Some research and treatments can carry across diseases, including stem cell research, genetic therapies, and technologies like CRISPR (or the like).

With expanded genetic testing, screening can become cheaper, leading to treatments at an earlier age and the prevention of unnecessary disease progression.

The government can continue to provide incentives like the Orphan Drug Act to encourage companies to invest in rare disease treatments and research.

Databases with wider access can be created to allow professionals and advocates to make connections themselves.

According to the professionals (as discussed in the Rare Disease Impact Report), physicians are not sufficiently aware of rare diseases. Many have no idea how to spot them or where a referral needs to be made. See also uicucengineer.

Finally, many of these diseases have traditionally been the things that people “just don’t talk about.” The stigma of genetic disease needs to go away. Our rare children are beautiful and the world needs to know about them. See Katherine Belle.

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